During the Congress in Barcelona last month we were delighted to speak to so many of our fantastic speakers and exhibitors as part of our Congress Conversations series. One of these speakers was myNEO Therapeutics’ Cedric Bogaert, who joined us for the cancer keynote and to chair the cancer and therapeutic vaccines track. We are grateful that Cedric made the time to speak to us and hope that you enjoy learning more about what his team is doing.
myNEO may be relatively young, but the approach the team is taking seems to work! We asked Cedric about their efforts and what sets them apart from others’.
“We try to identify what is going on within the tumour, how it interacts with the immune system, and how we can make sure that the interplay between the two is optimised.”
This involves making sure the immune system can “recognise” the tumour, equipping it with the “proper targets”. To approach this challenge, the team at myNEO takes a “very extensive approach”.
“We start from whole genome sequencing material, that means we generate a lot of data, and then we apply big data learnings, machine learning, AI, to be able to investigate what’s going on within that tumour, which targets are relevant to that tumour, not only looking at the surface targets but really looking at everything going on within the tumour, and based on that we apply a lot of selection criteria to identify these are the best targets’.”
Data, data, data
Cedric mentioned “a lot of data” in his previous answer, so we asked about how this is drawn and developed so quickly, and why this is important. He explains that, through a collaboration with Amazon, every time a patient joins the platform their data is efficiently generated, analysed, and then reported in a matter of days. Cedric describes their system as a “nice, interactive way of playing with data” to produce results.
“We’re very flexible in the way that we can analyse hundreds of patients at the same time.”
This is so important because everyone, from pharma to patient, is “waiting on the results”.
“When looking at personalised analysis, and each patient’s treatment is dependent on the analysis that we do, then we need to have it as soon as possible.”
Cedric refers to partners, so how important is it that he and his team is able to secure and sustain good relationships? He reflects that “we’re a technology player”, with a “unique” platform. Therefore, they need to get this “state-of-the-art” technology to patients “as soon as possible”.
“We cannot do everything ourselves, right; we need to find the best partners that allow us and enable us to bring that into the patients.”
In the past, these partnerships have involved everyone from “big pharma” to academics. However, the team has recently had some “developments” with “good data”, which has allowed them to shift into some of their own clinical programmes. They are now collaborating with a “different set of partners”: CDMOs and CROs, for example.
What does the future hold?
With this recent change in mind, we asked about the future of myNEO. Cedric comments that his organisation is “shifting” to become a drug development company: “it’s very nice”! He suggests that this is complemented by changes in “expertise” within the board.
“So far all the clinical data has been very promising, so we’re looking forward to that future of actually, not only being being dependent on other players bringing our technology to the patients, but actually pushing for it ourselves.”
As always, we invited Cedric to share his hopes for the Congress. He was looking forward to connecting with existing and future partners in person.
“You know, it’s always more interesting to have a physical conversation like we are having, than to have it via teams or zoom call.”
We hope Cedric was able to make the most of this opportunity!
In October 2023 Franco-Canadian Angany announced that it has received a Notice of Acceptance from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the first clinical study of its vaccine candidate to treat human allergy to cats. This first-in-human study will evaluate the safety, allergenicity, and immunogenicity of the ANG-101 vaccine in adults allergic to cat dander.
Angany states that cat allergy is a “very common and lifelong condition” that has no cure. Medications can relieve symptoms but do not prevent allergy progression. The “only” disease-modifying treatment against allergy is desensitisation, which is a form of allergen immunotherapy that requires “years” of cat allergen administration and is “associated with a poor success rate and the risk of allergic side effects”.
Angany’s therapeutic vaccine offers a “disruptive disease-modifying approach” for the treatment of cat allergy. The active immunotherapeutic ingredient is derived from the company’s proprietary eBioparticle-Potentiated Immunotherapy technology; it is a unique 140 nm enveloped bioparticle that “mimics a virus in shape and size”. The surface is covered with “thousands” of copies of cat major allergen Fel d 1.
“Angany’s first-in-class therapeutic vaccines are a new generation of immunotherapy biologics that are used to treat established pathologies. They are meant to restore or boost natural immune mechanisms and create sustainable immune protection and vigilance.”
Dr Louis-Philippe Vézina, President and CEO of Angany, states that the clinical study is called “HOPE” as it should “raise new hope for millions of people affected by allergy worldwide”. He is “very pleased” at the “first step of a comprehensive clinical development programme”. Professor Stephen Durham is Head of Section for Allergy and Clinical Immunology at NHLI, Imperial College, and Professor Allergy and Respiratory Medicine at Royal Brompton Hospotal London.
“The potential treatment of cat allergy using an auto-adjuvanted vector builds upon its known ability to induce strong allergen-specific IgG antibody responses, as observed in animal models.”
Dr Guy Scadding, clinical research fellow at the National Heart and Lung Institute at Imperial College London is also hoping the vaccine will reduce the strain of treatment.
“The ultimate goal in cat allergy is to find a safe, effective, and easy to administer vaccine that will not require the long treatment and often suboptimal response currently featured by classical desensitisation method.”
The “nexus of women, power, and cancer” is the subject of investigation by The Lancet Commission in September 2023. Through an intersectional feminist lens, the Commission investigates the “prevailing asymmetries of power” in relation to cancer across 3 domains:
In this article we unpack some of the findings and recommendations presented by the Commission in its publication, particularly as they pertain to the cancer vaccine community. If you have time to read it here, do let us know what you think.
Linguistic and theoretical fine points
Before we explore the publication in full, we will consider the definitions that are used throughout.
“The terms sex and gender are distinguished throughout this Commission with sex referring to a set of biological attributes associated with physical and physiological features (such as chromosomes, gene expression, immunological profile, hormonal milieux, and sexual or reproductive anatomy). Gender, as a social construct, refers to norms, roles, and behaviours that are considered appropriate for women and men in a given society.”
The authors reflect that gender identity, referring to the “feelings and identity of one’s gender”, can “deviate from the sex assigned at birth”. Although it would be preferable not to conflate the terms, many sources used by the Commission use the terms sex and gender “interchangeably”. Furthermore, they are “most often only binary”.
The publication also establishes a series of commitments within the umbrella of an intersectional feminist approach. The phrase was initially used in 1989 by American “civil rights activist, feminist, and legal scholar”, Professor Kimberlé Crenshaw. For the Commission it articulates a “prism for seeing the way in which various forms of inequality often operate together and exacerbate each other”.
“An intersectional feminist approach recognises that patriarchy and colonialism is embedded in society and institutions, forming visible and invisible gender hierarchies overlaying other power dynamics, resulting in discriminations, alienation, and marginalisation.”
With the understanding that this approach “recognises and seeks to disrupt power dynamics”, the Commission commits to:
Promote transformative action towards gender equality, equity, and social justice
Centre women’s bodies, realities, and voices to capture their real-life experiences in relation to cancer
Reflect the plurality of women’s experiences and the multiple intersecting dimensions of inequalities
Integrate an anti-racist and decolonial approach to all its work
Challenge the way cancer research is funded, conducted, and reported, and by whom, and foster interdisciplinary inclusive research and policy that transcends biomedical worldviews
Shift the culture of cancer away from individual blame by recognising the role of structural, social, and commercial determinants of health affecting cancer risks and outcomes in women
Address asymmetries of power by encouraging reflexivity, humility, and inclusiveness in approaches to cancer research, control, and care
The burden of cancer
“The topic of women and cancer spans broad terrain, beyond women’s cancers and the biomedical aspects of any type of cancer that women in all their diversities might experience. It is inclusive of the ways in which sex and gender influence exposures to cancer risk factors, interactions with the cancer health system, and specific challenges faced by health-care professionals, advocates, and caregivers.”
Cancer is a “top 3” cause of premature mortality in women, with 2.3 million women dying prematurely from cancer each year. The authors claim that 1.5 million premature deaths “could be averted” by primary prevention or early detection strategies, and 800,000 deaths could be averted by “optimal cancer care”. In 2020, 9.23 million women were diagnosed with cancer, and 4.43 died of cancer. These numbers are projected to increase by 2040; 13.3 million women will be diagnosed with cancer and 7.1 million women will die of cancer.
Within these increasing rates of diagnosis and death, the greatest burden is expected to be borne by lower-income countries. However, the risk of death from cancer is “similar globally”, regardless of where a woman lives.
The five leading cancer types in women, in terms of incidence, are breast, colorectal, lung, cervical, and thyroid cancer. Combined these five contribute to more than half of the total number. For cancer deaths, the same top four – breast lung, colorectal, and cervical, were the leading causes in 2020, with stomach cancer coming 5th. These comprised 54% of the total mortality burden.
“The true burden of cancer in women has gone largely unrecognised and has far-reaching consequences for families and society more broadly.”
Although the numbers laid out in the report give an insight into the significant effects that cancer has on women, the Commission demands more research and sustainable funding to ensure that data are collected and reported. Then, it is expected, the “current and future impact of cancer” can be “accurately described”.
The NIH National Cancer Institute describes the continuum of cancer control as a “useful framework”, despite its oversimplification. It has been in use since “at least the mid-1970s” and describes the following stages: aetiology, prevention, early detection, diagnosis, treatment, survivorship, end of life.
The Commission states that entry into the continuum of care is a varied occurrence, which can involve screening programmes or seeking health services in response to symptoms. From there, the detection, interpretation, and management of symptoms are determined by a “complex interplay of individual, contextual, sociocultural, economic health system, and policy factors”.
Key factors that affect stages within the continuum can be organised by the different levels of the Social Ecological Model proposed by Brofenbrenner. The Social Ecological Model suggests that health behaviours influence and are influenced by the social environment with five levels of influence: individual, interpersonal, organisational, community, and public policy. This is explored in the figure below.
For the purposes of understanding the Commission’s implications for the vaccine community, we will assume that a patient has decided to seek care and consider the stages that follow. However, we encourage you to read the report for more on the “perceived need for cancer care” if it is of interest. The first consideration offered in the report is access, and barriers to care.
“Once a woman recognises a need to seek care, gender norms can influence her decision regarding when and where to seek care.”
Before encountering barriers, the “anticipated barriers” come into play. Women are “more likely” to anticipate barriers or reflect on a past bad experience with a health-care provider. Once “perceived barriers” are overcome, gender norms can be identified.
“Gender norms combine with the ability of individuals to seek care on the basis of their financial resources, time availability, and power to act.”
Beyond gender norms, safety concerns and fear of physical violence are “important barriers”.
Who is behind treatment?
Section 4 of the Commission explores “new analyses” in the context of “intersectional biases” that affect health providers, researchers, caregivers, and advocates.
“One of the most important factors influencing gender equity and equality in the health workforce is broad representation of women among leaders at every level.”
An analysis of leadership at the Union for International Cancer Control (UICC) member organisations found that “although the organisations in North America, South America, and Oceania appear to have fostered gender-balanced oncology leadership”, this is not the case for leadership roles in Asia, Africa, and Europe. Furthermore, the researchers considered “gender balance according to type of organisation”, with men “overrepresented as leaders of hospitals, treatment centres, and research institutes”, while women are “overrepresented as leaders of patients support groups, public charities, or advocacy groups”.
This imbalance has a “detrimental effect” on the career trajectory of health personnel. The authors consider the metaphors of the glass ceiling and leaky pipeline. For women in the cancer workforce (as in others), “frequent and severe experiences of gender-based discrimination” inform mental health, perception of workplace safety, job satisfaction, and career development. These are “usually perpetrated” by men, whether colleagues or patients.
“To maximise the potential of the oncology workforce, gender equity and equality, as well as organisational culture transformation, must be promoted if diverse talent is to be retained and nurtured.”
“Academic career success is often measured in terms of grant funding awards, peer-reviewed publications, and promotion to professorial ranks – processes that are inherently discriminative to women.”
The Commission states that data reflect clear disparities in research roles; women are “more likely to be performing experiments”, whereas men are “more likely to be associated with designing experiments”. Men are also “more often in prominent authorship positions”. Furthermore, topics that are “disproportionately studied by women” are “generally published in lower impact journals and cited less often”. Editorial boards also reflect poor gender balance.
Authorship is another area of concern for the Commission. To establish a “global overview of women’s contributions” to cancer research publications they conducted a bibliometric analysis of first and last authors of cancer research papers processed for the Web of Science: Core Collection for 2009 and 2019. First authorship among women increased 41.6% and last authorship increased by 12%, but the percentage of women as first and last authors varied between countries and world regions.
Where do vaccines come in?
Women are implicated or involved throughout the continuum of vaccine demand, development, and deployment. Below are some recommendations from the report that relate to treatment, research, and approach that we consider relevant to the vaccine community but do read the full list if you are interested.
Let us know if you think this Commission adds value to the cancer vaccine community. Do you agree with the findings and recommendations? How does it engage with your experience of cancer, from a personal or professional capacity?
A paper in npj vaccinesin September 2023 presents the results of a study assessing the efficacy of VLP-based vaccines displaying linear peptides from PCSK9 in reducing cholesterol levels in non-human primates. The authors state that elevated low-density lipoprotein cholesterol (LDL-C) is an “important risk factor” in the development of atherosclerotic cardiovascular disease (ASCVD). Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown promise in reducing elevated LDL-C levels. Thus, the team evaluated the cholesterol-lowering efficacy of virus-like particle (VLP) based vaccines that target epitopes identified within the LDL receptor binding domain of PCSK9.
Why is cholesterol important?
The paper suggests that cardiovascular disease (CVD) is the “leading cause of global mortality”, responsible for about 19 million deaths in 2020. For atherosclerotic cardiovascular disease (ASCVD), elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a “major risk factor”.
“Reducing levels of circulating LDL-C can lower the risk of ASCVD.”
LDL is sometimes known as “bad cholesterol”, but it comprises “most” of the body’s cholesterol.
Although statins are usually used to decrease LDL-C levels and the risk of cardiovascular events, their effectiveness “varies amongst individuals”. They are “generally well-tolerated” but can be associated with “serious adverse effects”; these “limitations” have prompted the development of non-statin lipid-lowering therapies.
LDL-C is taken out of circulation by the low-density lipoprotein receptor (LDL-R), most abundantly expressed in the liver. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serum-associated secretory protein that “directly inhibits the recycling of LDL-R”. In doing so it “mediates higher levels of circulating LDL-C”. It has therefore become a “major therapeutic target” for preventing ASCVD by “lowering circulating LDL-C”.
The research team identifies three FDA-approved PCSK9 therapies that effectively reduce LDL-C levels in combination with statins. However, “both mAb- and siRNA-based PCSK9 inhibitors are expensive”.
“Vaccines are another promising approach for modulating PCSK9 activity. Vaccines have several potential advantages over other therapeutic approaches; they are relatively inexpensive to produce, which could reduce patient costs, and they will likely require fewer doses, potentially increasing patient compliance.”
The authors recognise that the immunological mechanisms of self-tolerance “normally restrict the ability to induce antibody responses against self-antigens” like PCSK9. However, these can be overcome by displaying self-antigens at “high density” on the surface of nanoparticle-based vaccine platforms, like virus-like particles (VLPs). These have been validated as an approach in trials.
Previously, the team engineered VLP-based vaccines that displayed different linear peptides from human PCSK9 that were “predicted to interact with LDL-R”. Several vaccine candidates were identified. This study expands on this by testing the efficacy of two VLP-based vaccines that display two species-specific linear peptides from PCSK9 in “multiple animal models”. There were several ways that the study extended preliminary studies:
Evaluated the immunogenicity of VLP-based PCSK9 vaccines that targeted species-specific PCSK9 sequences and confirmed they could “break immunological tolerance”
Showed that PCSK9 VLP vaccines could lower cholesterol levels in the LDLR+/- mice, which had “elevated cholesterol levels”
Compared the efficacy of vaccines targeting individual PCSK9 epitopes and bivalent vaccines targeting multiple epitopes, demonstrating that there are “important differences in how these vaccines affect circulating PCSK9 levels”
Measured the longevity of anti-PCSK9 antibodies in mice and macaques
Evaluated the efficacy of lead PCSK9 vaccines in lowering LDL-C in larger groups of non-human primates, both with and without statin co-administration
“These studies identified a PCSK9 vaccine regimen that induces long-lived anti-PCSK9 antibody responses and effectively lowers circulating LDL-C in primates without requiring co-administration of statins.”
The paper concludes that a bivalent vaccine comprising VLPs displaying two different PCSK9-derived peptides can induce robust anti-PCSK9 antibody responses, decrease serum PCSK9 levels, increase liver-expressed LDL-R, and efficiently lower cholesterol levels in mice and macaques.
“These findings strongly support the development of an alternative vaccine-based approach for inhibiting PCSK9 activity and lowering LDL-C.”
Do you think vaccine-based approaches can be developed to meet the medical need presented by LDL-C levels?
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In September 2023 Ose Immunotherapeutics announced the publication of new data supporting its cancer vaccine, Tedopi, in HLA-A2 positive patients with advanced or metastatic non-small cell lung cancer (NSCLC). The results, shared in Annals of Oncology, detail the randomised Phase III clinical trial and suggest that the novel cancer vaccine “improves overall survival” with a better safety and quality of life profile in monotherapy than chemotherapy. Tedopi is a T-cell epitope-based cancer vaccine that targets five tumour-associated antigens. It is an activating and differentiated off-the-shelf immunotherapy.
A need for better approaches and OSE2101
The paper states that the therapeutic strategy of treatment-naïve patients with advanced NSCLC lacking oncogenic drivers has been “revolutionised” by the approval of immune checkpoint blockers (ICBs). However, the “majority of patients will relapse”, will resistance to chemotherapy (CT)-ICB representing an unmet medical need. CT remains the standard of care.
OSE2101 is a T-specific immunotherapy that is designed to induce cytotoxic T lymphocytes (CTLs) against five tumour-associated antigens that are frequently overexpressed in NSCLC. This vaccine comprises nine synthetic peptides from the tumour-associated antigens that are presented in lung cancer cells by the human leukocyte antigen (HLA)-A2 phenotype.
The trial demonstrates a “significant therapeutic benefit” in patients with secondary resistance to immune checkpoint inhibitors, defined as patients with failure to platinum-based chemotherapy followed by a minimum of 12 weeks ICI treatment. The vaccine demonstrated a “favourable benefit/risk ratio” against the standard of care.
Professor Benjamin Besse, Director of Clinical Research at Gustave Roussy Institute and Principal Investigator of the trial commented that the vaccine is the “first cancer vaccine to demonstrate positive results on survival in a randomised Phase III trial in advanced and metastatic NSCLC cancer patients in 3rd line”.
“A significant reduction of the risk of death by 41% was achieved with a better safety profile and a maintained quality of life.”
Professor Besse calls for “clearly warranted” further evaluation to “potentially make this cancer vaccine available to hard-to-treat patients in failure and with high medical needs”. Nicolas Poirier, CEO of OSE Immunotherapeutics, agreed that Tedopi is the “most advanced cancer vaccine in clinical development”. He praised the “major achievement for all involved”.
“The clinical value of our results, re-activating specifically the anti-tumour immune responses, is particularly interesting in patients showing immune escape from checkpoint inhibitors.”
Dr Holen is head of development for Moderna’s therapeutics group. This includes oncology, rare disease, CV, pulmonary, and immunology. He will be involved in two sessions at the Congress. The first, on Wednesday 18th October, is the cancer vaccine keynote, which will bring together experts to discuss goals and timelines. The second will be on Thursday 19th October, and will explore mRNA-4157.
Individualised neoantigen therapy
If you’ve been part of our community for a while, you’ll know that we are very interested in Moderna’s individualised neoantigen therapy (INT), so we asked Dr Holen to give us the inside scoop. For starters, with so many challenges to overcome, how is Moderna demonstrating success?Dr Holen suggests that the team is “super excited” by their progress, and “frankly, a bit surprised” by the results! The randomised study showed a 44% reduction in melanoma recurrence and an even greater (65%) reduction in distant metastases.
“These results amount to a huge benefit for patients, as recurrence requires further invasive therapy and is highly correlated with survival from the disease.”
So, what sets Moderna apart from the rest? Dr Holen believes the “key to this advancement” is the “individualised nature of the vaccine”. The team identifies a “bespoke panel of targets” based on the tumour mutations.
“One common antigen or even a few common antigens will not be effective for the majority of people with cancer – so to tailor the vaccine to 34 unique antigens, all of which are predicted to mount an immune response, I think is the best way to elevate the potential of cancer vaccination.”
What’s next then?
With positive results rolling in, what can we expect to see from Moderna going forward? Dr Holen states that the goal is simple:
“To have the greatest possible impact to those affected by cancer as possible.”
He and his colleagues are “actively pursuing options for “other indications, combinations, earlier and later lines of therapy, and more”. Enrolment for the Phase III melanoma study has already been initiated, and they hope to open the Phase III non-small cell lung cancer study later this year.
“More to come, for sure!”
Participating in the conversation
Dr Holen will represent Moderna on an exciting panel with colleagues from the cancer field. We asked what he hopes Moderna is bringing to the table, and why it’s important that these conversations are happening. He commented that “progress across the entire field” is exciting.
“The progress that other companies are making is helping to elevate the perception of cancer vaccines, which is critically important because such a high degree of scepticism exists. The scepticism is there for good reason; many previous attempts at vaccines have failed.”
However, with “great data” and demonstrable progress from Moderna and others, “we are taken more seriously”.
“I firmly believe that the rising tide elevates all boats, and I look forward to seeing what we can all accomplish together to help those with cancer.”
Counting down to the Congress
Our final question, as always, invites our speakers to share their hopes for the event. For Dr Holen, the opportunity to “share our enthusiasm of mRNA-4157″ and learn from others is exciting. Furthermore, “potential new collaborations” and connections can be made.
“Should be a GREAT meeting and I am looking forward to it!”
We are grateful to Dr Holen and his team for delivering these insights to our community. We hope you enjoyed reading his comments and look forward to hearing more at the event. Have you bought your tickets yet? If you can’t join us, do subscribe to stay in the loop with VaccineNation.
A collaboration between Chinese company CARsgen and Texas-based Moderna was announced by the former in August 2023. The agreement was initiated to investigate a combination approach involving CARsgen’s investigational Claudin18.2 CAR T-cell product candidate (CT041) and Moderna’s investigational Claudin18.2 mRNA cancer vaccine. Claudin18.2 is an isoform of Claudin18, a member of the tight junction protein family. It is a “highly selective biomarker” with “limited expression” in normal tissues and “often abnormal expression during the occurrence and development of various primary malignant tumours”. It is associated with gastric cancer/gastroesophageal junction cancer, breast cancer, colon cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small-cell lung cancer.
CT041 and an mRNA vaccine
CT041 (satricabtagene autoleucel) is an autologous CAR T-cell product that is being investigated for the potential treatment of gastric, pancreatic, and other specified digestive system cancers. It is currently in “multiple” ongoing clinical studies in China and North America. Moderna’s investigational off-the-shelf mRNA cancer vaccine encodes for the Claudin18.2 protein. The agreement “contemplates” conducting preclinical studies and a phase I clinical trial to evaluate a combination approach.
Dr Zonghai Li, Founder, Chairman, CEO, Chief Scientific Officer of CARsgen described CT)41 as “the most advanced solid tumour CAR-T in development”. It “continues to show promise in treating gastric and pancreatic cancers”, he states.
“In our quest to make cancer curable, we are continuously exploring multiple modalities to eradicate tumours. Attacking tumours with CAR T-cell therapy in combination with a cancer vaccine could potentially provide greater clinical benefit to patients.”
Furthermore, Moderna has “clearly established themselves” as a “scientific and commercial leader” in the mRNA field, so Dr Li and his team are “pleased to partner” with Moderna to “explore a potential synergism”. Dr Lin Guey, Scientific Officer of External Research Ventures at Moderna echoes this optimism.
“Claudin18.2 is a promising therapeutic target to potentially treat multiple cancer types with high unmet medical need. We continue to deliver on the promise of mRNA science to create a new generation of transformative medicines in oncology.”
Although the World Vaccine Congress West Coast is a few months away, we and our speakers are already gearing up and preparing a fantastic agenda for the community. Part of this preparation will involve more exclusive interviews, and in this post we are thrilled to share a pre-event conversation with Solve M.E.’s President and CEO Oved Amitay. This was conducted via video call and a full transcript can be found at the bottom of the page. We are grateful to Oved and his team for their time and insights into their work, and hope you enjoy the interview.
Oved introduces himself as a “pharmacologist by training” and a “patient advocate by choice”. As President and CEO of Solve M.E., he leads a team that is focused on people who are living with post-infection conditions. Since 1987, the organisation has been serving this community and their “significant unmet needs”.
Patient support and advocacy
Since 1987, Solve M.E have been focused on the needs of the ME/CFS community. Oved kindly gave us a bit of background into the organisation, suggesting that a number of global outbreaks left a number of people “in a state where they did not recover” to full health. At the time Solve M.E. was established, patients were unable to use internet resources to connect with each other or learn more, so the need for a “patient support group” was clear. The condition Solve M.E. was founded to support has been described as chronic fatigue syndrome, or myalgic encephalomyelitis, and other names, but can be traced “throughout the literature”.
“Over the years our organisation took on the mission of not only supporting patients, but also advocating for more research, more funding for research, and that has been a major cause for us, really representing this community.”
What happened during COVID-19?
As Oved notes, COVID-19 affected us all in different ways and was a “tragic event”. However, for the community that Oved serves, it had a “profound impact”. In 2020, the team recognised that Long COVID was a related condition and (like many of their peer organisations) pulled in into the fold to begin addressing post-infection diseases more broadly.
“COVID-19 I think really helped, tremendously, getting into the mainstream consciousness that these are profound diseases that have very significant impact on individuals and, that the origin is an infection...and so, if there is a silver lining in this tragic pandemic it’s that we will finally get to the bottom of it.”
Prevalent diseases we’ve never heard of
A quick look at Solve M.E.’s website highlights the message that they are tackling the “most prevalent diseases you’ve never heard of”. So, what does this mean, and how does Oved hope to engage the vaccine community in this work? Oved refers to CDC estimates that there are about 4 million people in the US who are still experiencing “long COVID”, suggesting that the addition of those with a similar condition that emerged prior to COVID the number would be closer to 8 million.
“It’s a challenge because it’s an invisible disability.”
Another challenge for the industry and community is that “it’s a condition that has various manifestations”, necessitating a broader range of research approaches. However, with a “more intentional effort”, Oved thinks these challenges can be overcome.
“There are millions of people who are really waiting for better solutions.”
Solve at work
Oved has explained the importance of the work he and his team are taking on, so we asked a bit about what they are hoping to see in action. He responds that, as an organisation that predates COVID-19, they were “very concerned” during the early stages of the pandemic that it “may lead to the same outcome”. Thus, in the summer of 2020, the team started educating Congress to “appropriate more funding for research”. This ultimately led to the appropriation of over a billion dollars for NIH investigations into long COVID.
The Long COVID Alliance was co-founded by Solve M.E. to “use the collective influence and resources” of organisations and individuals to “transform our understanding of ‘long haul’ diseases”.
“Really it’s bringing the patient community together, but bringing other resources, government, public as well as the private sector, which is really needed to get to the point where we have more therapeutic options, vaccines, and treatments.”
The World Vaccine Congress
We are very much looking forward to Oved’s roundtable at the event in November, but what are he and his team looking forward to?
“We’re very much looking forward to the opportunity to engage with this community.”
Oved hopes to educate the vaccine community on the importance of incorporating these patients into research and planning.
“We hope to engage in a dialogue.”
In particular, Oved is looking forward to conversing with industry, which he feels has been missing from the post-infection community to date.
We are grateful to Oved and his team for their collaboration on this interview, and hope that you enjoyed it. Don’t forget to visit Solve’s website to learn more, and subscribe for more from us too! A full transcript can be read below.
In a study published in Nature Communications in August 2023 presents early findings for a “cutting-edge” vaccine candidate developed at QIMR Berghofer. This article suggests that the vaccine candidate, targeting Epstein-Barr virus (EBV), achieved “robust” and “persistent” immune responses and is in a good position to progress to “future clinical assessment”.
EBV is a herpesvirus, carried by at least 95% of the adult population across the world. It usually lies dormant after infection in early childhood but can cause severe illness in some people. The authors state that, while acquisition of EBV infection in adolescents or young adults is “often asymptomatic”, the development of “symptomatic infectious mononucleosis” (IM) occurs for some.
IM is considered a “major risk factor” for the later development of multiple EBV-associated diseases such as multiple sclerosis (MS), an “incurable neurological disease” that causes the immune system to mistakenly attack the protective coating around nerves. EBV is also considered the “primary etiological agent” associated with multiple lymphoid and epithelial cancers. In 2022 a study concluded that EBV is likely the leading cause of MS. Thus, prevention of EBV-associated IM could potentially prevent MS in the future.
MS affects around 3 million people around the world, including over 33 thousand Australians. The NHS suggests that it is “most commonly diagnosed” in people between the ages of 20 to 40 but can develop at any age. It is roughly 2 to 3 times more common in women than men. It causes symptoms such as fatigue, impaired mobility, pain, or brain fog.
Research at QIMR Berghofer
Although “several” prophylactic and therapeutic approaches are being pursued, there has been no licensed medical intervention for EBV infection. The goal, therefore, of “optimal” vaccines to control primary and latent infection would be induction of both humoral and cellular immune responses. These would target viral glycoproteins, lytic and latent antigens, and latent membrane proteins.
The article suggests that subunit vaccination would be an “attractive strategy for this purpose”, but full-length EBV latent proteins can “trigger oncogenesis by blocking apoptosis, promoting genomic instability, and supporting uncontrolled cell proliferation”. This “limits” their use as vaccine immunogens. Furthermore, “polyvalent strategies requiring manufacturing and co-formulation of numerous protein immunogens required to induce the necessary breadth of immunity” are challenged by cost and manufacturing complexity.
Thus, a strategy was developed to “specifically target multiple latent and lytic EBV protein epitopes”, overcoming the limiting factors for use in vaccine formulation. Through “extensive mapping” of human CD8+ T cell epitopes from EBV antigens by multiple groups, the team was able to design a polyepitope vaccine immunogen (EBVpoly) that incorporates multiple CD8+ T cell epitopes into an engineered protein immunogen.
QIMR Berghofer’s Professor Rajiv Khanna AO led the development of the vaccine and is collaborating with Atara Biotherapeutics, developers of ATA188, a cell-based therapy targeting the cause of MS. The vaccine may work in combination with this therapy, and Professor Khanna is encouraged by the results of the study.
“Other vaccine efforts have focused on inducing neutralising antibodies against the virus, which blocks infection of immune B cells during primary acute infection. But EBV in its latent state hides inside B cells, turning them into tiny virus factories ready to divide and spread whenever our immune defences are down.”
So, what does this vaccine offer in response? Professor Khanna thinks that for some people, EBV-infected B cells travel to the brain to “cause inflammation and damage”.
“If we can prevent this at an early stage of infection then the infected B cells can’t go on to cause the development of a secondary disease like MS.”
The study suggests that the vaccine induced “potent and persistent” humoral and cellular immunity in pre-clinical models. The immune response also eliminated or greatly delayed the growth of EBV-positive lymphoma tumour cells in laboratory models. After so many years of research, lead author Dr Vijayendra Dasari of QIMR Berghofer is “really proud” to see the work come together. The vaccine is “now heading towards the next important stages of development”.
“The data presented here clearly demonstrate that EBV protein subunit vaccine formulated with AMP-CpG can generate robust virus-specific cellular and humoral immunity, which is persistent and capable of rapid expansion upon recall through exposure to EBV antigens. These studies provide an important platform for future clinical assessment of this vaccine formulation in human volunteers.”
Collaboration with Elicio and Atara
The research team behind the study incorporated biotechnology company Elicio Therapeutics. Dr Peter DeMuth, co-author and Chief Scientific Officer of Elicio, commented that the Amphiphile vaccine adjuvant, AMP-CpG, was useful in taking the vaccine to the lymph nodes for immune response activation. He is “excited” by the data.
“Pre-clinical validation suggests that it not only demonstrates an exciting opportunity for a potential EBV vaccine, but also validates the utility of the AMP platform to improve lymph node immune activation resulting in potent immune responses against historically challenging pathogens.”
The research was funded by Atara Biotherapeutics, also supporting QIMR Berghofer with the development of another EBV-vaccine composition with a different adjuvant.
For more updates on novel vaccines against a range of pathogens, don’t forget to subscribe here.
In July 2023 IO Biotech announced that the University of California Davis Comprehensive Cancer Centre has dosed the first patient in an investigator-initiated trial of IO102-IO103. IO Biotech uses its T-win technology platform to develop novel, immune-modulating cancer vaccines like IO102-IO103, an investigational immune-modulating cancer vaccine. This is being tested in combination with pembrolizumab in patients with BCG-unresponsive or intolerant, non-muscle invasive bladder cancer (NMIBC). The trial is one of five investigator-initiated trials for IO Biotech to evaluate the vaccine in combination with different checkpoint inhibitor-based regimens across a range of cancer types.
Bladder cancer occurs when a growth of abnormal tissue, a tumour, develops in the bladder lining, or occasionally spreads to the bladder muscle. The NHS suggests that the most common symptom of bladder cancer is blood in urine. Once diagnosed, the cancer can be classified by how far it has spread; the most common type is non-muscle-invasive bladder (early bladder cancer). This is where the cancerous cells are contained within the lining of the bladder.
When the cancerous cells spread beyond the lining, into the surrounding bladder muscle, it is described as muscle-invasive bladder cancer (invasive bladder cancer). It is less common but has a higher chance of spreading to other parts of the body. When this spread occurs, it is known as advanced or metastatic bladder cancer. Most cases of bladder cancer seem to have been caused by “exposure to harmful substances”, such as tobacco smoke. More than 1 in 3 cases of bladder cancer are caused by smoking. These substances lead to abnormal changes in the bladder’s cells over time.
Dr Mamta Parikh, Associate Professor at the UC Davis School of Medicine, Division of Haematology Oncology, and PI for the clinical trial, commented that “bladder cancer is one of the most common forms of cancer”.
“There remains a critical unmet need for these patients who may be averse to invasive bladder removal surgery or unresponsive to currently available therapies.”
IO102-IO103 is designed to target the immunosuppressive mechanisms mediated by proteins indoleamine 2,3-dioxygenase (IDO) and PD-L1. It is already being investigated in a Phase III trial in combination with pembrolizumab in first-line advanced melanoma patients. It is also in a Phase II basket trial to investigate safety and efficacy in combination with pembrolizumab for the first-line treatment of non-small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial bladder cancer.
Dr Mai-Britt Bocca, President and CEO of IO Biotech is pleased to support the trial.
“In previous trials, we have seen that combination therapies with our lead product candidate, IO102-IO-103, induce meaningful tumour regression while still achieving manageable tolerability for patients.”
Dr Bocca looks forward to the results “to further support the development” of the vaccine as the “potential backbone of combination therapies for treating multiple types of cancer”.
A team from Japan’s Juntendo University suggest that their latest vaccine, “SAGP”, may revolutionise treatment of Alzheimer’s disease. Presenting at the American Heart Association’s Basic Cardiovascular Sciences Scientific Sessions 2023, the researchers hope to alleviate the suffering of the millions who suffer from the disease. The vaccine has recently been tested in mice presenting symptoms like those of Alzheimer’s.
“Alzheimer’s disease is a brain disorder that slowly destroys memory and thinking skills, and eventually, the ability to carry out the simplest tasks.”
It is ranked as the seventh leading cause of death in the US and is the most common cause of dementia in older adults. The “complex brain changes” that are associated with Alzheimer’s can begin around a decade before symptoms appear. In the early stages, toxic changes take place, such as abnormal buildups of proteins that form amyloid plaques and tau tangles. Neurons become unhealthy, lose connections, and die. Further changes are believed to contribute to Alzheimer’s.
Previous research led to the development of SAGP, a vaccine to eliminate senescent cells expressing senescence-associated glycoprotein (SAGP). This is a senolytic vaccine and has already demonstrated improvements in other age-related diseases in mice. Studies into the role of SAGP indicate that they “would become the novel cellular senescence and/or atherosclerotic disease marker”. They are highly expressed in glial cells in patients with Alzheimer’s disease, which further encouraged the use of this vaccine to target SAGP-overexpressed cells as an Alzheimer’s treatment.
In their most recent work, the team created a disease mouse model that mimics the human brain and simulates an amyloid-beta-induced Alzheimer’s disease pathology. Medical Xpress suggests that “people in the late stage of Alzheimer’s lack anxiety”, an indication of lack of awareness. The mice who received the vaccine at two and four months old demonstrated anxiety, becoming more cautious and aware of things around them. In a behaviour test the mice that received the SAGP vaccine responded better to their environment, behaving more like healthy mice than the mice that received the control vaccine. Furthermore, several inflammatory biomarkers of disease were reduced.
Post-doctoral fellow Dr Chief-Lun Hsiao commented that the vaccine test in mice “points to a potential way to prevent or modify the disease”.
“The future challenge will be to achieve similar results in humans. If the vaccine could prove to be successful in humans, it would be a big step forward towards delaying disease progression or even prevention of this disease.”
The difference between this research and earlier studies is that, not only have the team been able to reduce amyloid plaque deposits and inflammatory factors, but the SAGP vaccine “also altered the behaviour of these mice for the better”.
For more on novel treatments for a range of diseases check out our therapeutic section, or subscribe for a weekly newsletter.
In July 2023 Merck and Moderna announced the initiation of a Phase III clinical trial evaluating V940 (mRNA-4157), an investigational individualised neoantigen therapy (INT), in combination with KEYTRUDA in patients with resected high-risk melanoma. Recruitment for V940-001 has begun globally, with the first patients enrolling in Australia. The approach, which has already been awarded BTD and PRIME, demonstrated positive DMFS results last month.
The trial is global, randomised, double-blind, placebo- and active-comparator-controlled. It is expected to enrol around 1,089 patients at over 165 sites in more than 25 countries. The primary endpoint is recurrence-free survival (RFS), and secondary endpoints include distant metastasis-free survival (DMFS), overall survival (OS), and safety.
V940 is a novel investigational mRNA-based individualised neoantigen therapy, comprising a single synthetic mRNA coding for up to 34 neoantigens that is designed and produced in response to the “unique mutational signature of the DNA sequence of the patient’s tumour”.
An important step forward
Dr Marjorie Green, SVP and Head of Late-Stage Oncology, Global Clinical Development, Merck Research Laboratories, described the initiation of the trial as an “important step forward” in efforts to “advance novel treatment options” for patients with high-risk Stage IIB-IV melanoma.
“We look forward to continuing to collaborate with Moderna to evaluate this promising new approach with V940 (mRNA-4157), while also building on a standard of care laid by KEYTRUDA.”
Dr Kyle Holen, Moderna’s SVP and Head of Development, Therapeutics and Oncology, agreed that this is an “exciting and important milestone” as the team investigates the potential of individualised neoantigen therapy for transforming the treatment of “the most serious form of skin cancer”.
“We thank the patients, investigators, and clinical trial sites across the world for helping us advance our efforts in this area.”
Here at the World Vaccine Congress, we are thrilled that both Dr Holen and Dr Green are joining us for a cancer keynote in Barcelona later this year. Will you join us to learn more during this session? Don’t forget to subscribe for more like this.
Less than a month since we reported Vaxxinity’s “promising” results in a trial of UB-312, the company has released further encouraging news; new data demonstrates that UB-312 has established “clear target engagement” by slowing seeding of alpha-synuclein (αSyn) in cerebrospinal fluid (CSF) of patients with Parkinson’s disease (PD). This is described as “further validation” of Vaxxinity’s platform technology in neurodegenerative disease.
“Our candidate has shown target engagement of the toxic species of alpha-synuclein in patients, demonstrating not only proof of our technology platform, but also proof of the mechanism of our vaccine-derived antibodies specifically engaging with the toxic target in vivo.”
This target engagement has “always been a key challenge” for neurodegeneration, says Hu, who believes this milestone is “worth celebrating”.
“It is beyond our expectation to see this in our Phase I trial.”
She thanked the participating patients and The Michael J. Fox Foundation and collaborators for work on the “cutting-edge assays” that facilitated the breakthrough.
Why target αSyn?
We were lucky to reach Dr Jean-Cosme Dodart, SVP of Research at Vaxxinity, for a few comments on this exciting news, and so we asked for some insight into the approach they are taking. Dr Dodart explains that “although mutations in the alpha-synuclein gene are rare”, aggregates in the form of Lewy bodies and Lewy neurites are “common neuropathological hallmarks” of PD. This suggests a “key role” of αSyn in PD neuropathogenesis.
Furthermore, “preformed fibrils of αSyn can induce the formation of Lewy Body-like inclusions and cellular dysfunction in cell-based assays” and preclinical animal models. These data “strongly suggest” the therapeutic potential of targeting pathological forms of αSyn.
“It is not known, however, at what stage of the disease immunotherapy against αSyn will be required. We anticipate that the earlier we intervene, even before symptoms onset, the better the outcome of therapy.”
A promising candidate
As we know from last month, UB-312 was well tolerated in trial. Furthermore, it induced anti-αSyn antibody responses, of which antibodies were detectable in the CSF. Additional analyses, other target engagement assays, and further antibody characterisation studies will continue. Dr Mark Frasier, Chief Scientific Officer at Michael J. Fox Foundation stated that “integration of critical biomarker insight into therapeutic development programmes is essential” for encouraging confidence in the approach and “designing informative trials”.
“We’re pleased to support efforts of this kind that can have major impacts for people with Parkinson’s disease.”
Dr Dodart kindly outlined some of the advantages that this vaccine will have to therapeutic endeavours, and why it perhaps more encouraging than previous efforts.
“Vaccines offer a variety of advantages over monoclonal antibodies; they are easier to manufacture, easier for patients to take, and dramatically less costly.”
Consequently, they can be scaled for “millions, or even tens of millions of people”. They can also be used for prevention. However, for neurodegenerative diseases such as Parkinson’s, showing target engagement has “always been a key challenge to overcome”. Dr Dodart describes Vaxxinity’s demonstration of target engagement a “noteworthy success”.
Next steps and other applications
The demonstration of target engagement is “promising” for Dr Dodart, not just because the antibodies are “getting where they need to and doing what we want them to do”.
“This also represents a proof of technology for Vaxxinity’s platform that we expect to translate across our pipeline in other chronic diseases, such as Alzheimer’s.”
Looking forward, Dr Dodart anticipates further clinical development for UB-312.
To hear from from Mei Mei Hu about the work Vaxxinity does and how significant access is within this, click here. Don’t forget to subscribe for more updates like this.
During the Congress in April we were pleased to meet Dr Pravin Kaumaya for a conversation about the state of play in the cancer vaccine field. Dr Kaumaya joined us to chair the Cancer and Immunotherapy track, present a session and join a panel. Here we learn more about Dr Kaumaya’s approach, how it differs to those of his colleagues, and why he believes that vaccines are the way forward for cancer therapy. We are so grateful to Dr Kaumaya for his time and hope that you enjoy the interview!
Introducing Dr Kaumaya
Dr Kaumaya is a Professor at the Wexner Medical Centre in Columbus Ohio and has been there for 30 years! Originally from Mauritius, Dr Kaumaya was educated in the UK and has now made his home in the US.
“My lab is in involved in vaccine research for the last three decades.”
What does the cancer field look like now?
With Dr Kaumaya’s experience working in the field of cancer we were curious to hear his thoughts on the progress that has been made. He suggests that “a lot of progress has been made” particularly in recent years. He refers to the Nobel Prize winners Professor Honjo and Professor Allison for their work on checkpoint inhibitors, which he believes has “energised the field of cancer vaccines”.
“I think, in a positive way, I think we will have a cure very, very soon, because of all the combination immunotherapy that is going to be done.”
What does Dr Kaumaya’s lab address?
Within this promising field, we asked Dr Kaumaya to explain his work. His cancer vaccines are “based on peptides”. He tells us that there are two response options: the humoral response or the cellular response. Many of Dr Kaumaya’s colleagues, including Dr Disis, who we spoke to at the Congress, target T cell cellular responses.
“We’ve taken a different route for the last 20-25 years, is to look at B cell vaccines, so where you would generate a polyclonal antibody response.”
This is being applied to HER2, which is over-expressed in breast and colon cancer. The team has “translated” their work to the clinic, with a Phase II trial ongoing.
“The nice thing about what we do is we develop those peptide B cell epitope conformational; we engineer it to fall into 3-dimensional structure, and that is very unique to my lab.”
The lab has developed a “whole portfolio” of vaccines. These acknowledge the “mechanism of resistance that’s come in”, which leads to “up-regulation of all the other receptor tyrosine kynases”. When checkpoint inhibitors “came along”, Dr Kaumaya decided to use peptide vaccines. The beauty of “just peptides” in contrast to the toxicity of other approaches, is the long-established safety.
Some of Dr Kaumaya’s sessions were focused on combination approaches. We asked about the importance or the benefit that this focus provides.
“Of course, single mono-therapy is only valid in about 20% of patients. So, if you have a combination you can elevate the response.”
The combination could be with chemotherapy, radiotherapy, or other checkpoint inhibitors. For Dr Kaumaya’s team, combination is with the HER2 vaccine, currently in trial.
“You can see the synergy, the additivity of multiple targeting agents.”
Getting clinical trials right
Discussions at the Congress addressed the difficulty of clinical trials in this space. When we asked Dr Kaumaya about his, he reminded us that “we are dealing with biologics here”. Although peptides are “100% safe”, the work that he does is governed by the FDA as if it was small molecule work.
“We have to follow that regimen, and that is not very good.”
The example that Dr Kaumaya gives is their clinical trial with the HER2 vaccine, for all comers. These patients have been “subjected to multiple regimens of toxic events”. Consequently, the immune system is “depressed”. Therefore, to be able to use a vaccine approach the team get the patients to “lay low” without treatment for 6 weeks.
“Hopefully the FDA and the EMA will understand as we move forward, that when we do Phase I clinical trial they should allow us to be able to access patients that have not undergone multiple regimen, because it’s not beneficial to a vaccine approach. And hopefully that mentality will change.”
The importance of access
Another hot topic at the Congress was access, and how to develop vaccines with equitable intentions. When we asked whether access was a challenge or a worry for Dr Kaumaya, he replied emphatically: “not at all”. He contrasts current therapies in clinical trial, which don’t provide a cure but cost hundreds of thousands of dollars, with his vaccine. This is a 3-shot programme for $140 a shot.
“I don’t think you can beat vaccination… vaccines are a very good way to go forward.”
Joining us at the Congress
Our final question was on the reasons that Dr Kaumaya was joining us at the Congress. The focus of Dr Kaumaya’s time in Washington was education. He hoped to convince people that B cell vaccination was the way forward.
“I have to educate scientists.”
Taking us back a bit, Dr Kaumaya points out that currently FDA-approved treatments are monoclonal antibodies. Therefore he asks why we can’t “have the immune system make those antibodies”.
“We’ve got the technology to design those vaccines based on protein folding, biochemistry, and so on. And then when we put those in humans or in animals, you get a high-affinity, polyclonal antibody response, which should be as effective as a monoclonal antibody.”
We hope that the opportunity to “educate” his peers was successful for Dr Kaumaya, and look forward to hearing more at future events. To get more like this make sure you subscribe!
Following the signing of a memorandum of understanding between the UK government and BioNTech in January 2023, an agreement has been established to provide cancer patients with “improved access” to cancer trials. The partnership will ensure that more patients are able to explore personalised cancer treatments. Trials have already begun in the UK, but most patients are expected to enrol from 2026 onwards. The goal is to provide personalised treatments to around 10,000 patients by 2030.
Leading the field
BioNTech intends to establish new laboratories in Cambridge with over 70 “highly skilled” scientists, and a regional hub for the UK. Prime Minister Rishi Sunak commented that the “landmark new agreement” brings the country “one step closer” to life-saving treatments for thousands of patients.
“The UK is a global leader in life sciences – helping to create thousands of highly skilled jobs and pioneering research – and it is a testament to this success that BioNTech have chosen to make this significant investment here today.”
Mr Sunak believes that a personalised vaccine approach to cancer has potential to “completely revolutionise the way we treat this cruel disease”. Secretary of State for Health and Social Care, Steve Barclay, agrees that the partnership is a “huge step forward in the fight against cancer”.
“This further demonstrates that the UK is an attractive location for innovative companies to invest and pioneer cutting edge treatments for our patients and underlines this government’s commitment to research and development.”
Working with the NHS
The Cancer Vaccine Launch Pad (CVLP) will be led by NHS England and Genomics England. This will encourage quick identification of eligible cancer patients to join trials. It does this through a database of suitable NHS patients. The NHS CEO Amanda Pritchard emphasised that the NHS “will not stop” efforts to “pioneer new treatments”. The CVLP, she said, will give patients the “earliest possible access to cutting-edge technology”.
“Thanks to advances in treatment and care alongside NHS awareness campaigns, cancer survival is at an all-time high, but the potential to stop cancer from returning is truly remarkable.”
Chris Wigley is Genomics England’s CEO and describes the CVLP as a “rocket” being launched.
“Since the times of Darwin, Franklin, and Sanger, the UK has been a true world leader in genomic science and healthcare.”
He is “thrilled” that the partnership takes genomics “beyond diagnosis” towards “a future of personalised cancer treatment”.
The trials are centred around the revolutionary mRNA platform, with immunotherapies to target shared mutations or individual tumours. CEO and co-founder of BioNTech, Professor Uğur Şahin, is “truly honoured” to be an “integral part of this landmark partnership”.
“The United Kingdom’s expertise in genomic analyses in cancer patients is a critical component of our shared endeavour to make mRNA-based and precision cancer immunotherapies widely accessible through clinical trials.”
Professor Şahin hopes this partnership will facilitate better outcomes for patients “worldwide”.
In June 2023 Vaxxinity announced positive results from Part B of the Phase I clinical trial of UB-312, an investigational vaccine for Parkinson’s disease. The results show that the vaccine was well tolerated and induced anti-alpha-synuclein (aSyn) antibody responses in participants with early Parkinson’s disease. The primary endpoints of the trial were met and support the advancement of UB-312 to Phase II trials.
Parkinson’s disease and aSyn
Parkinson’s disease (PD) affects over 10 million people across the globe. It is a “chronic and progressive neurodegenerative disorder”, affecting predominately dopamine-producing (dopaminergic) neurons in the substantia nigra part of the brain. There are no approved disease- modifying therapeutics and current treatments aim to provide symptomatic relief whilst causing “significant side effects”.
Alpha-synuclein (aSyn) is a protein that is highly expressed in neurons, mostly at presynaptic terminals. Mutations in the gene encoding aSyn are “known to cause or increase the risk of developing PD” and have been shown to alter the secondary structure of aSyn. This produces misfolded and aggregated forms of the protein. Immunotherapies that target aSyn have demonstrated an ability to “ameliorate aSyn pathology” and functional deficits in mouse models of PD.
UB-312 in trial
The investigational vaccine is a synthetic peptide vaccine targeting toxic forms of aggregated aSyn to address PD and other synucleinopathies. The Phase I trial was placebo controlled and double blind, comprising two parts. Part A tested escalating doses of UB-312 against placebo in 50 health volunteers between the ages of 40 and 85. Part B tested two doses of UB-312 versus placebo in 20 age-matched subjects with early PD. These were conducte at the Centre for Human Drug Research (CHDR) in the Netherlands.
Previous results from 2022 have suggested that the vaccine is highly immunogenic. All individuals in the target dose group showed detectable anti-aSyn antibodies in serum and cerebrospinal fluid (CSF).
A closer look at Part B
Part B comprised a 20-week treatment period before 24 weeks of observation. The study evaluated the safety, tolerability, and immunogenicity of the vaccine in patients with PD, and primary endpoints were met. 92% of patients who completed the dosing developed anti-aSyn antibodies. The vaccine was “generally safe and well-tolerated” and all serious adverse events (SAEs) were resolved.
A promising candidate
Vaxxinity’s CEO Mei Mei Hu, whom we interviewed at the Congress in Washington this year, commented that the results demonstrate “several important features necessary for an immunotherapy”.
“UB-312 was observed to safely break immune tolerance, inducing antibodies against toxic aggregated forms of alpha-synuclein. Importantly, these antibodies crossed the blood brain barrier, and the data also suggest potential target engagement in the periphery, where pathological alpha-synuclein is known to be concentrated.”
She considers the candidate “promising” and looks forward to further development. Dr Geert Jan Groeneveld is the CMO/CSO of CHDR and principal investigator of the Phase I trial. He commented that this is a “revolutionary concept” that could have “immense impact” in the treatment of diseases like Parkinson’s.
To learn more about Vaxxinity’s work make sure you check out our exclusive interview with Mei Mei here. Subscribe to our newsletter for regular updates on vaccine development.
In June 2023 at the European Haematology Association event Mendus presented new clinical data from the Phase II ADVANCE II trial in acute myeloid leukaemia (AML) maintenance. The data show that treatment with vididencel led to increased levels of activated, cancer-killing T cells and reduced levels of immunosuppressive T cells in most patients.
Vididencel is an allogenic, leukaemic cell-based relapse vaccine that expresses co-stimulatory molecules, resembling activated dendritic cells and tumour associated antigens (TAA). It is delivered intradermally and generates an inflammatory response and “indirect priming of the immune system”.
The primary endpoint of the study was MRD response, or minimal residue disease, and patients with such a response had the highest levels of these tumour antigen-specific T cells. They also showed a “trend” towards higher levels of “circulating antigen-presenting cells (APCs) and B cells” after treatment with vididencel.
Dr Jeroen Rovers, Chief Medical Officer at Mendus, commented that “immunomonitoring is an important part” of the trial, providing “in-depth analysis of the interaction between vididencel and the immune system”.
“The results…demonstrate a clear correlation between the patients’ immune status and immune responses observed following vididencel administration and these previously reported survival outcomes.”
Following these results, Dr Rovers considers “priming the immune system to eradicate or control residual disease” an “effective strategy in AML”.
“The ADVANCE II trial continues to evaluate patients in long-term follow-up with updated survival results expected for Q4 2023.”
A closer look at the data
At the time of data collection 20 evaluable AML patients had been analysed. Functional T cell analysis revealed vaccine induced responses (VIRs) to antigens in vididencel in 17 out of 20 patients. The highest number of VIRs occurred in MRD responders, which indicates a “positive correlation of VIRs with clinical outcomes”.
To download the poster from Mendus click here. Make sure you subscribe to get more like this in your inbox!
In June 2023 Moderna and Merck, who have been collaborating on a Phase IIb study to evaluate mRNA-4157 (V940), announced distant metastasis-free survival (DMFS) results. The trial investigates the combination of KEYTRUDA, Merck’s anti-PD-1 therapy, with an investigational individualised neoantigen therapy (INT) in patients with resected high-risk melanoma (stage III/IV).
The overall intention-to-treat (ITT) population demonstrated that the combination treatment showed a “statistically significant and clinically meaningful improvement in DMFS”, which was a key secondary endpoint of the study, in comparison with KEYTRUDA alone. The risk of developing distant metastasis or death was reduced by 65%. The data are being presented orally at the American Society of Clinical Oncology Annual Meeting on 5th June 2023.
Rapidly advancing progress
Dr Kyle Holen, Moderna’s Senior Vice President and Head of Development, Therapeutics and Oncology, is “excited to be sharing these results with the oncology community”. Dr Holen was “thrilled to see such an exceptional result in distant melanoma or death”. Recognising that patients who experience metastases at distant sites “typically have worse survival outcomes and a poor prognosis”, he suggests that the results “add to the emerging picture” of the transformative potential of individualised neoantigen therapy.
“Together with Merck, we are rapidly advancing our efforts to move this forward for patients.”
Dr Eric H. Rubin, Senior Vice President, Global Clinical Development, Merck Research Laboratories, suggests that patients with stage III and IV melanoma can be at “high risk of having their cancer recur or metastasise to other sites”.
“These new DMFS results build upon the positive recurrence-free survival data previously observed from this Phase IIb study, and we look forward to working with Moderna to initiate a Phase III study in melanoma later this year.”
French-based biotechnology company Transgene announced in June 2023 that new data confirm that its novel investigational therapeutic cancer vaccine can induce immune responses against HPV16. The results are presented in a poster at the American Society of Clinical Oncology meeting in Chicago.
HPV16 is known as a “high-risk” human papillomavirus. Alongside HPV18 it causes most HPV-related cancers. The CDC suggests that type 16 is the cause of “approximately 50% of cervical cancers worldwide”. According to Transgene, treatment options “remain limited”.
The vaccine is an investigational viral vector based therapeutic cancer vaccine, based on non-propagative, highly attenuated Vaccinia vector (MVA). This has been engineered to express the HPV antigens E6 and E7. It also features an adjuvant: interleukin 2 (IL-2).
Transgene states that the vaccine is designed to “have a two-pronged approach”. The first element is to “alert the immune system specifically to cells presenting the HPV E6 and E7 antigens”, which are found in HPV16-related tumours. The second is to “further stimulate the infection-clearing activity of the immune system through interleukin 2”.
TG4001 in trial
TG4001 is under evaluation in a randomised controlled Phase II clinical study. The study compares TG4001 in combination with avelumab to avelumab in isolation. The patients enrolled in the study have HPV16-positive anogenital tumours.
46 patients have been included in both arms of the trial. A statement from Transgene suggests that 58% of patients who received the combination of TG4001 and avelumab demonstrated increased immune responses against HPV antigens, compared to 9% in the avelumab arm.
“These data clearly demonstrate that Transgene’s TG4001 could induce a specific immune response against the antigens vectorised within this vaccine.”
Results are expected in 2024, with the last patient to be randomised in the first half of that year.
Dr Alessandro Riva, Chairperson and CEO of Transgene commented that the team is “excited” by the data.
“These data further confirm that our therapeutic vaccine TG4001 can induce clinically meaningful immune responses, that are associated with antitumour response.”
The company looks forward to the final analysis of the study and the “potential next steps”.
Our next interview is with Dr Jay Berzofsky, Chief of the Vaccine Branch at NCI’s Centre for Cancer Research. He joined us at the Congress to participate in the Cancer and Immunotherapy Vaccines track, during which he explored triple synergistic combination immunotherapy. We are so grateful for Dr Berzofsky’s time and insights into cancer vaccine development and the challenges that come with it. We hope you enjoy the interview!
Introducing Dr Berzofsky
Dr Berzofsky kindly explains a bit about how his role works within the programme.
“We are government employees…we have nothing to do with grants for universities and so forth, but we do our own research.”
The branch is the vaccine branch, and they work on “basic science” and its applications to vaccines for HIV, cancer, and viruses that cause cancer, as well as COVID-19.
Triple synergistic combination immunotherapy
Dr Berzofsky kindly gave us a preview of his session the following day, which was to explore triple synergistic combination immunotherapy. He began by explaining that “there are different reasons why certain cancers may not respond well to immunotherapy”. He introduces “hot tumours”, those that are “inflamed” with T cells that “could kill the tumour cells”. However, the “tumour microenvironment” is “very immunosuppressive” and “prevents them from doing their job”.
“The T cells are there, but they need to be enabled.”
Next, Dr Berzofsky discusses “cold tumours”. These have no T cells infiltrating, often because the tumour doesn’t induce a good immune response. Essentially, the “immune system doesn’t see it as foreign”. These two different kinds of tumours need different strategies, suggests Dr Berzofsky.
“In the case of a hot tumour, you want to block the immunosuppression, to allow the T cells that are there to work.”
This is the case for melanoma, lung cancer, and a “number of other cancers”.
“In cold tumours, you need to generate an immune response, and that’s where the vaccine can come in.”
Inducing a T cell response that the “tumour itself failed to induce” converts the tumour from a cold tumour to a hot tumour. The vaccine, and the blockers of “negative regulation” such as checkpoint inhibitors, are synergistic!
“The vaccine can induce the T cells, but they won’t work if you don’t block the immunosuppressive environment.”
Clearly developing therapeutic cancer vaccines is a challenging task. When we asked Dr Berzofsky about this, he reckoned that “there are a number of challenges!” A major challenge that he does discuss is the need to encourage the immune system to “reject” the cancer as it might a transplant. The immune system can be “exquisitely specific”, unlike an external approach like chemotherapy; it can “distinguish very cleanly” what is foreign in the body.
“But remember, the cancer cells are not foreign organisms like bacteria or viruses that are completely different from your own cells – they arose from your own cells.”
The target therefore, is a vaccine that can “train the immune system to see those unique differences”.
Another challenge that Dr Berzofsky identifies is that there are “many immunosuppressive mechanisms” beyond checkpoints.
“One has this panoply of suppressive mechanisms to overcome.”
We don’t have “really good ways” of overcoming these in humans yet, so Dr Berzofsky calls for research to “more effectively illuminate these other suppressive mechanisms”.
“It may be a daunting task to try to block 8 or 10 different suppressive mechanisms at the same time…so we need to find common nodes of intersection where some of these suppressive mechanisms interact, so we can block more than one at the same time.”
What more can be done?
As Dr Berzofsky has suggested, more work can be done, as always! We asked about potential areas for development that he can identify. Following from his previous answer, he emphasises the importance of finding “better ways, that are safe, to eliminate these immunoregulatory cells”. However, we also have to “strike the right balance”; they are there for a reason.
“It’s just going to take more research.”
Although we can make progress in animals, Dr Berzofsky suggests that the next step is “human clinical trials”.
Coming to the Congress
When we asked Dr Berzofsky about why he was joining us, he commented on the quality of his colleagues’ presentations!
“Hearing all the wonderful speakers that come to this meeting every year!”
Apart from the opportunity to learn, Dr Berzofsky was looking forward to meeting and developing potential collaborations.
“One of the things that’s important in science as in so many fields, is networking, because none of us can do everything in our own small laboratory.”
We are so grateful to Dr Berzofsky for his time and insights into some of the most challenging vaccine endeavours of our time. We hope to continue this conversation at future events. For more like this, make sure you subscribe to our weekly newsletters.