by Charlotte Kilpatrick | Oct 21, 2024 | Therapeutic |
Research in Nature in October 2024 leverages evidence that bacteria “naturally home in on tumours and modulate antitumour immunity” to explore potential vaccine applications. The authors engineered a probiotic Escherichia coli Nissle 1917as an antitumour vaccination platform, revealing a promising immune response. In mouse models of advanced colorectal cancer and melanoma, the vaccine triggered the immune system to suppress the growth of primary and metastatic cancers. The team hopes that this research can advance personalised cancer vaccine approaches.
Bacteria as ideal vectors
The authors identified bacteria as “ideal vectors to augment and direct” antitumour immune responses thanks to their support of the activation of both innate and adaptive immunity. Furthermore, bacteria can be synthetically engineered with ease for “safe delivery” of immunomodulatory compounds. Although various tumour neoantigen vaccines have demonstrated “promising” clinical trial results, benefit is “limited to only a subset of patients”. Thus, programming bacteria with genetic directives to release high levels of specific tumour neoantigens offers a system for the precise instruction of neoantigen targeting in situ.
The study
The researchers developed an engineered bacterial system in probiotic Escherichia coli Nissle 1917 (EcN) to “enhance expression, delivery, and immune-targeting of arrays of tumour exonic mutation-derived epitopes”. These epitopes are “highly expressed” by tumour cells and predicted to bind major histocompatibility complex (MHC) class I and class II. The system engages several “key design elements” to enhance therapeutic use:
- Optimisation of synthetic neoantigen construct form with
- Removal of cryptic plasmids and deletion of Lon and OmpT proteases to increase neoantigen accumulation
- Increased susceptibility to phagocytosis for enhanced uptake by antigen-presenting cells (APCs) and presentation of MHC class II-restricted antigens
- Expression of listeriolysin O (LLO) to induce cytosolic entry for presentation of recombinant encoded neoantigens by MHC class I molecules and T helper 1 cell (T H1)-type immunity
- Improved safety for systemic administration due to reduced survival in the blood and biofilm formation
Through exome and transcriptome sequencing of subcutaneous CT26 tumours the researchers developed a repertoire of neoantigens, which were predicted from highly expressed tumour-specific mutations. They then endeavoured to create a microbial system that could “accommodate the production and delivery of diverse sets of neoantigens” to lymphoid tissue and the tumour microenvironment (TME).
“Synthetic neoantigen construct optimisation and genetic engineering achieved a microbial platform (EcNcΔlon/ΔompT/LLO+) capable of robust production across diverse sets of tumour neoantigens, which was attenuated in immune-resistance mechanisms, effectively taken up by and proficient in activating APCs, and able to drive potent activation of T cells specific for encoded recombinant antigens to support enhanced cellular immunity.”
Vaccine applications
The study revealed that antigen sets encompassing predicted MHC-II and MHC-II binding neoantigens mediated antitumour efficacy. Enhanced frequencies of neoantigen-specific CD4+ and CD8+ T cells were seen. Across distinct tumour models and genetic backgrounds, the antitumour effect of vaccination was “accompanied by broad modulation of the immune compartment within the TME”.
“The coordinated regulation of APCs, reduction of immunosuppressive myeloid, regulatory T and B cell populations, and activation of NK cells and CD4+ and CD8+ T cells together indicate the advantage of precisely engineered microbial platforms as next-generation antitumour vaccines that align several arms of immunity.”
Furthermore, the “unique ability” of microbial vaccines to “directly remodel” the TME could “promote synergy” across various forms of immunotherapy. Microbial neoantigen vectors locally increase neoantigens density, recruit and activate dendritic cells and CD4+ and CD8+ T cells, and reduce immunosuppressive populations and ligands within the TME. Therefore, in combination with adoptive T cell therapy (ACT), they could “oppose these resistance mechanisms and provide synergistic benefit”.
“Through extra programming of the microbial vectors and rational incorporation of other immunotherapeutics, this system may achieve reliable eradication of established solid tumours and metastases through precision cancer immunotherapy using living antitumour vaccines.”
Getting closer
Jongwon Im, PhD student at Columbia University, helped lead bacterial engineering aspects of the study, and commented on the “net effect”.
“The bacterial vaccine is able to control or eliminate the growth of advanced primary or metastatic tumours and extend survival in mouse models.”
These vaccines are personal, programmed to “direct the immune system” to target “distinct genetic mutations”, said Dr Nicholas Arpaia, associate professor of microbiology and immunology at Columbia University’s Vagelos College of Physicians and Surgeons.
“As we continue to integrate additional safety optimisations through further genetic programming, we are getting closer to the point of testing this therapy in patients.”
Dr Tal Danino, associate professor of biomedical engineering at Columbia’s School of Engineering, reflected that the time to treatment will “first depend on how long it takes to sequence the tumour” for each patient.
“Then we just need to make the bacterial strains, which can be quite fast. Bacteria can be simpler to manufacture than some other vaccine platforms.”
Another benefit of bacteria is the enabled delivery of a “higher concentration of drugs that can be tolerated when these compounds are delivered systemically throughout the entire body”, suggested Dr Arpaia.
“Here, we can confine delivery directly to the tumour and locally modulate how we’re stimulating the immune system.”
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by Charlotte Kilpatrick | Oct 16, 2024 | Technology |
A paper in Nature Biotechnology in October 2024 presents an “end-to-end clinical proteogenomic pipeline” to address the challenges associated with identification and prioritisation of antigenic peptides. NeoDisc combines “state-of-the-art publicly available and in-house software” with in silico tools to identify, predict, and prioritise tumour-specific and immunogenic antigens from multiple sources. The authors demonstrate the pipeline’s superiority over recent prioritisation pipelines and showcase the features that enable “both rule-based and machine-learning approaches”. They also reveal how NeoDisc’s multiomics integration identifies “defects in the cellular antigen presentation machinery”.
Antigen discovery
The researchers comment on the importance of personalised antigen discovery for the development of cancer vaccines. Common approaches for translational research and clinical trials include whole-genome sequencing (WGS) or whole-exome sequencing (WED) and RNA sequencing (RNAseq). However, the recent application of mass spectrometry (MS) to identify HLA-bound peptides and the use of proteogenomics have “facilitated the exploration of novel targets from a variety of antigens naturally processed and presented in cancer”.
“Their identification is laborious and current clinical pipelines do not support immunopeptidomics and are restricted to predicted neoantigens.”
Although immunotherapies are “remarkably effective” against some indications, “robust immune pressure” can force immune editing. Therefore, it is “essential” to understand the heterogenous antigenic landscape and the tumour’s capacity to present antigens.
The study
In the study, the authors introduce an “end-to-end” clinical antigen discovery proteogenomic pipeline: NeoDisc. It compiles publicly available and in-house software for the identification of immunogenic tumour-specific HLA-I and HLA-II antigens from genomics and transcriptomics and MS-based immunopeptidomics and enables their prediction and prioritisation with rule-based and machine-learning (ML) tools. It allows assessment of tumour heterogeneity and the functionality of the antigen processing and presentation machinery (APPM). The study compares NeoDisc’s performance with other tools, demonstrating its application for personalised antigen discovery and clinical implementation.
NeoDisc is a “dedicated computational framework” combining genomic, transcriptomic, and immunopeptidomic data and integrating curated public databases of known immunogenic TSAs, TAAs, oncoviral elements, and noncanonical transcripts. It uses matched tumour and germline genomic data for sample-specific variant characterisation, tumour content estimation, and copy number variation (CNV) and somatic mutation (SM) identification.
Four variant-calling algorithms are applied to WES and WGS data; variants that are detected by two or more callers are considered to have “high identification confidence”. Although highly mutated tumours usually respond better to immunotherapy, the selection of immunogenic neoantigens among “numerous possibilities” is “challenging”. Recent screening of large datasets of neoantigens in tumours from 112 participants has allowed the training of ML for prioritisation. ML classifiers trained on a fraction of this dataset have been integrated into NeoDisc to ensure “effective prioritisation”.
When NeoDisc’s rule-based and ML ranking approaches were compared with existing tools, the ML prioritisation algorithm “surpassed all the evaluated tools”. The researchers demonstrated NeoDisc’s “efficient prioritisation” on a cervical adenocarcinoma (CESC-1) characterised by an “exceptionally high mutational burden” (25 SMs per Mb).
Of the 393 identified actionable mutations, representing a pool of 19,051 peptides with a predicted binding rank ≤2%, 66 HLA-I neoantigenic short peptides (minimal epitopes) were selected through rule-based prioritisation for T cell screening of autologous tumour-infiltrating lymphocytes (TILs) by IFNγ ELISpot. 11 of the 66 peptides were immunogenic, including two that “ranked among the top ten candidates”. The NeoDisc ML model reordered the tested neoantigens, resulting in an “impressive” ranking of six immunogenic peptides in the top ten. NeoDisc also successfully identified two confirmed immunogenic neoantigens in the CESC-1 tumour MS immunopeptidomic data.
Personalised vaccines
While the default NeoDisc settings “exhibit good performance”, biopsies with low tumour content and low mutation burden could result in the detection of an “insufficient number of actionable high-confidence expressed mutations”. This would lead to a “suboptimal vaccine”. Thus, NeoDisc offers two additional modes:
- “Sensitive mode” considers the union of mutations called by all four variant-calling tools, to be used when an insufficient number of mutations are detected.
- “Panel mode” uses mutations listed in the available diagnostic clinical gene panel (GP) as input, allowing the design of vaccines for persons lacking dedicated biopsies. Note that GPs “often provide insufficient number of mutations leading to suboptimal lists of neoantigens or potentially none”.
The paper states that, in cancer vaccines, long sequences are favoured over minimal short peptides, motivated by the “efficient uptake and processing by APCs”. The NeoDisc ML tool ranks mutations according to their potential immunogenicity. Long sequences are “optimally” designed through maximised coverage of high-quality predicted HLA-I and HLA-II neoantigens.
In use in the field
NeoDisc is already being used in Phase I clinical trials for personalised cancer vaccines and adoptive T cell therapies in Switzerland; the authors hope that these demonstrate its “practical utility and potential for clinical translation”. Dr Michal Bassani-Sternberg of the Lausanne Branch of the Ludwig Institute for Cancer Research comments that NeoDisc provides “invaluable” insights into the immunobiology of tumours and the “mechanisms by which they evade targeting by cytotoxic T cells”.
“Notably, NeoDisc can also detect potential defects in the machinery of antigen presentation, alerting vaccine designers and clinicians to a key mechanism of immune evasion in tumours that can compromise the efficacy of immunotherapy. This can help them select patients for clinical studies who are likely to benefit from personalised immunotherapy, a capability that is also of great importance to optimising patient care.”
Florian Huber, first author, also reflected on the significance of this research.
“NeoDisc can detect all these distinct types of tumour-specific antigens along with neoantigens, apply machine learning and rule-based algorithms to prioritise those most likely to elicit a T cell response, and then use that information to design a personalised cancer vaccine for the relevant patient.”
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by Charlotte Kilpatrick | Oct 14, 2024 | Therapeutic |
Transgene announced in October 2024 that the primary objective of its randomised Phase II study of TG4001 has not been met. The study was evaluating TG4001 in combination with avelumab versus avelumab alone in patients with recurrent or metastatic HPV16-positive cervical and anogenital tumours. The primary objective was improvement in progression-free survival. Although this failure is “disappointing” to the company, Transgene states that it is evaluating the full results to “determine the best way forward”.
TG4001
Transgene’s TG4001 is an “innovative therapy capable of combating papillomavirus-induced cancers”. It teaches the immune system to identify and destroy the cancer cells expressing HPV-16 antigens, specifically E6 and E7.
Results and implications
The pre-planned subgroup analysis showed a positive efficacy trend in favour of the TG4001-containing regiment in cervical cancer patients. However, this requires further confirmation through additional analyses. These patients account for around half of the total patients enrolled in the study. Treatment was well tolerated, with adverse events “consistent” with previous observations.
“Transgene is currently evaluating the full study results in detail to determine the best way forward for this programme and will communicate further once this is completed.”
Dr Alessandro Riva, Chair and CEO of Transgene, acknowledged that “failure to meet the primary objective in our Phase II study with TG4001 is disappointing”.
“Nevertheless, we are encouraged by the positive efficacy trend in favour of the combination regiment in cervical cancer patients. We plan to complete a full and rigorous analysis of the data before deciding on any path forward for this asset.”
Dr Riva thanked patients and caregivers for their “important contribution” to the study.
“With a diversified portfolio of novel immunotherapies targeting solid tumours, our strategy remains focussed on advancing our lead asset, TG4050, an individualised cancer vaccine for head and neck cancers for use following surgery and adjuvant therapy.”
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by Charlotte Kilpatrick | Oct 8, 2024 | Therapeutic |
A study in the Journal for ImmunoTherapy of Cancer finds that vaccination in a clinically relevant genetic cancer mouse model generated a population of functional progenitor tumour-specific CD8 T cells (TST) and halted cancer progression, in contrast to immune checkpoint blockade (IBT) therapies. The authors hope that immunisation could be the “most effective strategy” for patients with early cancers or at high risk of cancer recurrence. This study takes a different approach to many cancer vaccine studies, which tend to focus on patients with advanced tumours.
Cancer vaccine potential
The authors recognise the transformational role of immunotherapies in the cancer treatment landscape, particularly in the case of immune checkpoint blockade (ICB). However, vaccines for non-viral cancers have had “more limited success”. Many studies on tumour-specific CD8 T cell (TST) vaccine responses are conducted in the established/late tumour setting, so less is known about how TST “respond and differentiate” in response to immunotherapy during early stages of tumorigenesis.
Previously, the authors developed an autochthonous mouse model of liver cancer (AST;Cre-ERT2) to initiate liver carcinogenesis with tamoxifen (TAM)-induced Cre-mediated SV40 large T antigen (TAG) expression in hepatocytes. TAG functions as an oncogene and a tumour-specific neoantigen recognised by CD8 T cells, so the model enables “precise temporal control” of the duration of TST interactions with transformed hepatocytes and tumours. In contrast to human tumours, which “arise sporadically and progress clonally”, TAM-induced oncogene induction is “highly efficient”, resulting in high antigen burden even at early stages.
The study
The researchers allowed AST;Cre-ERT2 mice to undergo stochastic TAG oncogene activation through sporadic, TAM-independent Cre-mediated activity. To explore TST responses against TAG-driven tumours they used congenic donor lymphocytes from transgenic mice, in which CD8 T cells express a single T cell receptor (TCR) specific for TAG epitope-I (TCRTAG). They found that TST became dysfunctional in TAM-treated AST;Cre-ERT2 mice and were “unable to halt tumour progression”. TAM-treated AST;Cre-ERT2 mice had a “substantial” tumour antigen burden, even at early stages of tumorigenesis.
To compare initial TST differentiation in mice with early liver lesions against those with late liver lesions, the researchers transferred CFSE-labelled naïve TCRTAG into early and late time point AST;Cre-ERT2 mice. TCRTAG in mice with early lesions divided at a slower rate, particularly in the spleen and ldLN, and there were fewer TCRTAG in the spleens, ldLN, and livers of early mice. Decreased TST proliferation in mice with early lesions could be due to the lower TAG antigen burden. Although nearly all TCRTAG in mice with late lesions and most in mice with early lesions failed to produce effector cytokines TNFα and IFNγ within 60 hours of transfer, a population of TCRTAG in were identified in the spleen and liver of mice with early lesions. These could produce effector cytokines TNFα and IFNγ.
“Thus, in hosts with sporadic early lesions, a subset of TST resisted rapid differentiation to the dysfunctional state, raising the possibility that this subset might be amenable to immunotherapeutic reprogramming/rescue.”
To see if this functional TST subset persisted, the authors examined TCRTAG immunophenotype and function 5 days and 21 days post-transfer into early or late AST;Cre-ERT2 mice. While fewer TCRTAG were found in mice with early lesions compared to late lesions at 5 days, the difference became less pronounced at 21 days. In both groups TCRTAG upregulated CD44, which indicates antigen exposure and activation. TCRTAG in early mice continued to express higher levels of PD1 than naïve TCRTAG, suggesting that PD1 expression can identify tumour-reactive TST in hosts with early lesions.
The next consideration was if the functional TST subset in mice with early lesions could be harnessed to stop tumour progression. LM, a gram-positive intracellular bacterium, induces strong CD4 and CD8 T cell responses. The researchers used an actA inIB deficient attenuated LM vaccination strain to test if early vaccination of AST;Cre-ERT2 would protect mice against liver cancer progression. Mice were either left untreated, given a single dose of empty LM, or vaccinated with a single dose of LM- TAG.
“LM- TAG–immunisation conferred a major survival advantage, with all mice remaining tumour-free and one mouse euthanised for dermatitis without any evidence of liver tumours.”
The mice in untreated and empty LM groups reached endpoint with “multiple” large liver tumours and increased liver weight. At endpoint, most TCRTAG in the LM- TAG–immunised made effector cytokines, in contrast to the TCRTAG in tumour-bearing mice in the other groups, which were “largely unable to produce effector cytokines”.
Vaccination vs ICB
“An important and open question in cancer immunotherapy is how ICB versus vaccination compares in boosting anticancer immune responses, and how best to combine and sequence these therapies.”
A comparison of ICB, LMTAG vaccination, and combined ICB/LMTAG vaccination found that ICB conferred no benefit in comparison with isotype control antibodies (iso). By contrast, LMTAG and ICB/LMTAG treated mice had no evidence of tumour progression at 400+ days. Furthermore, LMTAG vaccination, whether alone or in combination, led to a “substantial increase” in TST numbers and IFNγ production, while ICB alone had “little impact”.
LM-based vaccines have had “poor or mixed results” in clinical trials, often with a target of patients with advanced or refractory cancers. The authors hope that their studies offer “mechanistic insight” as to why these fail in patients with advanced cancers: “for vaccines to be effective, a progenitor TST population must be present”. Although the apparent superiority of vaccination over ICB “may be surprising at first glance”, the authors highlight an important point, that “not all TCF1+TST are functional, nor does ICB alone lead to functional TST”. However, the findings suggest that LMTAG vaccination maintains or rescues functional progenitor TCF1+TST.
Timing is important
Dr Mary Philip, associate director of the Vanderbilt Institute for Infection, Immunology, and Inflammation, commented that the study “suggests that the timing of vaccination is important”.
“A unique feature of our study is that these mice are at high, essentially 100% risk of developing cancers, so the fact that a single immunisation at the right time can give lifelong protection is pretty striking.”
Dr Philip reflected that very few studies follow mice “so long after vaccination” and find them tumour free for two years.
“ICB works by taking the brakes off T cells, but if the T cells have never been properly activated, they are like cars without gas, and ICB doesn’t work. The vaccination boosts the T cells into a functional state so that they can eliminate early cancer cells.”
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by Charlotte Kilpatrick | Oct 7, 2024 | Technology |
In October 2024, WHO announced that a fourth WHO-prequalified human papillomavirus (HPV) vaccine product, Cecolin, has been confirmed for use in a single-dose schedule. This update is an “important milestone” that will contribute to “improving sustainable supply of HPV vaccines”, ensuring that more people get access to the vaccines that prevent cervical cancer. HPV vaccine programmes have been “hampered” by supply shortages since 2018, and recent production challenges have led to further shortfalls, which will affect girls in need of HPV vaccines Africa and Asia.
Eliminating cervical cancer by tackling HPV
More than 95% of the 660,000 annual cervical cases are caused by HPV. Every two minutes, a woman dies from the disease, and 90% of these deaths happen in low- and middle-income countries. 19 out of the 20 “hardest hit” countries are in Africa. However, vaccination is an effective way of addressing this health need. Dr Tedros Adhanom Ghebreyesus, WHO Director-General, states that “we have the ability to eliminate cervical cancer, along with its painful inequities”.
“By adding another option for a one-dose HPV vaccination schedule, we have taken another step closer in consigning cervical cancer to history.”
Dr Kate O’Brien, Director of the Department of Immunisation, Vaccines, and Biologicals at WHO, reflected that achieving a 90% coverage in girls by the age of 15 is the target of the first pillar of WHO’s global strategy for cervical cancer elimination.
“Given the continuing supply challenges, this addition of single dose vaccine product means countries will have greater choice of vaccines to reach more girls.”
Cecolin
Cecolin is a bivalent HPV vaccine delivered intramuscularly as a single dose. It is manufactured by Xiamen Innovax Biotech and should be stored between 2°C and 8°C. It is designed to protect against HPV types 16 and 18, which are commonly associated with the development of cancer. When Cecolin received prequalification, PATH stated that it had provided “technical assistance” for the process to facilitate greater accessibility. PATH’s China country representative Yuan Yuan commented that the vaccine would put the world “on its way to more equitable HPV vaccination”.
Single-dose coverage
Several products that were initially prequalified for use in a 2-dose schedule can now be used in a single-dose schedule. Cecolin can be recommended for “off-label” use after data support the modified schedule until the manufacturer adds the modified use to the label. Data from July 2024 show an increase in one dose HPV vaccine coverage among girls aged 9-14 years, from 20% in 2022 to 27% in 2023. In 2023, 37 countries were implementing a single-dose schedule; this increased to 57 by September 2024. WHO suggests that the adoption of a single-dose schedule has resulted in “at least” 6 million additional girls being reached with HPV vaccines in 2023.
For insights into the role of vaccination in elimination strategies, why not join us at the Congress in Barcelona this month? Don’t forget to subscribe to our weekly newsletters here for more vaccine news.
by Charlotte Kilpatrick | Oct 4, 2024 | Global Health |
The University of Oxford announced in October 2024 that scientists working on ‘OvarianVax’ a vaccine to encourage the immune system to “recognise and attack” the earliest stages of ovarian cancer, have secured funding from Cancer Research UK. The team will receive up to £600,000 over the next three years to support research from establishing targets to possible clinical trials. Although getting a vaccine to the point where it is “widely available to women at risk of ovarian cancer” is “many years” away, the funding is an “exciting step” towards preventing ovarian cancer at an early stage, rather than treating it after it has taken hold.
Ovarian cancer
Ovarian cancer is the 6th most common cancer in women, causing around 7,500 new cases every year in the UK. There is currently no screening programme for the disease, and some women with are at higher risk with inherited copies of altered genes. Compared to women without gene alterations, women with altered BRCA1 genes face a higher risk by up to 65%, and women with altered BRCA2 genes face a higher risk by up to 35%.
Women with these alterations are recommended to have their ovaries removed by the age of 35, which has implications for having children and brings on early menopause. Many cases of ovarian cancer are only identified at a late stage. Professor Ahmed Ahmed is the Director of the Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine at the University of Oxford, and lead for the OvarianVax project and comments that “we need better strategies to prevent ovarian cancer”.
“Currently women with BRCA1/2 mutations, who are at very high risk, are offered surgery which prevents cancer but robs them of the chance to have children afterwards.”
However, a possible “solution” could be on the horizon with the OvarianVax project, focussed on women at high risk but with potential to expand if trials are successful.
“Thanks to this funding, our research can take a big step forward towards a viable vaccine for ovarian cancer.”
Vaccine development
The researchers will identify the proteins on the surface of early-stage ovarian cancer cells that are most strongly recognised by the immune system and work out how effectively the vaccine kills organoids, “mini-models” of ovarian cancer. If this proves successful, they will move forward to clinical trials in the hope that one day women could be offered the vaccine to prevent ovarian cancer.
“Teaching the immune system to recognise the very early signs of cancer is a tough challenge. But we now have highly sophisticated tools which give us real insights into how the immune system recognises ovarian cancer.”
Professor Ahmed’s team has already found that immune cells from patients with ovarian cancer can “remember” the tumour. They will use this discovery to train the immune system to recognise over 100 proteins on the surface of ovarian cancer, known as tumour-associated antigens. The research will uncover which antigens trigger the immune system to recognise and kills cells that are becoming ovarian cancer, using tissue samples from the ovaries and fallopian tubes of people with ovarian cancer to recreate the early stages of disease.
The team will also work with patient and public representatives to understand who would be willing to take the vaccine, who would receive the most benefit from it, how it could be administered, and how to ensure it is taken up by as many eligible women as possible if it is successful in clinical trials.
Prevention research strategy
This is one of several projects that Cancer Research UK is funding within its prevention research strategy, which seeks to use discoveries from the lab to find more precise ways to prevent cancer. Cancer Research UK’s Chief Executive, Michelle Mitchell, described these projects as “a really important step forward into an exciting future, where cancer is much more preventable”. The funding should “power crucial discoveries” that can be used to “realise our ambitions to improve ovarian cancer survival”.
“OvarianVax builds on the exciting developments in vaccine technology during the pandemic. This is one of the many projects which we hope will give women longer, better lives, free from the fear of cancer.”
For more on using the latest lab discoveries to improve patient outcomes with vaccines, get your tickets to the Congress in Barcelona this month, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Oct 2, 2024 | Therapeutic |
Interim Phase II data from Gritstone bio’s study evaluating GRANITE in September 2024 are described as “encouraging” in a company statement. The study evaluates Gritstone’s individualised neoantigen targeting immunotherapy in frontline microsatellite stable colorectal cancer (MSS-CRC) as maintenance therapy in combination with immune checkpoint inhibitors and fluoropyrimidine/bevacizumab. These data show the vaccine’s potential to extend progression-free and overall survival, but “fell short” of the target that some suggest is needed to “transform its fortunes”.
Encouraging data
104 patients were randomised 1:1 in the study, and the treated analysis shared by Gritstone includes 69 patients. Highlights from the data include:
- An emerging progression-free survival (PFS) benefit to all GRANITE recipients
- 21% relative risk reduction of progression or death with GRANITE compared to standard of care (SOC) control in all treated population
- 33% of GRANITE and 23% of control patients remain on study and free of progression
- Clinical benefit was most notable in patients with low disease burden (defined as patients with circulating tumour DNA (ctDNA) equal to or below the trial population median value at study entry)
- 38% relative risk reduction of progression or death with GRANITE compared to SOC control with low ctDNA subgroup
- Low baseline ctDNA is a likely prognostic and predictive factor
- Immune data were consistent with clinical activity
- Functional neoantigen-specific T cells observed in all 16/16 GRANITE patients tested by ELISPOT
- Association of PFS and peak ex vivo ELISPOT responses was apparent, indicating that ex vivo ELISPOT may be a surrogate for PFS
- GRANITE demonstrated a favourable safety and tolerability profile
- No patients discontinued study treatment due to an adverse event (AE)
- Common AEs were the mild systemic and local effects associated with any potent vaccine
- One treatment-related serious AE (fatigue) occurred in the GRANITE arm but patient continued GRANITE treatment without recurrence upon recovery
Gritstone recognises a need for continued follow-up to “fully assess” the effects of GRANITE and determine whether a plateau of improved PFS, which indicates durable clinical benefit, is achieved. Gritstone bio’s co-founder, President, and CEO Dr Andrew Allen is “excited by the potential” seen in GRANITE to extend both progression-free and overall survival “in a disease where relentless progression is the rule with existing therapies”.
“The field of neoantigen-targeting immunotherapy is evolving rapidly, and the focus is shifting to patients with lower volume disease. Notably, patients with newly diagnosed metastatic disease who have lower ctDNA at study entry and thereby relatively low disease burden, could benefit from this type of immunotherapy.”
More time needed
Dr Allen commented that “typically”, success for immunotherapy “manifests as an elevated plateau in PFS and overall survival Kaplan-Meier curves, and we may be seeing this in our low disease burden population.”
“We need more time to let these data mature.”
The “low and stable” ctDNA measurements in “most” GRANITE patients are “encouraging”, says Dr Allen, as that pattern is “not typically seen in patients about to develop disease progression”. There is also “opportunity for greater effects in tumours more typically amenable to immunotherapy” in the potential benefit observed in MSS-CRC, a “notoriously ‘cold’ tumour”.
“These data support further exploration of GRANITE in frontline MSS-CRC and in other low burden (neo)adjuvant settings. With this new dataset in hand, we continue to actively explore several strategic and funding alternatives to rapidly advance our innovative immunotherapy for the benefit of patients.”
Head above water
The company statement also confirmed that Gritstone has engaged a financial advisor to support its exploration and review of potential “value-maximising strategies”. While Gritstone “does not intend to discuss or disclose further developments”, speculation continues.
Evercore ISI analyst Jonathan Miller is quoted by Fierce Biotech wondering if the company’s cash runway is “functionally no later than” the end of the year. Although “on the face of it” the progress is positive, the data have “limitations”, such as a shift away from patients with more aggressive disease. Miller believes that if Gritstone can keep tracking patients, the extend follow up can continue to look encouraging, but questions the company’s future.
“They don’t have flexibility to run this data out much further, add [patients], or explore [the] adjuvant setting.”
We look forward to welcoming Gritstone’s EVP and Head of R&D, Dr Karin Jooss, to the Congress in Barcelona this month, to share insights in the Cancer and Therapeutic Vaccines track. Get your tickets to join us here, and don’t forget to subscribe to our weekly newsletters for the latest vaccine news.
by Charlotte Kilpatrick | Oct 1, 2024 | Therapeutic |
In an article for npj vaccines in October 2024, researchers present their investigation into the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 in preventing and treating multiple myeloma (MM). MM “remains largely incurable”, but the GPRC5D, “highly expressed” in MM, presents a “compelling” immunotherapy candidate. The research suggests that GPRC5D-targeted DNA vaccines are “versatile platforms” for treating and preventing MM.
Managing MM
Multiple myeloma (MM) is the second most prevalent haematological malignancy, characterised by the accumulation of malignant plasma cells in bone marrow. Most MM cases are preceded by monoclonal gammopathy of undetermined significance (MGUS), which can reduce a person’s life expectancy by “more than 4 years”. Around 3.5 million people are affected by MGUS in the United States. Smouldering MM (SMM), distinguished from MGUS for clinical reasons, is an asymptomatic clonal plasma cell disorder between MGUS and MM.
MM treatment has been “transformed with the advent of antibody-based therapies”, with chimeric antigen receptor (CAR) T-cell therapies that target the B-cell maturation antigen (BCMA) showing “considerable promise”. However, the pattern of BCMA expression is heterogeneous, responsible for “varied treatment responses” and the surface expression can “fluctuate” because of gamma secretase-mediated shedding of the extracellular domain. Furthermore, antigen escape has been noted in patients with MM who experienced relapse after BCMA-targeted CAR T-cell therapy.
“Exploring immunotherapies targeting alternative antigens may help counteract antigen escape and provide effective treatment options for patients who relapse after BCMA-targeted CAR T-cell treatment.”
A new vaccine target
C protein-coupled receptors (GPCRs) are the “largest and most diverse” group fo membrane receptors in eukaryotes; humans have almost 1000 different GPCRs. GPCRs are classified into six classes (A-F), among which class C GPCRs initiate metabolic steps to modulate cellular activity.
Orphan GPCR class C group 5 member D (GPRC5D) is expressed in the hair follicle and the bone marrow of patients with MM, as well as in MGUS and SMM. The GPRC5D mRNA is overexpressed between two and four times in MM plasma cells compared to normal plasma cells, and immediate expression is seen in MGUS and SMM.
“GPRC5D is an emerging novel immunotherapeutic and preventive target for MM.”
Although DNA vaccines are a “promising” alternative to mRNA vaccines, with “lower cost and better stability”, they have not yet been widely adopted in clinical practice. DNA cancer vaccine development faces “significant challenges” such as nonspecific formulations, thermal instability, toxicity, and ineffectiveness. However, the authors believe that recent advancements have “greatly enhanced” the clinical efficacy of DNA vaccines in cancer treatment.
The study
In their research, the authors attempted to develop DNA vaccines against MM using plasmids expressing GPRC5D. First, they evaluated a mouse GPRC5D DNA vaccine in the 5TGM1 murine myeloma model, which “closely mimics” human MM. Cancer prevention activity was examined through administration of the DNA vaccine before tumour cell inoculation. The mice that received the mGPRC5D vaccine developed “significantly smaller” tumours than the control mice, and all animals in the mGPRC5D group were alive at day 33.
With ELISA, the authors evaluated the humoral response by measuring the levels of mGPRC5D-specific antibody in the serum collected 5 days after boost. They found a “marked increase” in serum IgG levels in the mGPRC5D group. To explore the possible mechanisms of the antitumour effect of the vaccine, they analysed immune cells in the spleen and tumours through flow cytometry. The percentage of various immune cell populations “significantly increased” in the mGPRC5D-immunised mice.
The research also considered the therapeutic efficacy of the mGPRC5D vaccine in combination with PD1 Ab treatment. After tumour inoculation, mice received two injections of 20µg mGPRC5D vaccine or the control plasmid at 2-week intervals, along with intraperitoneal administration of anti-PD1 antibody. Mice that received either the vaccine or anti-PD1 Ab showed a “moderate inhibitory effect”, but those treated with the combination exhibited “significant inhibition of tumour development”.
When comparing tumour weights in mice, the authors found “significantly” lower weights in the mGPRC5D and PD1 Ab group than in the control group or each monotherapy group. They also assessed the ability of the vaccine to induce TNFα or IFNγ responses in mouse splenocytes with the ELISPOT assay. Splenocytes from mice that received either mGPRC5D or PD1 Ab exhibited a “significant” increase in the number of spots, and a further increase was observed in the group that had the combination. The combination group had higher frequencies of TNFα+CD8+, IFNγ+CD8+, TNFα +CD4+, and IFNγ+CD4+ T cells in the spleen.
In a flow cytometric analysis of immune cell populations in the spleen, the authors found that treatment with mGPRC5D increased the frequency of CD4+ T cells by over 150% and CD8+ T cells by over 30%. PD1 Ab treatment increased the frequency of both cells by more than 100%. The combination had a “more pronounced effect”; CD4+ T cells increased more than 350% and CD8+ T cells increased by more than 130%. Similar observations were made for DCs, Mϕ, and NK cells in the spleen. For tumour-infiltrating lymphocytes (TILs), the combination approach increased the population of CD8+ and CD4+ T cells, DCs, Mϕ, and NK cells more than the monotherapies.
A human vaccine
As the peptide sequences of mGPRC5D and hGPRC5D are only ~81% identical, a human version of the vaccine is needed. The researchers developed a nanoplasmid construct expressing human GPRC5D (Nano-hGPRC5D). Prophylactic studies found that tumour growth was “significantly suppressed” in the mice group that received Nano-hGPRC5D, which also presented a “marked increase” in serum IgG levels. Other findings include a “significant increase” in the levels of cytokines in the Nano-hGPRC5D group, which suggests a “robust activation of inflammatory cytokines” upon vaccination.
In the spleen and tumours of hGPRC5D-immunised mice, percentages of CD3+, CD4+, and CD8+ T cells and DCs were “significantly increased”. Furthermore, higher frequencies of Th1 secretory cytokine-positive CD3+ T cells were observed in this group. A long-acting protective effect against tumours was implied in “significantly higher percentages” of effector and central memory T cells in the splenocytes of the hGPRC5D group. CD8+ T cells stimulated with the hGPRC5D peptide pool exhibited “superior proliferative ability” compared to the control.
Therapeutic combination
To evaluate the therapeutic efficacy of Nano-hGPRC5D in combination with PD1 Ab, the authors used syngeneic murine models. The combination resulted in “significant tumour regression” compared to either treatment alone. Levels of TNFα, IFNγ, IL-6, IL-12p40, and IL-12p70 increased “significantly” in the combination group, and ELISpot analysis revealed more TNFα- or IFNγ-positive cells in the combination group.
In a flow cytometric analysis of immune cell populations in the spleen and tumour, the combination caused an increase in effector CD8+ and CD4+ T cells, DCs, Mϕ, and NK cells, but a decrease in Treg cells. H&E staining of tumour sections revealed necrotic lesions in the hGPRC5D and combination groups, but the lack of gross histological damage in several major organs supports the safety and clinical potential of the vaccine or combination.
Analysis of the immune cells revealed a “marked increase” in CD3+, CD8+, and CD4+ T cells in the splenic marginal zones of the combination group, consistent with flow cytometry data. There was also an increase in B lymphocytes and follicular DCs in this group. For TILs, the combination therapy also increased the number of CD8+ and CD4+ T cells.
Improving outcomes
Despite therapeutic advancements, high-risk patients with MM “continue to have poor outcomes”, and there are limited agents to prevent MM or progression from MGUS and SMM. The results from the study suggest that PD1 blockade “enhances tumour growth inhibition” in mice treated with the DNA vaccine and highlight the potential of the DNA-based GPRC5D vaccine to “overcome self-tolerance and the prospects of advancing” into clinical trials.
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by Charlotte Kilpatrick | Sep 25, 2024 | Therapeutic |
Anixa Biosciences announced a strategic plan for a Phase II study of its breast cancer vaccine in September 2024. The proposed trial follows a Phase I trial at Cleveland Clinic with grant funding from the United States Department of Defence. The trial will evaluate the efficacy of the vaccine administered in combination with chemotherapy and Keytruda in the neoadjuvant setting. This means that it can enrol a broader range of patients across multiple types of breast cancer.
A unique target
Researchers at Cleveland Clinic identified a protein called alpha-lactalbumin, present only in healthy breast tissue engaged in lactating; it becomes “retired” when the person stops nursing their child and does not exist in any other cell in the body. However, it does appear in “many types” of breast cancer, including the “aggressive and deadly” Triple Negative Breast Cancer (TNBC). By developing vaccines that target alpha-lactalbumin, Anixa hopes that the immune system can destroy cancer cells and prevent tumours from forming.
Moving forward
The Phase I clinical trial in the breast cancer vaccine has produced “positive” clinical data, so a cancer vaccine discovery programme has commenced in collaboration with Cleveland Clinic. This will explore additional cancer vaccine opportunities for “intractable” cancers such as high incidence malignancies in lung, colon, and prostate.
The Phase II trial will evaluate the efficacy of a combination of the vaccine, chemotherapy, and Keytruda in a neoadjuvant setting, seeking to reduce tumour burden and prevent recurrence, with “intent to improve survival”. Trial objectives include evaluating the immunological response to the vaccine and comparing clinical efficacy of standard of care therapy alone with the vaccine plus standard of care therapy. It is expected to begin in 2025 and will last between two and three years.
The trial will enable Anixa to engage more patients with various types of breast cancer. This has potential to address the increasing therapeutic market for breast cancer as prevalence and screening increases drive demand for treatment. The development path for breast cancer treatment is expected to be shorter than primary prevention.
Accelerated treatment
Dr Amit Kumar, Chair and CEO of Anixa Biosciences is excited to unveil the plan, “bringing us one step closer to a potentially transformative therapy for breast cancer patients”.
“By targeting treatment rather than prevention, we can reach a broader patient population and potentially expedite the process of regulatory approval and partnerships. This trial marks a key milestone in advancing our mission to fight cancer through innovative therapies.”
As the Phase II trial will focus on the therapeutic market, data will be used for other studies for “both recurrence prevention and primary prevention with partners in the future”.
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by Charlotte Kilpatrick | Sep 19, 2024 | Therapeutic |
In September 2024, Brenus Pharma announced the completion of a $25 million Series A financing round and receipt of non-dilutive funding to take the STC-1010 cancer vaccine through proof-of-concept in first-line settings for metastatic colorectal cancer patients. STC-1010 is the first candidate based on Brenus Pharma’s STC (Stimulated Tumour (ghost) Cells) technology platform, which offers a new type of precision treatment for a “significant public health challenge”. The platform will be deployed in humans from the end of the year, beginning with STC-1010.
STC platform
Brenus Pharma’s STC platform is designed to educate the immune system to “recognise and anticipate escape mechanisms” in cold tumours. Four key stages happen after injection:
- APC (antigen-presenting cell) cross-priming activation
- TILs (tumour-infiltrating lymphocytes) pool generation
- TILs expansion
- Tumour cell destruction
The technology “not only treats the immediate threat, but also defends the immune system against tumours that may appear later”, reducing a risk of relapse. This is achieved through the education of a patient’s immune system through the “widest panel of therapeutic targets currently available”.
Trials
STC-1010 will be administered as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) resistant to immunotherapies. It will also be tested in other types of gastric tumours, including those of the pancreas and liver. The second candidate in development, STC-1020, will be developed in other solid tumour indications. The team is optimistic that the platform products can become a “permanent part of precision medicine”.
The Phase I/IIA study of STC-1010 is known as “BreAK-CRC”; it is under review by the European regulatory authorities in preparation for participation of clinicians in early-phase immuno-oncology units in Europe and the United States. Phase I will evaluate the tolerability of different dose levels, combined with low dose immunostimulants and standard chemotherapy. The Phase IIA study will evaluate treatment efficacy, with a focus on progression-free survival at 12 months.
Achieving ambitious goals
Jacques Gardette, Chair of BIOJAG, confirmed that “Brenus Pharma now has our full attention to help the company achieve its ambitious goals” as it takes a “major step forward”.
“The arrival of investment professionals in our young company confirms the interest we are arousing…I’m convinced that the constant commitment and innovation of the Brenus team have built a solid foundation for tackling one of the world’s most complex therapeutic challenges.”
Mr Gardette commented on the “boldness, achievement, and resilience” demonstrated by Brenus in its “rapid development”. Dr Paul Bravetti, CEO of Brenus Pharma, reflected that the investment interest is an “important milestone” that confirms the platform’s potential.
“I would like to thank all our team for their motivation and their passionate work to rapidly bring a new therapeutic solution to patients. Our shared ambition is to position our platform at the forefront of the national and international scene, and to become a leader in next-generation cancer immunotherapies.”
Marie Chambodut, Partner and Investment Director at Angelor, is “proud” to lead the strategic transaction.
“We look forward to joining Paul and his exceptional team in transforming Brenus into a global player in precision immuno-oncology, bringing solutions to millions of patients experiencing treatment failure, and contributing to the development of the French biotherapeutics industry.”
Investment Manager at Noshaq, Hélène Sabatal, is “delighted” to support the development of the “cutting-edge technological platform”.
“We are convinced of its future impact for patients currently without concrete therapeutic solutions.”
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by Charlotte Kilpatrick | Sep 18, 2024 | Technology |
PharmaJet announced in September 2024 that it has entered a long-term license and supply agreement with Scancell Holdings to use PharmaJet’s Stratis Intramuscular (IM) Needle-free System for the delivery of its advanced melanoma DNA vaccine. Through the agreement, Scancell will use Stratis for the clinical development and commercialisation of ImmunoBody, the advanced melanoma DNA vaccine. PharmaJet will receive development and regulatory milestone payments and royalties on net sales upon commercialisation.
Stratis
PharmaJet’s Stratis technology is a needle-free system for 0.5 ml intramuscular and subcutaneous injections that enhances the performance of nucleic acid vaccines and therapeutics. Stratis delivery has demonstrated the ability to enable “effective uptake” of the Scancell DNA melanoma vaccine; 60 patients across 15 clinical trial sites have received a total of 171 doses of SCIB1/iSCIB1+ through Stratis. This approach offers the “convenience of an off-the-shelf therapeutic cancer vaccine with the speed and enhanced patient experience of needle-free delivery”.
ImmunoBody vaccines
Scancell’s ImmuoBody vaccines are designed to generate “potent” T cell responses that provide a broad anti-tumour effect. They are DNA vaccines that encode a protein in antibody form, with the elements of the antibody that would normally bind to the target protein replaced with cancer antigen epitopes. ImmunoBody vaccine design features include:
- Epitopes that bind to MHC class I and MHC class II
- Retention of the Fc region of the protein, which targets activated dendritic cells via its specific receptor
However, Scancell highlights the “most important aspect” of the technology as the ability to initiate both direct and cross-presentation of epitopes to T cells. The “highest avidity T cell responses” are generated if different pathways are used to present the same epitope. In ImmunoBody, the DNA form is taken up and processed directly by dendritic cells and the protein form binds to the high affinity Fc receptor on dendritic cells, leading to cross-presentation.
Advancing innovation
Professor Lindy Durrant, Chief Executive Officer of Scancell, is pleased that PharmaJet delivery “works effectively” with the SCIB1/iSCIB1+ vaccines and offers a “well-received immunisation for patients”.
“Securing long term supply for the PharmaJet Stratis Needle-free Injection System is important to allow clinical and commercial development of iSCIB1+…Our ultimate goal for Scancell has been to deliver an off-the-shelf, safe, tolerable, effective therapy that can provide potent and durable anti-tumour responses for unresectable stage IV melanoma, which currently has a 5-year survival of 35%.”
PharmaJet’s Chief Scientific Officer, Nathalie Landry, looks forward to working with Scancell to “advance their innovation further in clinical development and commercialisation” with benefits for melanoma patients.
“The Scancell strategic partnership further solidifies PharmaJet’s commercial delivery platform as a leader in the delivery of nucleic acid vaccines and immunotherapies.”
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by Charlotte Kilpatrick | Sep 16, 2024 | Global Health |
WHO Africa announced in September 2024 that more than 1,400,000 doses of human papillomavirus (HPV) vaccine have arrived in Angola as part of the national strategy for prevention and protection against cervical cancer. HPV is recognised as the “leading cause of more than 90% of cervical cancer”, but all approved vaccines are “highly efficacious” in preventing infection with virus types 16 and 18, with some conferring protection from additional types. Another batch of vaccines is expected in the coming days to bring the total number of doses to 2.2 million. This will ensure immunisation of around 2,136,000 girls between the ages of 9 and 12.
Preventing cancer
WHO Africa comments that cervical cancer is a “severe public health problem” that disproportionately affects African women; it affects five times more and kills seven times more African women than women in developed countries. WHO estimates that around 117,300 women in Africa are diagnosed with cervical cancer each year. More than 76,000 die from the disease.
Data from the Angolan Cancer Control Institute show that 915 cases of cervical cancer were treated in Angola in 2022. This number represents around 17% of all cancer cases in the country. However, the health authorities suggest that the actual incidence is higher, with cases going undetected due to “diagnostic limitations”.
Vaccination efforts
Angola is responding with urgency; the government has “boldly” acquired CECOLIN vaccines, manufactured by the INNOVAX laboratory, to reach 2,136,000 girls in a few weeks. The vaccine received WHO prequalification in 2021 for single-dose administration; it is considered “highly effective and safe”. More than 50 million doses have already been administered worldwide.
Alongside these vaccines, the government and partners are working to “consolidate other aspects” of the campaign, including planning and financing, training health workers, and engaging communities. The operation requires an estimated budget of US$20,926,809 and will involve vaccination in two phases at schools and communities.
Angola’s Minister of Health Dr Silvia Lutucuta stated that the vaccination campaign “represents a commitment by the Angolan Executive to protect the health and future of our girls”. The strategy is in line with the Global Strategy, contributing to a “healthier and more economically sustainable population”.
“This is a unique opportunity to protect future generations from a devastating disease. Let’s join forces and ensure that all girls in Angola, regardless of where they live, receive this life-saving vaccine.”
Acting WHO Representative in Angola, Dr Zabulon Yoti, recognised the “significant step” taken by the government to ensure that “Angolan girls grow up in a world where cervical cancer is a preventable disease, not a death sentence”.
“Now is the time to unite and support the initiatives underway to vaccinate our girls, drastically reduce the incidence of cervical cancer, and build a healthier future for the Angolan population.”
Antero Pina, UNICEF Representative in Angola, described the introduction of the vaccine as “another opportunity to transform the lives of adolescent girls”.
“This measure goes beyond the prevention of cervical cancer as it can promote other critical sexual and reproductive health interventions, thus making a further contribution to promoting and protecting the well-being of girls in Angola.”
Sustainable Development Goals
UN Development Programme Resident Representative in Angola, Dr Denise António, acknowledged funding from the European Investment Bank (EIB) and the government’s commitment to preventing cervical cancer. This is a “significant” milestone in national population health goals and the Sustainable Development Goals.
“By vaccinating these girls, we are safeguarding their future and contributing to the Sustainable Development Goals (SDGs). This milestone symbolises the strength of our joint commitment. It reflects the alignment of interests between the main partners involved, contributing to Angola’s National Development Plan 2023-2027 objectives and the 2030 Agenda.”
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by Charlotte Kilpatrick | Sep 16, 2024 | Therapeutic |
In September 2024, IO Biotech announced “promising” data from its Phase II basket trial of IO102-IO103 in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab). These results were shared in a conference presentation that included clinical and biomarker data from patients with recurrent or metastatic (advanced) squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 CPS ≥ 20. The study met its primary endpoint and identified a safety profile consistent with prior studies.
IO102-IO103
IO Biotech’s lead product candidate is IO102-IO103, which combines two wholly owned T-win vaccines designed to “activate and expand” T cells specific for IDO and PD-L1. T-win is an immune-modulating vaccine technology that is directed against tumour cells and the “most important” immune-suppressive cells in the tumour microenvironment (TME). Many types of solid tumours and immune-suppressive cells (Tregs and TAms) in the TME overexpress IDO and/or PD-L1. Thus, the combination of the two vaccines is intended to “have a synergistic effect” that leads to “enhanced cell killing”.
The Phase II basket study is a non-comparative, open-label trial that investigates the safety and efficacy of a combination of IO101-IO103 with pembrolizumab as a first-line treatment in up to 60 patients with metastatic non-small cell lung cancer (NSCLC) with PD-L1 TPS ≥ 50% and recurrent or metastatic SCCHN with PD-L1 CPS ≥ 20. The primary endpoint is overall response rate (ORR).
Promising data
Data from 18 efficacy evaluable patients revealed:
- The achievement of the primary endpoint – confirmed 44.4% overall response rate (ORR) in a PD-L1 high population of patients with SCCHN irrespective of HPV status.
- An “encouraging” 6.6-month median progression-free survival (PFS).
- A 66.7% disease control rate (DCR).
- A safety profile that is consistent with previously reported data from a combination approach.
- The detection of T-cell responses to both IO102 (targeting IDO) and IO103 (targeting PD-L1) after treatment.
Dr Jonathan Riess, principal investigator of the trial and Director, Thoracic Oncology at UC Davis Comprehensive Cancer Centre, is encouraged by the data in support of the combination approach.
“Given the need for new treatment options that are effective, safe, and accessible for head and neck cancer patients, further investigation of this combination should be conducted to build on the findings of this Phase II trial.”
Chief Medical Officer of IO Biotech, Dr Qasim Ahmad described “accumulating” evidence that the combination could be a “safe and efficacious first-line treatment for patients with a range of cancers”. This includes those with metastatic and “difficult-to-treat disease”.
“Importantly, with mPFS of 6.6 months, more than half of the patients in this trial had over 180 days of progression-free survival. These data are supportive of further investigation of this combination regimen as part of our commitment to transform the lives of cancer patients through our novel therapeutic vaccine.”
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by Charlotte Kilpatrick | Sep 13, 2024 | Therapeutic |
King’s College London shared in September 2024 that an mRNA cancer immunotherapy (mRNA-4359), targeted for patients with lung cancer, melanoma, and other solid tumours, has shown promise in a Phase I trial. The first-in-human study of the therapy involved 19 patients with advanced stage cancers and found that the immunotherapy prompted an immune response against cancer and was well tolerated. Although this was a small study, the researchers are encouraged that their results support further investigations.
Potential in trial
The Phase I trial was designed to test the safety and tolerability of the immunotherapy, with secondary and tertiary objectives exploring the radiographic and immunological responses. 8 out of 16 patients whose responses could be evaluated demonstrated that tumour size did not increase, and no new tumours appeared.
The immunotherapy also activated the immune system in patients, generating immune cells that could recognise two proteins of interest: PD-L1 and IDO1. In some patients the immunotherapy increased levels of “important immune cells that can kill cancer cells” and reduced levels of other immune cells that inhibit the immune system’s response. The researchers acknowledge that their study was small and focussed on safety and finding an optimal dose. However, they continue to recruit patients with melanoma and lung cancer.
An important first step
UK Chief Investigator of the trial is Dr Debashis Sarker, Clinical Reader in Experimental Oncology in the School of Cancer and Pharmaceutical Sciences and consultant in medical oncology at Guy’s and St Thomas’ NHS Foundation Trust. Dr Sarker described the study as in “important first step in hopefully developing a new treatment for patients with advanced cancers”.
“We have shown that the therapy is well tolerated without serious side effects and can stimulate the body’s immune system in a way that could help to treat cancer more effectively. However, as this study has only involved a small number of patients to date, it’s too early to say how effective this could be for people with advanced stage cancer.”
The trial is continuing recruitment of patients in a “huge international effort” across the UK, USA, Spain, and Australia. Dr Kyle Holen, Senior Vice President and Head of Development, Therapeutics and Oncology, Moderna, is “encouraged” by the results. They demonstrate “potential to elicit strong antigen-specific T-cell responses while maintaining a manageable safety profile”.
“This novel approach could be a key component in shifting the tumour microenvironment towards a more immune-permissive state, offering potential hope for patients with advanced solid tumours.”
Professor Tariq Enver, Director of the Cancer Research UK City of London Centre, congratulated the team for “taking us a step closer to personalised cancer vaccines”.
“Through his role supporting training at our centre, Debashis continues to inspire the next generation of clinician scientists to drive life-saving breakthroughs in biological cancer therapies.”
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by Charlotte Kilpatrick | Sep 12, 2024 | Therapeutic |
Researchers at the University of Birmingham announced the launch of a trial to study the use of an mRNA cancer vaccine in the treatment of pancreatic cancer in September 2024. In collaboration with the University Hospitals Birmingham NHS Foundation Trust (UHB), the researchers aim to recruit patients who are undergoing surgery to remove pancreatic ductal adenocarcinoma (PDAC). These patients will either receive the investigational cancer vaccine in combination with chemotherapy or chemotherapy alone.
Pancreatic cancer
Pancreatic cancer is “among the deadliest cancer globally”, with a survival rate over 10 years of just 5% in England. Physical symptoms often appear only when the cancer has developed to an advanced stage, limiting treatment opportunities. Pancreatic ductal adenocarcinoma (PDAC) is an “extremely aggressive” that accounts for 90% of all pancreatic cancers.
Dr Shivan Sivakumar, Principal Investigator of the trial, Associate Professor in Oncology at the University of Birmingham, and Consultant Medical Oncologist at Queen Elizabeth Hospital Birmingham (QEHB), is “more familiar than most with the devastating nature of this disease”, which is the 5th biggest cancer killer in the UK.
“Sadly, pancreatic cancer is typically diagnosed at a late stage, when curative surgery is no longer an option. The problem is exacerbated by the fact that for the ‘lucky’ 1 in 10 who are eligible for surgery, the recurrence rate of pancreatic cancer after surgical treatment is over 80%.”
A new hope
The investigational therapeutic cancer vaccine deploys mRNA to deliver “instructions” for neoantigens found in a patient’s cancer. Samples of each patient’s tumour tissue and blood are sent to laboratories after surgery for vaccine design and manufacture. This approach of “training the immune system to recognise and attack cancer cells” could potentially prevent cancer recurrence and increase the possibility of curing the patient.
Dr Sivakumar is “incredibly proud” that the Queen Elizabeth Hospital Birmingham is the first site in Europe to enrol a patient in the trial.
“This achievement highlights Birmingham’s leading role in advancing cancer treatment, offering new hope for patients battling one of the most challenging cancers we face today.”
Professor Kiran Patel, Chief Medical Officer at University Hospitals Birmingham NHS Foundation Trust commented that “we are very fortunate to have exceptional infrastructure and world-class talent that positions us perfectly to lead in vital areas of cancer research”.
“This trial showcases the expertise and dedication of our medical professionals, and the fantastic teams supporting them, who are at the leading edge of clinical research here in Birmingham. To be the first site to open in Europe reaffirms our role as a national and international centre for cutting-edge oncology and highlights our commitment to improving patient outcomes through pioneering approaches.”
Head of Research and Development Operations at UHB Jo Gray recognised the role of the National Institute for Health and Care Research (NIHR) Wellcome Trust Clinical Research Facility (CRF) in providing “expert care to patients receiving experimental therapies”.
“Birmingham is the first site outside of North America to open and to enrol a patient onto this complex, early phase trial that addresses an important need to identify better post-surgery treatments for pancreatic cancer.”
Professor Neil Hanley, Head of the College of Medical and Dental Sciences at the University of Birmingham stated that the research “epitomises why the University of Birmingham and its tremendous partnership with UHB is delivering life-changing impacts”. Professor Hanley hopes to “tilt” the discoveries of the pandemic towards a “much-needed world of new cancer treatments”.
“Birmingham is the ideal place to open this trial, with one of the leading pancreatic cancer units in the UK and serving a super diverse population.”
Head of Research at Pancreatic Cancer UK, Dr Chris Macdonald looks forward to “hope on the horizon”.
“We are absolutely delighted that Queen Elizabeth Hospital Birmingham is the first site in Europe to enrol a patient to an individualised pancreatic cancer vaccine trial. We will be following the results with great interest, as the potential here cannot be understated. If this research proves successful, the vaccine could be a vital new weapon against the deadliest common cancer.”
For more on the potential that mRNA might have for cancer therapy, join us in Barcelona for the Congress this October, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Sep 12, 2024 | Global Health |
In September 2024, Merck (MSD) announced positive top-line results from its pivotal Phase III trial evaluating the company’s 9-valent Human Papillomavirus (HPV) vaccine, GARDASIL 9, in young males in Japan. The trial met its primary and secondary endpoints, proving that administration of a 3-dose regimen of GARDASIL 9 reduced the combined incidence of anogenital persistent infection caused by 9 types of HPV compared to a placebo. Merck will share the data with regulatory authorities in Japan and other countries to support licensure for use in males.
V503-064
V503-064 is a Phase III, double-blind, placebo-controlled clinical study to evaluate the safety, tolerability, and efficacy of GARDASIL 9 (V503) in preventing HPV-related anogenital persistent infection in Japanese males between the ages of 16 and 26. It enrolled 1,059 participants. The primary efficacy objective was to demonstrate reduction in the incidence of HPV 6/11/16/18-related 6-month anogenital persistent infection. The secondary efficacy objective was to demonstrate reduction in the incidence of HPV 31/33/45/52/58-related 6-month anogenital persistent infection.
Dr Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, highlighted that “a decade after the first approval of GARDASIL 9, Merck continues to evaluate this important vaccine in additional patient populations”. Dr Barr emphasised Merck’s commitment to “helping prevent certain HPV-related cancers through broad and equitable access globally”.
“These data build on the clinical efficacy of GARDASIL 9 for the prevention of persistent infection in males and can potentially make a significant impact in addressing the global burden of certain HPV-related cancers and diseases.”
Merck’s clinical development programme evaluating GARDASIL 9 in males includes an ongoing confirmatory Phase III trial evaluating efficacy in preventing HPV oral persistent infection to support effectiveness against HPV-related oropharyngeal and other head and neck cancers.
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by Charlotte Kilpatrick | Sep 11, 2024 | Therapeutic |
In September 2024, OSE Immunotherapeutics announced the launch of an international Phase III clinical trial of its off-the-shelf neoepitope-based therapeutic cancer vaccine, Tedopi. The trial, named ‘Artemia’, will compare the efficacy and safety of Tedopi monotherapy with the standard of care in HLA-A2 positive patients with metastatic non-small cell lung cancer (NSCLC) with secondary resistance to immune checkpoint inhibitor (ICI). The primary endpoint is overall survival.
Tedopi and the Artemia trial
NSCLC accounts for 85% of all lung cancers, and the HLA-A2 phenotype represents around 45% of the population. The target population for Tedopi in second line is “considered as rare with high unmet medical needs”. This could be up to 46,000 patients a year across “seven major markets”.
Tedopi is a novel T-cell epitope-based cancer vaccine that targets five tumour-associated antigens. It is an activating and differentiated off-the-shelf immunotherapy expanding tumour specific T-lymphocytes in HLA-A2 cancer patients. It is being investigated in several Phase II trials as well as Artemia, a confirmatory Phase III clinical trial. This is intended to support the registration of Tedopi in second-line treatment of NSCLC in Europe and North America, alongside the companion diagnostic test for HLA-A2 positive patients.
Artemia is an international, randomised, open-label Phase III trial in the United States, Canada, Europe, and the United Kingdom. It is expected to include 363 patients.
Extending survival
Dr Silvia Comis, Head of Clinical Development and Regulatory Affairs at OSE Immunotherapeutics is “very pleased” that the last registration development step of the vaccine has started, supported by “positive and promising results” from the first Phase III in third-line treatment in NSCLC.
“These results demonstrated that re-arming the immune system with vaccine in metastatic patients can extend survival and preserve quality of life in the targeted population.”
Dr Nicolas Poirier, OSE Immunotherapeutics’ Chief Executive Officer looks forward to “confirming the therapeutic benefit of Tedopi for metastatic cancer patients”.
“Tedopi is the most advanced therapeutic cancer vaccine in clinical development and the first treatment option to address the high unmet medical need and large untapped market in advanced and metastatic second-line NSCLC.”
Dr Stephen Liu, associate professor and director of Thoracic Oncology at Georgetown University Lombardi Comprehensive Cancer Centre, is coordinating investigator for the United States and Steering Committee member. Dr Liu is “excited to see the Artemia trial activated in the US”.
“With an off-the shelf vaccine approach, we can offer a safer and more tolerable approach than chemotherapy for patients with advanced lung cancer. By properly engaging a patient’s own immune system, we hope to significantly extend survival.”
For more insights into cancer vaccine development and research, join us at the Congress in Barcelona this October, and don’t forget to subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Sep 10, 2024 | Therapeutic |
In September 2024, Evaxion Biotech announced positive topline data from a Phase II trial of EVX-01. This is part of a one-year interim analysis of the trial assessing EVX-01 in combination with MSD’s anti-PD-1 therapy, KEYTRUDA, in patients with advanced melanoma. These data show that 11 out of 16 patients had objective clinical responses and 15 out of 16 patients had a reduction in tumours (target lesions). Complete data will be presented at a conference in September 2024.
EVX-01 in trial
EVX-01 is Evaxion’s lead clinical asset, a personalised peptide-based cancer vaccine intended for first-line treatment of multiple advanced solid cancers. The personalised therapy is designed with Evaxion’s AI-Immunology platform and is tailored to target each patient’s unique tumour profile and immune characteristics.
The Phase II study is a self-sponsored open-label, single-arm, multi-centre trial to evaluate the efficacy and safety of EVX-01 vaccination in combination with MSD’s KEYTRUDA in treatment-naïve patients with metastatic or unresectable malignant stage III or IV melanoma. It is being carried out in collaboration with teams from Italy and Australia.
Evaxion reports that these topline data reveal a 96% Overall Response Rate (ORR) with 11 of 16 patients having objective clinical responses and 15 of 16 patients having reduction of their tumours. CEO of Evaxion, Christian Kanstrup, is “very excited” about the data, which “strongly support both the clinical profile of EVX-01 as a promising personalised cancer treatment” and the “unique predictive capabilities” of AI-Immunology.
“To present Phase II efficacy data for an AI-designed vaccine is a major milestone for Evaxion. Huge unmet medical needs remain in the field of melanoma, and we believe that EVX-01 could potentially be an improved treatment option for patients.”
We look forward to hearing from senior representatives of Evaxion at the Congress in Barcelona this October, so do get your tickets to participate in their sessions, and don’t forget to subscribe to our weekly newsletters for more vaccine updates.
by Charlotte Kilpatrick | Sep 10, 2024 | Global Health |
The University of Oxford’s Centre for Cancer Early Detection and Prevention announced in September 2024 that Cancer Research UK has awarded a team of scientists up to £550,000 to carry out “underpinning work” to test a vaccine for patients with Lynch syndrome. Lynch syndrome is associated with a higher overall risk of developing some types of cancer. The vaccine, if successful, could protect people with Lynch syndrome before cancer begins to develop.
Lynch syndrome
A heritable genetic condition, Lynch syndrome is caused by an altered copy of a gene that is involved in processes that support DNA repair. Failure to repair DNA can cause damage to genes that control growth. This increases the risk of cancer. People with Lynch syndrome have a “higher overall risk” of developing bowel cancer and other cancers such as womb cancer (endometrial cancer) and ovarian cancer.
Up to 7 in 10 people with Lynch syndrome develop bowel cancer in their lifetime. It is estimated to cause around 3% of bowel cancer cases in the UK each year. Although between 175,000-200,000 people are estimated to have Lynch syndrome in the UK, fewer than 5% have been diagnosed.
Vaccine potential
The team at Oxford will analyse pre-cancerous cells from people with Lynch syndrome to determine which parts of a pre-cancer are potential immune targets. They will then design a vaccine that encourages the immune system to recognise pre-cancer cells and destroy them before they develop into cancer. The researchers will continue working with people with Lynch syndrome, who have helped to co-develop the project so far. They will also consult people living with Lynch syndrome to understand their views about using vaccination to prevent cancer.
Free from fear of cancer
Associate Professor David Church, Cancer Research UK Advanced Clinician Scientist Fellow and co-lead of the LynchVax team at Oxford reflects that “less than 5% of people with Lynch syndrome are aware that they have the condition”. However, “it accounts for an estimated 1,300 cases of bowel cancer and increases the risk of other types of cancer”.
“We hope our research will lay the early foundations to potentially prevent these cases through vaccination, removing the fear of cancer from people whose chances of developing it in their lifetime are far higher.”
Professor Simon Leedham, Honorary Consultant Gastroenterologist and co-lead of the LynchVax team agrees that LynchVax “has the potential” to reduce the “very high risk” of developing these cancers for people with Lynch syndrome.
“While our work is in its infancy, we are excited by the prospect of a vaccine that can potentially be used to prevent the multiple types of cancer that typically occur in people with Lynch syndrome and deliver tangible improvements in survival.”
Helen White is a member of the LynchVax patient and public involvement group and is “delighted” to be a part of developing the “potentially life-changing vaccine for people like me with Lynch syndrome”.
“As passionate advocates for involving people with lived experience in research, we fully endorse the plans to reach out to the wider Lynch syndrome community to gather their views on a cancer-preventing vaccine. This is a crucial step in preparing for future clinical trials.”
Michelle Mitchell, Cancer Research UK’s Chief Executive comments that cancer vaccines “continue to show promise in helping to create a world where people can live longer, better lives, free from the fear of cancer”.
“Projects like LynchVax are a really important step forward into an exciting future, where cancers that occur in people with Lynch syndrome could potentially be prevented. This is one of many cancer vaccine projects Cancer Research UK is funding that we hope will reduce the number of cancer cases over the coming decades.”
To hear from experts working to address various cancers with vaccines, get your tickets to the Congress in Barcelona this October. Don’t forget to subscribe for more vaccine updates every week.
by Charlotte Kilpatrick | Sep 3, 2024 | Therapeutic |
A paper in Science Advances in August 2024 describes XPO1 (Exportin-1/CRM1) as a “bona fide tumour antigen” recognised by natural killer (NK) cells. With implications for vaccine development, the research identifies an opportunity for a personalised approach to NK cell therapy for solid tumours. The authors, led by a team at the University of Southampton, believe that “hijacking” the protein is a viable avenue of investigation.
Natural killer cells
The paper states that natural killer (NK) cells are becoming “increasingly recognised for their anticancer activity”. Their functions are “tightly controlled by a diverse repertoire of cell surface receptors”. Killer cell immunoglobin-like receptors (KIRs) are an “important family” of NK cells receptors, forming a polymorphic family of receptors with human leukocyte antigen (HLA) class I ligands. KIRs are “implicated in susceptibility to, and the outcome of”, a range of cancers, and contribute to heterogeneity within the innate immune response to malignancy.
KIRs can be activating or inhibitory; although the HLA class I ligand specificities of the inhibitory KIR are “relatively well defined”, the ligand specificities of the activating KIR are “much harder to identify”. However, recent research suggests that activating KIR can have an HLA class I-restricted peptide specificity. KIRs recognise families of peptide:HLA complexes in a motif-based manner, which allows recognition of different combinations of peptide and HLA.
Activating KIRs have been linked to protective responses to several cancers, including haematological malignancies. There is “potential” for KIR2DS2 binding peptides to be tumour-associated antigens derived from endogenously expressed proteins that are up-regulated during tumorigenesis. In the context of a lack of cancer-associated peptides that bind activating KIR, the authors sought to investigate this in a proof-of-concept study.
The study
XPO1, a nuclear export protein, is “frequently overexpressed” in cancer and serves as a “driver of oncogenesis”. The paper describes a molecular mechanism underlying a KIR2DS2 specific response against cancer, identifying that the combination of XPO1 and NK cells is associated with longer survival in “multiple” cancers. XPO1 is expressed at “low” levels in healthy cells, which the authors infer are too low to generate an activating signal in KIR2DS2-positive NK cells. They propose that the up-regulation of XPO1 found in cancer can “alter the balance” for NK cell activation in favour of activation of KIR2DS2-positive NK cells.
Professor of Hepatology at the University of Southampton, Salim Khakoo, challenges previous assumptions that killer cells attack cancer cells randomly.
“Our findings actually show how our body’s immune system recognises and attacks these cancer cells.”
Killer cells as “emerging” as a form of immunotherapy that “shows huge promise”, says Professor Khakoo.
“They don’t attack health tissue in the way chemotherapy and other immunotherapies do, so are safer and have [fewer] side-effects than traditional forms of cancer treatment.”
The peptide derived from XPO1 appeared to attract natural killer cells to trigger an immune response, leading to “significantly better survival rates” across a “range of cancers”. This included cancers with higher rates of death, such as liver cancer. Professor Ralf Schittenhelm of Monash University hopes that the research offers a new way of activating killer cells to treat disease effectively.
“We hope it could lead to personalised cancer treatment, especially in cases where traditional therapies have failed. The potential to develop targeted therapies that utilise the body’s own immune system is incredibly exciting.”
The team at Southampton will move to vaccine development in pursuit of the “first vaccine that uses natural killer cells to fight cancer”.
For the latest cancer vaccine development updates at the Congress in Barcelona this October get your tickets here, and don’t forget to subscribe to our weekly newsletters for more.
