by Charlotte Kilpatrick | Aug 6, 2024 | Therapeutic |
In August 2024 researchers at the University of California, Los Angeles (UCLA) announced the launch of a “first-of-its-kind” clinical trial to evaluate the safety and effectiveness of a cancer vaccine that targets H3 G34-mutant diffuse hemispheric glioma, a “highly aggressive” brain tumour that is “typically” found in adolescents and young adults. The vaccine, developed at UCLA, is designed to target genetic mutations of the H3-3A gene. The trial will start with patients over the age of 18 before expanding to include patients as young as 5 years who have a confirmed diagnosis of H3 G34-mutant diffuse hemispheric glioma.
“The clinical trial aims to improve survival rates and provide new insights into how the immune system responds to primary brain cancers and understand whether these targets engender a lasting anti-tumour immune response.”
H3 G34-mutant diffuse hemispheric glioma
One of the “most lethal forms of paediatric brain cancer”, H3 G34-mutant diffuse hemispheric glioma is a “highly aggressive brain tumour” primarily characterised by a mutation in the H3-3A gene. This gene encodes an “important regulatory component” on histone H3. The mutation causes “significant disruptions” in RNA processing, which has “wide-ranging influences on cancer behaviour and response to treatment”. UCLA Health is the only centre in the US that is investigating immunotherapy for this type of glioma.
Dr Anthony Wang, director of the Paediatric Brain Tumour Programme at UCLA Health and principal investigator of the trial, commented that the brain tumour “evades current therapies with shocking efficiency”, even in the face of “aggressive treatments”.
“These cancers show a host of escape pathways, allowing small populations of cells to survive initial treatment and to adapt. The data from our pre-clinical studies make us hopeful that an active, targeted cancer vaccine will be able to adapt with the tumour, in order to eliminate cancer cells more effectively.”
A vaccine opportunity
The vaccine will be manufactured by the UCLA Human Gene and Cell Therapy Facility; it is a dendritic cell vaccine that “works by arming a patient’s dendritic cells” against products of the altered RNA regulation. After the dendritic cells have been activated against the targets they are injected back into the patient.
Dr Dawn Ward, medical director of the UCLA Human Gene and Cell Facility and associate clinical professor of pathology and laboratory medicine at the David Geffen School of Medicine, said that “our job is to help accelerate the development of novel cures”.
“We do this by providing a highly regulated environment to ensure the identity, strength, quality, and purity of drug and cell products.”
Dr Robert Prins, professor in the departments of neurosurgery and molecular and medical pharmacology at the David Geffen School of Medicine, stated that the development of “effective” cancer immunotherapies “requires a deep understanding of the tumour antigens targeted by the immune system”.
“We found that the histone H3 G34R mutation significantly alters mRNA regulation, inducing a conserved set of mRNA splicing changes that result in neoantigens potentially targetable by T lymphocytes.”
This dysregulation is described as an “attractive target” for dendritic cell vaccination by UCLA Health. Through a collaboration with Professor Yi Xing of the Children’s Hospital of Philadelphia, the team developed a computational tool called IRIS (Isoform peptides from RNA splicing for Immunotherapy target Screening). This tool enables the identification of neoantigen targets.
Dr Linda Liau, chair of neurosurgery at UCLA Health, described the trial as a “novel and potentially transformative approach” to the treatment of high-grade gliomas in children and young adults.
“We are optimistic that this research could lead to more advanced studies and eventually a new standard of care for this challenging subtype of brain cancer.”
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by Charlotte Kilpatrick | Aug 6, 2024 | Therapeutic |
In August 2024 Ultimovacs announced topline data from the FOCUS Phase II trial combining UV1 and pembrolizumab in patients with metastatic or recurrent head and neck squamous cell carcinoma, revealing that the combination did not meet primary or secondary endpoints. Although the vaccine “continues to show a positive safety profile”, adding it to the standard of care did not lead to clinical benefits in progression free survival or overall survival in late-stage HNSCC patients. Head and neck cancer is the seventh most common type of cancer globally, with squamous cell carcinoma representing about 90% of those patients.
“Despite advances in treatment strategies, the prognosis for these patients is poor.”
UV1
UV1 is Ultimovacs’ therapeutic cancer vaccine, designed to induce a specific T cell response against telomerase. It comprises long, synthetic peptides representing a sequence in the reverse transcriptase subunit of telomerase (hTERT), which is shown to induce CD4+ T cells. After intradermal injection, antigen presenting cells (APCs) in the skin are exposed to vaccine peptides. The APCs process the peptides and present vaccine epitopes on Human Leukocyte Antigen (HLA) molecules to naïve T cells in the lymph nodes.
FOCUS
The trial is an investigator-initiated randomised Phase II clinical trial, sponsored by Martin-Luther-University Halle-Wittenberg with support from Ultimovacs, taking place across 10 sites in Germany. It investigates Ultimovacs’ therapeutic cancer vaccine, UV1, in combination with pembrolizumab, compared to pembrolizumab alone, as a first-line treatment in patients with recurrent PD-L1 positive head and neck squamous cell carcinoma (HNSCC). The primary endpoint is progression free survival at 6 months.
A disappointing result
Dr Carlos de Sousa, Chief Executive Officer at Ultimovacs, reflected that the cancer vaccine has been tested in a “range of different indications” through a “broad Phase II clinical development programme”.
“Unfortunately, the FOCUS study did not provide us with the results we had hoped for, and we are disappointed that UV1 was not able to provide added clinical benefit for these HNSCC patients.”
Dr de Sousa stated that a cash preservation programme, implemented earlier in the year, enabled the team to “extend our runway” to the fourth quarter of 2025, beyond the anticipated DOVACC Phase II topline readout.
“Further, the Ultimovacs team is actively developing a novel technology platform identified during the TET development and we look forward to providing more details before year-end.”
Dr Jens Bjørheim, Ultimovacs’ Chief Medical Officer, echoed Dr de Sousa’s disappointment that the FOCUS trial “did not achieve the desired outcome for patients”, adding that this “underscores the complexities of treating metastatic and recurrent head and neck cancer”.
“This cancer type is particularly aggressive with limited treatment options and high rates of recurrence. Our broad clinical development programme was designed to identify the best patient populations for UV1 and we are now focusing our efforts on the upcoming DOVACC data readout in the first half of next year.”
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by Charlotte Kilpatrick | Jul 30, 2024 | Therapeutic |
In July 2024 BioNTech announced positive topline data from its ongoing Phase II trial in patients with unresectable stage III or IV melanoma whose disease had progressed after anti-PD-(L)1-containing treatment. The trial evaluates the clinical activity and safety of BioNTech’s investigational mRNA cancer immunotherapy, BNT111, in combination with Libtayo (cemiplimab), Regeneron’s anti-PD-1 monoclonal antibody, and assesses the two single agents alone.
Melanoma
BioNTech states that melanoma is among the leading causes of cancer-related deaths across the world; it is responsible for around 58,000 deaths each year. Anti-PD-1 refractory/relapsed unresectable stage III or IV melanoma is an “aggressive form” that “remains particularly lethal”. Although checkpoint inhibitor therapies “substantially improve the life expectancy” of many patients, others exhibit resistance to approved therapies.
“The 5-year survival rate for patients with distant metastatic melanoma is approximately 35%. This underscores the significant unmet medical need.”
BNT111 in trial
BNT111 is an mRNA-based off-the-shelf cancer immunotherapy candidate for intravenous administration, which encodes a fixed set of four non-mutated melanoma-associated antigens (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE), delivered as uridine mRNA-lipoplex formulation. More than 90% of patients with cutaneous melanoma express “at least one” of these antigens.
The trial, BNT111-01, is an open-label, randomised Phase II trial to evaluate the efficacy of BNT111 and cempilimab and the contribution made by each component in patients with anti-PD-1/PD-L1-refractory or relapsed, unresectable stage III or IV cutaneous melanoma. It takes place across around 60 sites in 7 countries and seeks to demonstrate anti-tumour activity and overall response rate (ORR) of the combination and each agent alone. Other endpoints include duration of response (DOR), disease control rate (DCR), overall survival (OS), safety, and tolerability.
A significant step
The trial met its primary efficacy outcome measure, demonstrating a “statistically significant improvement” in ORR in patients who received the combination treatment compared to historical control in this indication and treatment setting. Both randomised monotherapy arms showed clinical activity. The combination approach had a safety profile that was consistent with previous trials. The trial will continue as planned to further assess secondary endpoints.
Professor Özlem Türeci, Chief Medical Officer and Co-Founder of BioNTech, is pleased with the “significant step towards our vision of personalised cancer medicine”.
“We envision mRNA as a centrepiece in future treatment paradigms for cancer, helping to address unmet medical needs, such as for patients with anti-PD-(L)1 refractory or resistant melanoma.”
The data serve Professor Türeci and team in “three dimensions”:
“First, for our decade-long improved mRNA cancer vaccine technology that uses uridine mRNA chemistry, a non-coding backbone that is engineered for optimal translational performance and our proprietary lipoplex formulation for delivery. Second, for our computational approaches for selecting suitable tumour antigens for our cancer indication-specific FixVac platform candidates. Third, for our strategy to combine synergistic modalities, in this case BNT111 with an established immune checkpoint treatment.”
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by Charlotte Kilpatrick | Jul 18, 2024 | Therapeutic |
Diakonos Oncology Corporation announced in July 2024 that the US FDA has granted Fast Track designation for its dendritic cell vaccine (DCV) for pancreatic ductal adenocarcinoma. This is the second Fast Track designation Diakonos has received for the DCVs; the first was for the lead vaccine for glioblastoma multiforme (GBM). The company also announced the addition of Dr Daniel D. Von Hoff, Distinguished Professor at the Translational Genomics Research Institute in Phoenix and City of Hope to the Scientific Advisory Board.
DCV
Diakonos states that Dr Will Decker, Chief Science Officer, identified that dendritic cells can detect and initiate Th1 immunity against viral threats after they “confirm matching antigens on MHC Class 1 and 2”. Dr Decker developed a dendritic cell vaccine that loads a patient’s cancer antigens onto MHC Class 1 and 2, which triggers a “powerful and natural” immune response against their cancer. While first attempts loaded tumour antigens on MHC Class 1 (mRNA) and MHC Class 2 (lysate), they “failed” to initiate the required Th1 to be effective against cancer. However, by “double-loading” the dendritic cells, the team can induce “powerful” Th1 immunity and corresponding killer T cell activation.
Mike Wicks, CEO of Diakonos, is glad to have “another acknowledgment” of the “incredible potential of this innovative immunotherapy” against deadly cancers. He is “thrilled” that Dr Von Hoff is joining the team as an advisor as they pursue clinical development. Dr Von Hoff commented that the “unique” dendritic cell vaccine has “shown encouraging results in treating glioblastoma”.
“Pancreatic cancer patients also need additional treatment options. I look forward to working with Diakonos to help develop effective treatments for patients with pancreatic cancer with the same targeted technology.”
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by Charlotte Kilpatrick | Jul 8, 2024 | Therapeutic |
In July 2024, HOOKIPA Pharma announced that the first person has been dosed in a Phase Ib clinical trial of HB-500, an investigational therapeutic vaccine for the treatment of HIV. The trial is to evaluate the safety and tolerability, reactogenicity, and immunogenicity of repeated doses of HB-500 in participants with HIV on suppressive antiretroviral treatment. The arenaviral vaccine was developed in collaboration with Gilead Sciences, and the beginning of the trial ensures that HOOKIPA achieves a $5 million non-dilutive milestone payment through the collaboration and license agreement.
HB-500
HB-500 comprises two genetically engineered replicating vectors based on the arenaviruses Pichinde virus and lymphocytic choriomeningitis virus. The vectors have been engineered to deliver HIV antigens that have been derived from parts of “key, immunogenic regions” of HIV type 1 (HIV-1) proteins that are highly conserved in HIV-1 clade B variants. The designed immunogens differ by amino acid sequence to allow coverage of >80% of circulating HIV-1 viral variants.
HOOKIPA states that the adenovirus technology has “several key advantages” including:
- The ability to induce a robust CD8+ T cell response by directly targeting and activating dendritic cells
- The ability to induce a robust antibody response to disease-specific target antigens
- The possibility for repeat administration to boost immune response
- No need for an adjuvant to stimulate the immune system
- Demonstrated good tolerability in preclinical studies and clinical trials
The trial began with the first participant on 1st July 2024 and comprises two dose escalation cohorts that will be randomised to receive either HB-500 or placebo. Enrolment is ongoing. HOOKIPA takes responsibility for “advancing the HIV programme” through the completion of the Phase Ib clinical trial. Following this, Gilead has the exclusive right to assume further development of the programme.
Taking an important step
CEO of HOOKIPA, Joern Aldag, commented that HIV “impacts the daily lives of millions globally, with no known curative treatment”.
“While current treatments effectively block viral replication and can prevent progression to AIDS, they have not been shown to clear the virus from people living with HIV, requiring lifelong treatment.”
Aldag states that the team is “happy to have begun the Phase Ib trial” after “impressive findings” at the preclinical stage.
“Our team has worked tirelessly, alongside our great collaboration partners at Gilead, to reach this point, and we are excited to take in important step toward finding a curative treatment for HIV.”
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by Charlotte Kilpatrick | Jul 3, 2024 | Therapeutic |
A report shared by WHO in July 2024 presents the importance of designing therapeutic human papillomavirus (HPV) vaccines for use in lower resource settings to ensure “maximum public health benefits”. WHO preferred product characteristics for therapeutic HPV vaccines provides guidance to encourage innovation and development of therapeutic vaccines to “clear or treat” HPV infections or HPV-associated precancers or cancers. The report outlines ideal “parameters” such as vaccine indications, target populations, safety and efficacy considerations, and immunisation strategies.
Another tool against HPV-related cancers
The report states that the development of therapeutic vaccines for human papillomavirus (HPV) could provide an “important addition” to current methods for the prevention and treatment of HPV-related cancers. This includes cervical cancer, which is caused “almost exclusively” by sexual transmission of oncogenic types of HPV and represents an “important public health problem globally”. In 2022, an estimated 662,000 women were diagnosed with cervical cancer, and approximately 349,000 women died from the disease.
WHO states that “over 90%” of cervical cancer-associated deaths were among women in low- and middle-income countries (LMICs), which is attributed to “inequitable access to effective cervical cancer prevention and management measures”. Efforts to eliminate cervical cancer as a public health problem will involve three key targets:
- Vaccination of 90% of girls with prophylactic HPV vaccines
- Screening of 70% of women for cervical cancer with a high-performance test twice in their lifetime
- Provision of treatment to 90% of women with cervical precancers and invasive cancers
However, progress towards elimination is lagging, with issues such as the “cost and complexity” of screening and treatment programmes and “persistent inequities in access”. Therefore, therapeutic HPV vaccines, currently in early clinical development, could offer an “additional tool” to address gaps in cervical cancer programmes.
Considerations for vaccine development
A group of experts explored the “feasibility, pipeline, and clinical development considerations” for future therapeutic HPV vaccines to meet public health needs. They focused on vaccines that “primarily clear high-risk HPV infection and/or cause regression of high-grade cervical precancers”.
Feasibility
The report states that all HPV types encode “early” proteins (E-proteins: E1, E2, E4-E7) and “late” virion structural proteins (L-proteins: L1, L2). Infection is caused when HPV virions bind to basal cells in the epithelium using the viral capsid protein L1, so current prophylactic HPV vaccines target L1. In infected cells, E1 and E2 proteins facilitate viral replication and transcription, while E6 and E7 proteins drive cell proliferation. E6 and E7 are the main targets of “most” therapeutic vaccine candidates to date. However, to target early stages of pathogenesis, including proteins like E1 and E2 could be “critical for successful termination of HPV infection and the prevention of precancer”.
There are several challenges for therapeutic HPV vaccine development. For example, it has a “relatively slow life cycle that is non-cytolytic, actively evades the innate and adaptive immune response, and does not induce a high level of inflammation that would alert the host to infection”. As antibodies are “insufficient to clear persistent HPV infection” or reduce precancerous lesions, post-exposure therapeutic vaccines will likely need to induce cell-mediated immunity with effective T cell responses against early viral proteins across genetically diverse populations.
Furthermore, advanced cervical lesions have often undergone immune selection and present a highly immunosuppressive local environment that poses “scientific and immunological challenges”. Thus, WHO suggests that it could be easier to develop efficacious therapeutic HPV vaccines that target HPV infection or low-grade precancerous lesions than vaccines that target high-grade precancers or invasive cervical cancer. The experts considered an effective single-dose vaccine “unlikely” for targeting persistent high-risk HPV infection or more advanced cervical disease.
“Mucosal delivery, such as oral or intravaginal, for either initial or booster dosing might improve the immune response and could allow self-administration. Intravaginal administration may have the added benefit of recruiting T cells into the relevant tissue site.”
Pipeline
Although there are no licensed therapeutic HPV vaccines, the pipeline is “active”, with a “wide variety of approaches” deployed, including peptide, protein, DNA, RNA, and bacterial- and viral-vectored vaccine platforms. Development has primarily focused on candidates targeting the regression of CIN2/3 lesions and invasive cervical cancer, but a few candidates target clearance of high-risk HPV infection. All candidates have been multiple-dose products administered at set intervals over several months, and the most common route of administration has been parenteral (subcutaneous and intramuscular) delivery. Other methods include oral delivery and direct injection at the site of the cervix.
Clinical development
Vaccine candidates designed primarily to clear HPV infection have not yet progressed to late-stage clinical development, with no specific regulatory pathways identified. Vaccine candidates designed primarily to cause regression of CIN2/3 lesions should be “carefully designed” to ensure they are “ethically and methodologically sound”. For both approaches, some outcomes could be evaluated post-licensure.
Preferred characteristics
WHO outlines several preferred characteristics in the report, divided into characteristics for vaccines used to clear oncogenic HPV infections, characteristics for vaccines used to treat cervical precancers, and characteristics common to both types of vaccines.
A catalytic innovation
Dr Sami Gottlieb, medical doctor and epidemiologist in WHO’s Department of Sexual and Reproductive Health and Research, commented on the importance of expanding access to existing interventions to eliminate cervical cancer as we advance the development of this tool.
“Therapeutic HPV vaccines could be a catalytic innovation to complement these efforts, increasing options for the millions of women who have already acquired HPV and reducing their risks of developing life-threatening cancer in the future.”
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by Charlotte Kilpatrick | Jun 25, 2024 | Therapeutic |
In June 2024, Defence Therapeutics announced that its second-generation ARM-X anti-cancer vaccine is “therapeutically effective” against pre-established ovarian cancer (ID8 model) in combination with an anti-PD-1 immune-checkpoint inhibitor. Using the Accum platform, Defence previously demonstrated that AccuTOX treatment of MSCs resulted in the induction of antigen cross-presentation capacity (ARM-X cells), which can mount strong anti-tumoral responses in animal pre-clinical models
Accum Technology
Defence suggests that Accum Technology is the first-of-its-kind solution to previous cancer treatment challenges. It has “proven its ability to deliver drugs” to the infected parts of infected cells at “10x the rate” of current solutions by:
- Accumulating more ADCs into a target cell
- Breaking the cell membrane
- Successfully reaching the intercellular target site
- Delivering more of the intended drugs to the intended sites
Defence states that a “major” advantage of the ARM-X vaccine is the lower threshold of antigen quantities to manufacture the vaccine. This “avoids the need of a big tumour sample” in vaccine generation. Sebastian Plouffe, Chief Executive Officer of Defence Therapeutics, emphasises that this is the 4th cancer model to be “efficiently targeted” with the AMR-X anti-cancer vaccine.
“The purpose of testing our vaccine in various models is to highlight how ARM-X can be adapted to the needs of any patient, no matter the type of cancer, given that we have access to a tumour biopsy.”
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by Charlotte Kilpatrick | Jun 24, 2024 | Therapeutic |
In June 2024 Vaxxinity announced the publication of “groundbreaking exploratory data” from a Phase I clinical trial of UB-312 in patients with Parkinson’s disease (PD). UB-312 is an active immunotherapy medicine (AIM) designed to “slow or stop” the progression of Parkinson’s by “addressing the root cause”. The trial was a 44-week, randomised, placebo-controlled, double-blind, single-centre Phase I study to investigate the safety, tolerability, and immunogenicity of UB-312.
Tackling the root cause
The authors state that Parkinson’s disease (PD) is “characterised by progressive deterioration of motor, cognitive, behavioural, and autonomic function”. While mechanisms of dopaminergic cell loss are “not fully understood”, it is known that α-synuclein (αSyn) has a “central role” in neurodegeneration, and the team believes that targeting pathological, aggregation-prone forms of αSyn has potential for therapeutic approaches.
UB-312 was chosen from over 60 synthetic peptide immunogens and has already demonstrated high immunogenicity in preclinical studies across species. Antibodies induced by UB-312 selectively targeted pathological oligomeric and fibrillar αSyn forms, binding specifically to αSyn inclusions in postmortem brain sections from patients with PD. Additionally, UB-312-derived antibodies demonstrated neuroprotective effects in vitro, reduced αSyn in the brain and gut, and prevented motor function deficits in a transgenic synucleinopathy mouse model.
The study
In Part A of the study, escalating doses of UB-312 were tested against a placebo in healthy volunteers aged 4-85 years, which suggested that it was “safe and well tolerated” up to 300/300/300 μg three-dose ‘prime-boost’ regimen. Prime-boost regimens of 300/100/100 μg and 300/300/300 μg were selected based on safety and immunogenicity profile for evaluation in patients with PD. This was followed by Part B, designed to assess the safety, tolerability, and immunogenicity of the two chosen UB-312 regimens in patients with PD.
The trial in patients with PD met the primary outcomes and showed that UB-312 was “generally safe and well tolerated” and generated a time-dependent increase in anti- αSyn antibodies in both serum and cerebrospinal fluid (CSF). Vaxxinity infers from this that UB-312 can “help to eliminate the buildup of harmful, toxic forms of the protein αSyn in the brain”. Patients with detectable UB-312-induced antibodies in CSF exhibited “significant improvement in motor experiences of daily living” according to the MDS-UPDRS Part II.
Leading the charge
Lou Reese, Co-Founder and Executive Chair of Vaxxinity, suggests that the publication of the team’s data “immortalises the profound impact of UB-312, leading the charge against the very core of Parkinson’s”.
“It sparks a beacon of hope and anticipation for a future where Parkinson’s no longer determines the trajectory of lives. This is more than just a scientific breakthrough; it’s a battle cry for change, declaring that the status quo in Parkinson’s care is no longer acceptable.”
Professor Geert Jan Groeneveld, neurologist and principal investigator of the trial at the Centre for Human Drug Research in Leiden, states that UB-312 “has the potential to become an important and potent disease-modifying therapy”.
“It would be truly amazing if we could vaccinate people against Parkinson’s disease in the future!”
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by Charlotte Kilpatrick | Jun 11, 2024 | Therapeutic |
In June 2024 Nykode Therapeutics announced updates to its mRNA platform, highlighting the “significant advantages” of its APC-targeted neoantigen vaccine, delivered in an mRNA-lipid nanoparticle (LNP) format. A recent study demonstrates that the APC-targeted vaccine “consistently achieved a broader and more robust immune response across doses” in comparison with an untargeted neoantigen vaccine. Furthermore, it provided “superior tumour control” and resulted in “dramatically improved” survival rates in a mouse model of colorectal cancer.
Poster presentation
Nykode’s poster for the Cancer Immunotherapy meeting in Boston recognises that individualised cancer vaccines based on tumour-specific neoantigens are a “groundbreaking approach” with “promising efficacy”. The company has developed a vaccine platform, VaccibodyTM, to target antigens directly to antigen presenting cells (APCs).
In their study, researchers used a model Vaccibody modular fusion protein containing Chemokine ligand 3-like 1 (CCL3L1) to bind and attract APCs, a dimerization domain to facilitate strong bivalent binding, and an antigen unit encoding 20 neoantigens. They compared the immunogenicity and tumour control of an mRNA-encoded Vaccibody vaccine to an untargeted antigen vaccine.
The Vaccibody vaccine elicited a “much stronger response” than the antigen vaccine on day 7 after single (prime) vaccination. After a second (boost) vaccination, the Vaccibody vaccine continued to elicit a stronger response, although the difference was reduced. The authors note that the Vaccibody vaccine reached a peak response at a lower dose than the antigen vaccine, which highlights “increased potency”.
Platform potential
Chief Scientific Officer, Dr Agnete Fredriksen, commented that the latest data “not only emphasise the effectiveness of the APC-targeted approach” but also confirm the platform’s “potential across modalities to significantly advance the treatment landscape for cancer”.
“The strong data demonstrating Nykode’s potential to improve mRNA vaccines underscore our commitment to leading the way in next-generation immunotherapies.”
For more on innovative vaccine approaches to cancer treatment, why not join us at the Congress in Barcelona by getting your tickets here? Don’t forget to subscribe for weekly vaccine updates.
by Charlotte Kilpatrick | Jun 4, 2024 | Therapeutic |
In June 2024 Moderna and Merck announced the first presentation of results from a planned analysis from the Phase IIb randomised KEYNOTE-942/mRNA-4157-P201 study. The study evaluates mRNA-4157 (V940) in combination with KEYTRUDA in patients with resected high-risk melanoma (stage III/IV) after complete resection. Moderna states that, with a median follow-up of around three years (34.9 months), adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA “continued to demonstrate a clinically meaningful and durable improvement” in recurrence-free survival (RFS), which was the primary endpoint of the study. Risk of recurrence or death was reduced by 49% when compared with KEYTRUDA alone. The combination also “continued to demonstrate a meaningful improvement” in distant metastasis-free survival (DMFS), reducing the risk of developing distant metastasis or death by 62%.
Study highlights
Data from an exploratory subgroup analysis of the study showed that improvement in RFS was observed in the combination approach compared to KEYTRUDA alone regardless of tumour mutational burden (TMB) or programmed death-ligand 1 (PD-L1) status. The RFS benefit of the combination compared to KEYTRUDA alone was maintained across both TMB high, TMB non-high, PD-L1 positive, PD-L1 negative, and circulating tumour DNA (ctDNA) negative subpopulations. ctDNA positive HR was not estimable due to the small sample size. There were “no significant associations” between individual human leukocyte antigen (HLA) alleles and RFS observed for mRNA-4157 (V940) in combination with KEYTRUDA.
“The exploratory endpoint of overall survival (OS) favoured mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone, with a 2.5-year OS rate of 96.0% vs 90.2%.”
The safety profile of the combination of mRNA-4157 (V940) and KEYTRUDA “remains consistent with the primary analysis” with the most common adverse events being fatigue (60.6%), injection site pain (56.7%), and chills (49.0%).
Encouraging results
Dr Kyle Holen, Moderna’s Senior Vice President and Head of Development, Therapeutics and Oncology, is “encouraged by the latest results”.
“These data highlight the sustained benefit in RFS and DMFS of mRNA-4157 (V940) as adjuvant treatment in combination with KEYTRUDA in people with resected high-risk melanoma. Importantly, this benefit was observed across various patient exploratory subgroups, reflecting the potential of mRNA-4157 (V940) for a broad range of these patients.”
Dr Holen suggests that the findings “reinforce our commitment to advancing this innovative treatment” with Merck.
“We are dedicated to harnessing mRNA technology to potentially transform cancer therapy and improve patient outcomes.”
Dr Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, commented that the “sustained improvements” identified in the study “provide further support of the potential of mRNA-4157 (V940) in combination with KEYTRUDA to help patients with resected high-risk melanoma”.
“We look forward to building on our legacy of turning breakthrough science into medicines that may have a meaningful impact on patients’ lives as we continue advancing our broad clinical development programme evaluating this novel approach with Moderna.”
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by Charlotte Kilpatrick | Jun 3, 2024 | Therapeutic |
Transgene announced in June 2024 that the first patient has been enrolled in the Phase II part of a randomised Phase I/II clinical trial of TG4050 in the adjuvant treatment of head and neck cancer. Patient screening and enrolment are underway, with hopes of enrolling 80 patients internationally to continue the trial after Phase I data showed immunogenicity and first signs of clinical benefit. TG4050 is based on Transgene’s myvac viral vector platform and NEC’s cutting-edge AI capabilities for the identification and prediction of the most immunogenic neoantigens for every patient.
“TG4050 is the only individualised neoantigen cancer vaccine currently being developed in a randomised trial in the adjuvant treatment of head and neck cancer.”
The vaccine shows promise
Transgene states that “promising” data from Phase I showed “strong immunogenicity” and a “persistent cellular immune response” as well as “signs for clinical benefit for patients”. At the time of analysis all patients who received TG4050 were disease-free. Therefore, Transgene and partner NEC are moving into an extension of the randomised trial.
The Phase II will continue investigating single-agent TG4050 in patients with newly diagnosed, locoregionally advanced, HPV-negative, squamous cell carcinoma of the head and neck (SCCHN) in the adjuvant setting following completion of surgery and chemoradiotherapy. The international, multicentre, open label, two-arm trial is screening patients in Toulouse and Paris, in France, with other sites to be added in Europe and the US in the coming months.
A significant medical need
Despite advancements in the treatment of SCCHN, Transgene identifies a “significant medical need” for patients, including in the adjuvant setting. With the current standard of care, 30% to 40% of patients are expected to relapse within 24 months after surgery and adjuvant therapy. Dr Maud Brandely, Chief Medical Officer of Transgene, described the inclusion of the first patient as a “further milestone” for the company.
“In the ongoing trial, TG4050 is targeting patients with head and neck cancer at high-risk of relapse, with the aim of extending disease-free survival. The Phase I data we have generated indicate that TG4050 enables the induction of specific cellular immune responses that persist up to 7 months post treatment initiation, with all treated patients remaining disease-free after a median follow-up of 18.6 months.”
Dr Brandely is “encouraged” by the “promising clinical outcomes” and looks forward to generating more data.
“Personalised cancer vaccines are an extremely exciting development and, if successful, could also be utilised to treat other forms of cancer to improve and extend the lives of patients.”
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by Charlotte Kilpatrick | May 31, 2024 | Therapeutic |
NHS England announced in May 2024 that “thousands” of cancer patients across the country will get “fast-tracked” access to trials of personalised cancer vaccines through a new “matchmaking” service: the Cancer Vaccine Launch Pad (CVLP). The CVLP is platform intended to accelerate access to mRNA vaccine trials for people who have been diagnosed with cancer. The platform assesses patients who are receiving treatment in the NHS to see if they are eligible to join a cancer vaccine clinical trial, before referral to a hospital running the trial.
“This collaboration, initially with pharmaceutical company BioNTech, is a significant step towards realising the potential of these personalised vaccines in cancer treatment, in the hope of transforming patient outcomes in the future.”
First patient treated
The first patient has been treated with a personalised vaccine against bowel cancer through a clinical trial with CVLP. Elliot Phebve was given a vaccine at University Hospitals Birmingham NHS Foundation Trust, a site that is participating in a colorectal cancer vaccine trial sponsored by BioNTech. Mr Phebve, a higher-education lecturer, was reportedly diagnosed through a routine health check with his GP despite having no cancer symptoms.
After confirmation that he had colon cancer, Phebve had surgery to remove the tumour and a section of his large intestine. He was then referred to the Queen Elizabeth Hospital Birmingham for initial chemotherapy and participation in the trial. He commented that “taking part in this trial tallies with my profession as a lecturer, and as a community-centred person”, who wants to “impact other people’s lives positively”.
“Through the potential of this trial, if it is successful, it may help thousands, if not millions of people, so they can have hope, and may not experience all I have gone through. I hope this will help other people.”
How it works
The trial is one of several across the country that are tackling different types of cancer. Patients who agree to have a sample of their cancer tissue and a blood test taken can be assessed for clinical trial eligibility. If eligible, they can be referred to the nearest participating NHS site to take part in “groundbreaking” research. Thirty hospitals in England have already signed up to the CVLP, with more to join over the next few months.
In the colorectal cancer trial, the investigational cancer vaccines are based on mRNA and developed to target specific mutations for each participant’s cancer. They are designed to induce an immune response to prevent cancer from returning after surgery. These vaccines are being developed by BioNTech and Genentech and have not yet been approved by regulators.
A landmark moment
NHS chief executive, Amanda Pritchard, described this as a “landmark moment for patients and the health service”.
“Thanks to advances in care and treatment, cancer survival is at an all-time high in this country, but these vaccine trials could one day offer us a way of vaccinating people against their own cancer to help save more lives.”
Pritchard suggests that the NHS is “in a unique position to deliver this kind of world-leading research at size and scale”.
“As more of these trials get up and running at hospitals across the country, our national match-making service will ensure as many eligible patients as possible get the opportunity to access them.”
Professor Peter Johnson, national clinical director for cancer at the NHS, recognised that “even after a successful operation” there is a chance that cancers can return “because a few cancer cells are left in the body”. However, using a vaccine to “target those remaining cells” could prevent this.
“Access to clinical trials could provide another option for patients and their families, and I’m delighted that through our national launch pad we will be widening the opportunities to be part of these trials for many more people, with thousands of patients expected to be recruited in the next year.”
Dr Victoria Kunene is Principal Investigator for the trial at Queen Elizabeth Hospital Birmingham and Consultant Clinical Oncologist. Although it is “too early yet to say” if these individualised investigational vaccines will be successful, “we are extremely hopeful”.
‘Based on the limited data we currently have of the in-body response to the vaccine, this could prove to be a significant and positive development for patients, but more data is yet needed and we continue to recruit suitable patients to the trial to establish this further.”
Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, is “incredibly” excited by this progress.
“This technology pioneers the use of mRNA-based vaccines to sensitise people’s immune system and in turn detect and target cancer at its earliest stages. Clinical trials like this are vital in helping more people live longer, better lives, free from the fear of cancer. If successful, the vaccine will be a game changer in preventing the onset or return of bowel cancer.”
For more on new strategies to overcome cancer with vaccines, why not join us at the Congress in Barcelona or subscribe to our newsletters here?
by Charlotte Kilpatrick | May 29, 2024 | Therapeutic |
Researchers at Oregon Health & Science University (OHSU) shared in May 2024 that their platform for cytomegalovirus-based vaccines has “promise” as a “shield” against cancer. Their paper in Science Advances presents the results of immunising rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors that were genetically programmed to elicit major histocompatibility complex E (MHC-E)-restricted CD8+ T cells and to expressed established tumour-associated antigens (TAAs). They found that their vaccine established a “long-lasting” defence.
HIV applications
The team began working on the vaccine platform in the early 2000s, with initial research focusing on an HIV T cell vaccine. Early clinical trials established the safety of the platform, and the researchers have since modified the vaccine in search of the “desired immune responses”. Results from these efforts are expected later in the year.
The latest study expands the research to investigate the CMV vaccine platform against cancer. The researchers used genetically modified RhCMV to induce cancer-specific T cells, which “recognise infected cells in a unique manner”. The data indicate that CMV-based vectors can be used to generate MHC-E-restricted CD8+ T cells to “common cancer antigens” and that cancer cells can “present tumour antigens to these T cells via HLA-E”.
“Targeting HLA-E is therefore a new modality for cancer immunotherapy.”
Unconventional T cells
Dr Klaus Früh, professor in OHSU’s Vaccine & Gene Therapy Institute, commented that the team’s research reveals that cytomegalovirus can induce unconventional T cells to cancer antigens; these unconventional T cells can recognise cancer cells.
“The idea is that by throwing a type of T cell against the cancer that the cancer hasn’t seen before, it will have a harder time evading immunity.”
Dr Früh suggests that “eliciting T cells to cancer antigens is not easy” because it goes against what the “immune system has been trained not to do”.
“Overcoming this immunological tolerance is a challenge for all cancer vaccines.”
The platform’s potential is exciting, with lasting protection suggesting that it could prevent cancer reoccurrence.
“If you’ve had a cancer, you are worried the rest of your life that it may come back. So having a vaccine that can elicit cancer-specific T cells that act as an immune shield continuously patrolling your body and that would protect you for the rest of your life, it’s just really exciting.”
For more on innovative efforts to address cancer challenges, why not join us for the Cancer & Therapeutic track at the Congress in Europe this October, or subscribe to our weekly newsletters here?
by Charlotte Kilpatrick | May 22, 2024 | Therapeutic |
In May 2024, CureSearch for Children’s Cancer announced a partnership with LifeArc intended to create “far-reaching impact for kids with cancer”. Funding will be provided for a CureSearch Acceleration Initiative by Dr Gregory Friedman, which aims to transform treatment options in paediatric high-grade gliomas (pHGGs), a “devastating” form of childhood brain cancer. Current treatment options can result in “signficant toxicity and limited efficacy”, highlighting the need for innovative therapeutic approaches.
“Children with brain tumours need safer, more effective treatments, and they need them now.”
Dr Friedman’s project
Dr Friedman is working on a treatment for brain tumours that enables the child’s immune system to attack tumour cells without causing damage to normal cells in the body. He and his team are combining a genetically modified herpes virus with a unique tumour vaccine called SNAPvax, designed to increase the immune attack. With support from CureSearch, Dr Friedman has assembled a “dream team”, comprising academia and industry representatives, that has already identified the ideal brain tumour proteins to target with the vaccine. The team is developing a tumour model to test these vaccines.
The researchers have also found that the combination therapy of the cold-sore virus and the novel tumour vaccine is “more effective” than either of the therapies alone and that the timing of therapies is “very important”. Delivering the vaccine before the virus is more effective than giving the virus before the vaccine as it “excites the immune system” to attack the tumour instead of removing the virus, which allows the virus to kill more tumour cells.
Dr Friedman commented that “outcomes for children with high-grade gliomas” are “unacceptably poor” with standard therapies “minimally effective and toxic”.
“We plan to quickly translate the combination therapy to paediatric clinical trials with the goal of improving outcomes and lessening the side effects for these children in desperate need of improved, targeted therapies.”
An international collaboration
Kay Koehler, CureSearch President and CEO, is “thrilled to expand” the co-funding model internationally and “grateful for LifeArc’s support of Dr Friedman’s groundbreaking work”.
“Because promising research projects in children’s cancer often go unfunded, our goal is to fill that gap by ensuring the quick advancement of these promising projects into the clinic where they can help children today.”
The partnership “demonstrates confidence” in the “unique funding model”, and Kay believes that Dr Friedman’s work will “continue to deliver these impactful results”. Dr David Jenkinson, Head of Childhood Cancer at LifeArc, commented that the project “really stood out to us”.
“This novel approach holds real promise in an area of high unmet medical need – aligning with our strategy…Our mission at LifeArc is to do better for children with cancer by helping to progress research that could lead to the development of new, less toxic treatments, ultimately saving lives.”
To learn more about innovative efforts to tackle cancer challenges with vaccines and combination therapies do join us in Barcelona for the Congress this October or subscribe to our newsletters here.
by Charlotte Kilpatrick | May 14, 2024 | Therapeutic |
In May 2024, Nykode Therapeutics announced that it has expanded its collaboration with MSD to include a clinical trial collaboration and supply agreement for a phase II trial to evaluate Nykode’s lead candidate, VB10.16, in combination with MSD’s KEYTRUDA. KEYTRUDA is an anti-PD-1 therapy. The study will enrol HPV16-positive high-risk patients with locally advanced cervical cancer undergoing chemoradiotherapy.
VB10.16
The wholly owned lead product candidate, VB10.16, is an immunotherapy that targets malignancies caused by the cancer-inducing HPV16 (Human Papillomavirus 16), the predominant cause of 630,000 cases of HPV-caused cancers each year. It is a “potentially first-in-class off-the-shelf” therapeutic cancer vaccine, built on Nykode’s technology platform.
“Nykode Therapeutic’s proprietary, targeted immunotherapy platform centres around the Vaccibody molecule format designed to induce potent, long-lasting, and specific immune responses.”
Nykode has already reported “promising” data from the Phase II VB C-02 trial, which support “ongoing efforts” with the Phase II VB C-04trial.
The platform
The Vaccibody molecule’s targeting unit determines the subsets of Antigen Presenting Cells (APC) or cell type the antigen is delivered to, which “may critically influence the associated immune response”. The most used targeting unit in Nykode’s vaccine candidates is CCL3L1, C-C motif chemokine ligand 3 like 1.
“The unique ability to induce broad and strong T cell responses distinguishes Nykode’s platform from both conventional vaccines, including non-targeted DNA vaccines, RNA vaccines, and peptide-based vaccines.”
Expanded efforts
Dr Agnete Fredriksen, EVP, Chief Scientific Officer and Business Development at Nykode, is “excited to expand our clinical development” to include “early stages of cervical cancer”.
“There is a significant unmet medical need, and we see a huge potential for cancer vaccines. We are thrilled to continue building on our already established, highly valued collaboration with the experienced and talented team at MSD.”
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by Charlotte Kilpatrick | May 13, 2024 | Therapeutic |
Takeda announced in May 2024 that it has entered an exclusive, worldwide option and license agreement with AC Immune for the latter’s active immunotherapies targeting toxic forms of amyloid beta (Abeta). This includes the vaccine ACI-24.060, which targets Alzheimer’s disease. It is being investigated in the ABATE trial to assess its safety, tolerability, immunogenicity, and pharmacodynamic effects in subjects with prodromal Alzheimer’s disease and adults with Down syndrome.
Under the terms of the agreement, AC Immune will receive an upfront payment of ¢100 million and be eligible for an option exercise fee and additional potential development, commercial, and sales-based milestones of up to around $2.1 billion, if “all related milestones are achieved” during the agreement.
ACI-24.060
ACI-24.060 is an anti-Abeta active immunotherapy candidate that is intended to trigger a “robust” antibody response against the toxic forms of Abeta that are understood to drive plaque formation and Alzheimer’s disease progression. It has the potential to “delay or slow” disease progression by “inducing plaque clearance and efficiently inhibiting plaque formation” in the brain. Preclinical results suggest that immunisation with ACI-24.060 should produce a “broad immune response”.
Changing the paradigm
Dr Andrea Pfeifer, CEO of AC Immune, described the team as “pioneers in the field of active immunotherapy”, and hopes that this could “change the treatment paradigm” for Alzheimer’s disease, addressing the “multifaceted burden that patients and the broader community face”. Dr Pfeifer suggests that the “maximum impact” of ACI-24.060 can be realised through this partnership at a “critical juncture”.
“This agreement allows us to leverage the developmental expertise, strategic vision, and financial capacity of an accomplished organisation that has demonstrated its ability to execute the type of comprehensive global programme required for Phase III trials in Alzheimer’s disease.”
AC Immune is responsible for completing the ABATE trial and Takeda will conduct and fund further clinical development and be responsible for all global regulatory activities and worldwide commercialisation after option exercise.
Sarah Sheik, Head, Neuroscience Therapeutic Area Unit and Head, Global Development at Takeda, is “committed to tackling some of society’s most debilitating illnesses” and is “excited to partner with AC Immune on this ground-breaking treatment approach”. It “leverages novel technology with the potential to offer patients a treatment with differentiated efficacy, safety, and ease of administration”.
“Combining AC Immune’s deep experience with active immunotherapy approaches with Takeda’s expertise in neuroscience drug development and commercialisation, we have an incredible opportunity to deliver real impact to the Alzheimer’s community.”
To hear more about the ways that therapeutic vaccines are making a public health difference, why not join us at the Congress in Barcelona this October; you can get tickets here or download the agenda here. Don’t forget to subscribe for more vaccine insights.
by Charlotte Kilpatrick | May 2, 2024 | Therapeutic |
Researchers at the University of Florida shared in May 2024 that in a first in human trial of four adult patients, an mRNA cancer vaccine “quickly reprogrammed the immune system” against glioblastoma, the “most aggressive and lethal” brain tumour. Their results, published in Cell (not open access), reportedly mirror data from dogs and preclinical mouse models, and represent a “potential new way to recruit the immune system” to defend against “notoriously treatment-resistant cancers”.
Glioblastomas
Glioblastomas are a “fast-growing” type of brain tumour in the glioma group, develop from glial cells, which support the brain and the spinal cord. As the “most common type” of malignant brain tumour in adults, it’s “among the most devastating diagnoses”, with “median survival around 15 months”. The current standard of care is surgery, radiation, and some combination of chemotherapy.
Revolutionary technology
The technology is an “iteration” of mRNA technology and lipid nanoparticles with “two key differences”: the vaccine is personalised with the patient’s tumour cells and incorporates a “newly engineered complex delivery mechanism”. Instead of single particles, the injection contains “clusters of particles” that wrap around each other “like onions”, suggests senior author Dr Elias Sayour.
“The reasons we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”
Dr Sayour remarks that the team was impressed by the quick response to the vaccine, which took place in “less than 48 hours”.
“We could see these tumours shifting to what we refer to as ‘cold’ – immune cold, very few immune cells, very silenced immune response – to ‘hot’, very active immune response.”
This was a surprise but told the team that the early response of the immune system had been activated “very rapidly”, which is “critical to unlock the later effects”.
The research progression into humans
The latest publication comes after seven years of studies, from preclinical mouse models and a clinical trial of 10 pet dogs. These dogs, who had no other treatment options, offered a naturally occurring model for malignant glioma, because they are the “only other species” to develop spontaneous brain tumours with “some frequency”, says Dr Sheila Carrera-Justiz, who partnered with Dr Sayour in the trials. These tumours are often fatal for dogs.
The trial involved four patients. After surgical removal of the tumour, the team extracted RNA and then amplified their mRNA and “wrapped” it in the biocompatible lipid nanoparticles “packaging”. This presented the tumour cells as a threat to the immune system when reintroduced. Dr Duane Mitchell, co-author of the paper, suggests that the progression from mice to dogs to humans is a “really important finding” because it’s hard to predict how animal studies will translate into human contexts.
“While mRNA vaccines and therapeutics are certainly a hot topic since the COVID pandemic, this in a novel and unique way of delivering the mRNA to generate these really significant and rapid immune responses that we’re seeing across animals and humans.”
Early indications
Although it is too soon in the trial to evaluate the clinical effects of the vaccine, patients either lived disease-free longer than expected or survived longer than expected. The dogs lived a median of 139 days, compared with the median survival of dogs with the condition: 30-60 days.
However, the authors recognise that there is “continued uncertainty” about balancing the immune response with the potential for adverse side effects. Dr Sayour is “hopeful” that this could be a “new paradigm for how we treat patients”.
“I am hopeful for how this could now synergise with other immunotherapies and perhaps unlock those immunotherapies. We showed in this paper that you actually can have synergy with other types of immunotherapies, so maybe now we can have a combination approach.”
Next steps
With support from the FDA and the CureSearch for Children’s Cancer Foundation, the researchers intend to conduct an expanded Phase I clinical trial, including up to 24 adults and paediatric patients. After an optimal and safe dose has been confirmed, up to 25 children would participate in Phase II. This next clinical trial will deliver the immunotherapy to children’s hospitals across the country through a partnership with the Paediatric Neuro-Oncology Consortium.
For more on therapeutic advances and changing the way we manage cancer, do subscribe to our weekly newsletters here.
by Charlotte Kilpatrick | Apr 26, 2024 | Therapeutic |
In April 2024 we learnt of a trial of a personalised mRNA vaccine against the most dangerous form of skin cancer, melanoma. Recruitment for the University College London Hospital trial began in October 2023, and is expected to involve more than 60-70 patients at 8 centres. The treatment is a combination approach using mRNA-4157 (V4940) and Keytruda. Principal Investigator, Dr Heather Shaw, hopes that this therapy could be a “gamechanger”.
Melanoma
Melanoma skin cancer is caused by abnormal cell growth and division in an “uncontrolled” way, starting in melanocytes, found in the epidermis. Melanocytes provide melanin, which gives the skin colour and protects the body from ultraviolet light from the sun. In people with white skin, melanoma is “more common on skin that has been exposed to the sun” but can start anywhere. In people with brown or black skin, melanocytes are “more active”.
Although melanoma is often associated with sun exposure, it can also “rarely” develop in areas that have not been exposed to the sun, which is called acral melanoma. An estimated 16,700 people are diagnosed with melanoma skin cancer in the UK each year, and this number has been increasing over recent decades. Melanoma skin cancer is the 5th most common cancer in the UK.
A possible solution
The treatment, developed by Moderna and MSD, is being investigated in several countries. The personalised vaccine encodes up to 34 neoantigens determined from analysis of the tumour removed from the patient in surgery. Dr Shaw explains that this is “one of the most exciting things we’ve seen in a really long time”.
“It is absolutely custom built for the patients – you couldn’t give this to the next patient in the line…it’s truly personalised.”
Dr Shaw describes the vaccine as a “finely honed tool”, which she is excited to offer to patients.
“To be able to sit there and say to your patients that you’re offering them something that’s effectively like the Fat Duck at Bray versus McDonalds – it’s that level of cordon bleu that’s coming to them.”
Fighting an unseen enemy
One of the first patients in the trial is Steve Young, who had surgery to remove a melanoma growth on his scalp last year. He told BBC Radio 4’s Today Programme that the opportunity to participate in the trial “gave me a chance to feel like I was actually doing something to fight a potential unseen enemy”. While scans suggest that Mr Young is “radiologically clear”, there is a chance that there are “cancer cells floating around undetected”.
“Rather than just sit there and wait and hope it was never going to come back, I actually had this chance to get involved in putting on some boxing gloves and squaring up to it.”
Modern developments
Professor Lawrence Young from the University of Warwick commented that “this is one of the most exciting developments in modern cancer therapy”, with the approach having “already shown great promise” in earlier trials. The new study is part of a global trial to assess “more fully” the efficacy of the combination immunotherapy.
“Interest in cancer vaccines has been reignited in recent years by a deeper understanding of how the body controls immune responses and by the advent of mRNA vaccines.”
Professor Young is hopeful that the approach “could be extended to other cancers” such as “those of the lung and colon”.
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by Charlotte Kilpatrick | Apr 12, 2024 | Therapeutic |
In April 2024 Gritstone bio announced “positive” preliminary data from an ongoing Phase II portion of the Phase II/III study to evaluate GRANITE. GRANITE is Gritstone’s personalised neoantigen cancer vaccine and is being evaluated in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC). The study is designed to quantify the clinical benefit of maintenance therapy with GRANITE in combination with immune checkpoint blockade and fluoropyrimidine/bevacizumab compared to fluoropyrimidine/bevacizumab alone.
Gritstone takes on cancer
Gritstone outlines how its founders identified that, in patients with solid tumours who respond to checkpoint inhibitors, new targets called tumour-specific neoantigens are produced. These are unique to the tumour cells and can be “recognised and targeted for destruction by the patient’s own immune system”. Although these neoantigens present a critical target, identifying them is a “key therapeutic challenge”.
“Some tumours have hundreds of mutations, but only a minority result in true tumour-specific neoantigens found on the surface of tumour cells – making them difficult to find and target appropriately.”
New progress
Gritstone “successfully manufactured” GRANITE product candidate for every eligible patient; 104 patients were randomised in the study and 67 patients were included in the treated analysis shared. 36 patients left the study before randomised treatment due to early progressive disease or withdrawal of consent, and 1 patient is yet to begin study treatment start.
Key highlights from the data include:
- Progression Free Survival (PFS) – an early trend in PFS benefit was observed for GRANITE recipients.
- Biomarker results – Circulating Tumour DNA (ctDNA) – short-term molecular response is “uninformative” but long-term ctDNA responses “align with PFS trends and favour GRANITE”.
- Safety and tolerability – GRANITE demonstrated a “favourable” safety and tolerability profile.
Encouraging results
Dr Andrew Allen, Co-founder, President, and CEO of Gritstone bio commented that the preliminary Phase II results are “highly encouraging” and “represent the first randomised trial evidence, albeit early, that a personalised neoantigen-directed vaccine can potentially drive efficacy in a metastatic ‘cold’ tumour”.
“The overall trend of PFS improvement in GRANITE recipients is great to see, and the exploratory PFS hazard ratio of 0.52 in the high-risk group, a more mature dataset, is a striking signal.”
Dr Allen reflected that “pioneering new spaces carries inherent risks”, suggesting that regarding defining molecular response, “we simply got it wrong”. As ctDNA levels in both arms “decreased on chemotherapy for longer than we anticipated”, the protocol measure of ctDNA change was “uninformative”.
“Fortunately, long-term analysis demonstrates the expected correlation of ctDNA with clinical benefit and favours GRANITE patients. We believe these preliminary findings put us in a strong position to share mature PFS data in the third quarter and then enter regulatory discussions.”
Dr Allen described the “growing body of evidence” that favours GRANITE as “exciting”, stating that it “suggests GRANITE is working in this notoriously underserved patient population”.
Dr J. Randolph Hecht, Professor of Clinical Medicine and Director of the UCLA GI Oncology Programme, is an investigator in the Phase II/III study.
“Up to 97% of patients with metastatic colorectal cancer, the second most common cause of cancer death, are MSS. Unlike patients with melanoma and lung cancer, they have not benefited from standard immunotherapies such as checkpoint inhibitors.”
Considering the preliminary results, Dr Hecht infers that GRANITE is “inducing a potentially significant immune response in a disease that has been felt to be immunologically cold”. Not only does the PFS difference, in a “poor prognosis group of patients”, indicate the “potential for clinical benefit”, but the team is learning “how to better analyse ctDNA continuously to “study the efficacy of this novel immunotherapy”.
“Expanding the scope of immunotherapy to a broader spectrum of cancer patients is the ‘holy grail’ of oncology, especially for MSS colorectal cancer. While early, these promising results suggest GRANITE has potential to deliver clinically meaningful benefit in MSS-CRC and other cold tumours.”
It was great to hear more from Dr Allen at the Congress in Washington as he joined us to chair and present, and we look forward to further updates from the Gritstone team. For more like this, don’t forget to subscribe here.
by Charlotte Kilpatrick | Apr 9, 2024 | Therapeutic |
In April 2024 Geneos Therapeutics announced the publication of “positive” safety, immunogenicity, and efficacy data from a full cohort of patients in the GT-30 clinical trial. The paper, in Nature Medicine, presents the 36-patient, single-arm, open-label, multi-centre Phase I/II study of GNOS-PV02. This is a DNA plasmid encoded PTCV in combination with DNA plasmid encoded IL-12, and is administered in combination with pembrolizumab in second-line (2L) patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with a multi-tyrosine kinase inhibitor. Geneos reports that the study “met” both primary and secondary endpoints.
HCC and the vaccines
The study describes hepatocellular carcinoma (HCC) as the “most common form of primary liver cancer”, a leading cause of cancer-related death globally. Although there have been “advancements” in systemic therapy for advanced HCC, the 5-year survival rate is <10%. Therefore, the team at Geneos conducted their study of a personalised therapeutic cancer vaccine (PTCV) in combination with pembrolizumab.
The PTCV comprised a DNA plasmid encoding up to 40 neoantigens (GNOS-PV02) identified through sequencing of each patient’s tumour DNA and RNA, as well as germline DNA. GNOS-PV02 is “coformulated” with a second DNA plasmid encoding the cytokine interleukin-12 (IL-12) as a vaccine adjuvant and is administered by intradermal injection before in vivo electroporation.
In study
Geneos states that PTCV-related adverse events were “all limited” to Grades 1 and 2, with no dose-limiting toxicities. The most common of these were injection site reactions, which were observed in 41.6% of patients. The ORR for GT-30 is currently at 30.6%, including three “complete responses” and eight partial responses, which is described as “statistically significant”.
“Immunological analysis confirmed both the induction of new T cell responses to vaccine-encoded antigens and an expansion of the TCR repertoire in both the peripheral blood and tumour.”
Although anti-PD-1 monotherapy can reverse T cell dysfunction in existing neoantigen-specific T cell clones, it is not known to induce new neoantigen-specific T cell clones. Thus, the study “provides evidence that a PTCV can enhance responses to anti-PD-1 therapy through the induction of neoantigen-specific T cells in the peripheral blood and tumour”.
Another feature of the current approach that is identified in the study is that it sought to include “all targetable neoantigens in each patients’ vaccine”: “drivers and passengers, truncal and branch, shared and private”.
Advancing the field
CEO and president of Geneos, Dr Niranjan Sardesai, commented that the current trial provides a “marked contrast” to other industry trials that have tested personalised cancer vaccines in “patients with highly immune-sensitive tumour phenotypes and no measurable disease”. The GT-30 trial “assess PTCVs in HCC, a cancer with very low tumour mutational burden and an immune-excluded phenotype, and in patients with significant late-stage unresectable and metastatic disease”.
“Despite the small size of this study, our results are important for the advancement of the field. We have not only met endpoints for safety, immunogenicity, and clinical efficacy based on ORR in this difficult to treat setting, but our mechanism of action data trace and confirm every step, from vaccination to tumour reduction, required to explain the immunological basis for the observed clinical responses.”
Dr Ildiko Csiki, chief medical officer of Geneos, believes that the study is the “first definitive demonstration of a personalised cancer vaccine enhancing clinical response to anti-PD-1 therapy by inducing new, neoantigen-specific T cells”.
“The fact that the PTCV regimen has produced this important result in a form of cancer as immunologically ‘cold’ as HCC, leading to multiple complete responses and a doubling of objective responses versus PD-1, is incredibly promising and shows the therapeutic potential of personalised cancer vaccines for cancer patients.”
We were glad to hear more from Dr Sardesai at the Congress in Washington this April and hope to follow Geneos’ progress on this front as they continue to push the field forward. For more updates on cancer therapy progress do make sure you subscribe to our weekly newsletters here!
