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.”
As we have previously noted , the results of the trial have resulted in the PRIME scheme award and Breakthrough Therapy Designation. We look forward to hearing future success stories as progress continues.
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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
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”.
TG4001
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.”
Initial challenges
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”.
Further challenges
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.
At the World Vaccine Congress last month we were lucky to meet Dr Nora Disis of the University of Washington (UW), an expert in oncology. We are delighted that she made time to discuss combination therapies, the role of vaccines in cancer treatment, and the significance of access in her work. We are grateful to Dr Disis for her time and hope that you enjoy this interview.
Introducing Dr Disis
Dr Disis kindly outlined her current role for us. She joined us at the Congress to discuss combination immunoprevention and immunotherapy strategies.
Combination approaches
We asked Dr Disis to tell us a bit more about the areas she was in Washington to discuss. She explained that, for cancer, the “antigens or immunogens are more weakly immunogenic” than other proteins.
“You’re kind of battling generating a robust immune response with a tumour that continues to grow.”
Therefore, “another strategy” that can slow the tumour’s growth or “hold the tumour at bay”, without compromising a vaccine’s efforts, “just makes sense”. In therapeutics, Dr Disis has seen that combination approaches “really potentiated the effect of both”. This is also true in prevention, where chemo-prevention agents can “help stimulate the immune response and make the vaccines more effective”.
What role do vaccines play?
To put it simply, Dr Disis thinks vaccines are going to be “very critical” for making immunotherapy drugs “more effective”. She suggests that “most patients” with common solid tumours do not have “highly mutated tumours”. This means that they are “not filled with T cells waiting to be unleashed”.
“I think that’s where vaccines may provide the key component.”
Dr Disis believes if you can immunise patients, get T cells “trafficking to tumour”, and “increase that tumour infiltrating lymphocyte load”, it makes sense!
“You’ll have a certain body of T cells that would be able to become activated and hopefully attack the tumour.”
Clinical trials and patient populations
With lots of discussion about clinical trials at the Congress, we asked Dr Disis what she thinks about improving the process to optimise outcomes. She suggests that “we’ve really struggled to figure out what should be the patient population that we immunise”. A conventional focus on “tumours that were rapidly growing” and “resistant to all chemotherapy” is now understood to be the equivalent of “trying to immunise someone who’s got an overwhelming infection”. In that context, vaccines are not particularly effective.
However, in the adjuvant setting, vaccinating fully treated patients with “no evidence of disease” but an “extremely high risk of relapse”, we are starting to see the “success of vaccines”.
“It’s taken us quite a long time to get to the point where we’re beginning to understand the specific patient populations that would be ideal for vaccination.”
What about access?
Following on from Dr Disis’ comments about patient populations we asked her a bit about access. Cancer treatments are renowned for being costly, so how can this be addressed? Dr Disis acknowledges that it’s “very hard in oncology” with some treatments being beyond reach for many. However, vaccines might offer a solution.
“Vaccines are the great levelling field.”
For her colleagues, she has advice on making vaccines.
“Do not make them complicated!”
She encourages people to think about things like transport potential when creating their vaccines. In fact, she believes that we have technologies that can be “widely applicable to a great number of vaccines and can be made very cheaply”.
“I would put out a call to my field; that should be one of the first things on their mind: “am I making this a therapy that is only going to be for people who have the money to afford it?”
Hopefully, with people like Dr Disis leading the charge, real change can be made in the field to ensure that therapies are available to more patients across the world. We are so grateful to Dr Disis for her time and look forward to hearing more at future events.
Make sure you subscribe to get more interviews sent to your inbox and check out the post-event report here.
An article in Nature in May 2023 presents work from a collaboration between Genentech, Memorial Sloan Kettering Cancer Centre (MSKCC), and BioNTech. Dr Vinod P. Balachandran, surgeon-scientist at MSKCC has been working on pancreatic ductal adenocarcinoma (PDAC) for years in the hope of replicating the rare survival of some patients for others. Through a personalised RNA neoantigen approach, he may have finally found a route.
PDAC
The article reports that PDAC is the “third leading cause of cancer death” in the US, and the seventh worldwide. Unfortunately, the survival rate of 12% has “remained largely stagnant for nearly 60 years” as incidence continues to grow.
“PDAC is projected to cause even greater global cancer deaths by 2025.”
Currently the only curative treatment is surgery, yet up to 90% of patients have disease recurrence at around 7-9 months and the 5-year survival is 8-10%.
“Radiation, biologics, and targeted therapies are also ineffective.”
Furthermore, PDACs are “almost completely insensitive to immune checkpoint inhibitors”. This is “partly attributed to the fact that PDACs have a low mutation rate”. They therefore generate few neoantigens, which mark the cancer as foreign to T cells. However, recent studies have shown that PDACs “harbour more neoantigens than previously predicted”, and studies of long-term survivors have suggested that “neoantigens may stimulate T cells in PDAC”.
Replicating survival traits
The authors state that, based on the observation that long-term survivors “mount spontaneous T cell responses” against “tumour-specific neoantigens not shared among patients”, they decided to investigate if “adjuvant individualised vaccines can stimulate neoantigen-specific T cells and provide clinical benefit”.
The known benefits of mRNA vaccine technology led the researchers to suggest that an effective mRNA vaccine could induce neoantigen-specific T cells in PDAC, eliminate micrometastases, and delay recurrence. To explore this, they conducted an investigator-initiated, Phase I clinical trial of sequential adjuvant atezolizumab (Genentech), autogene cevumeran restricted neoantigens in lipoplex nanoparticoles intravenously delivered, individualised NeoAntigen-Specific Therapy (iNeST), and mFOLFIRINOX in patients with surgically resectable PDAC.
A positive start
The study demonstrates that adjuvant autogene cevumeran, the individualised neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, in combination with atezolizumab and mFOLFIRINOX, is “safe, feasible, and generates substantial neoantigen-specific T cells in 50% of unselected patients with resectable PDAC”.
“Here, we provided evidence that despite the low mutation rate of PDAC, a mRNA vaccine can induce T cell activity against neoantigens in this cancer.”
The individualised mRNA cancer vaccines were tested in the adjuvant setting due to observations that vaccines against pathogens have “historically been most effective in preventative and not therapeutic settings”. From this the authors infer that “vaccine efficacy requires an optimally functioning host immune system”. However, in patients with advanced cancer, neoantigen vaccination is challenged by “global impairments in host immunity” and “knowledge gaps on neoantigen heterogeneity between tumours”. Therefore, the researchers recommend that vaccines are tested in patients with minimal residual disease.
Moving forward through challenges
The article shows that PDAC tumours do harbour neoantigens suitable for vaccines, and T cell can be generated in response to mRNA vaccines. Additionally, there is a correlation between vaccine-induced T cells and delayed cancer recurrence.
Although the trial was conceived in 2017, and began in December 2019, it encountered an enormous and familiar obstacle a few months in. Dr Balachandran told GEN that this “posed several unique challenges” such as “shutdowns and global supply chain disruptions”. Furthermore, the distraction presented by BioNTech’s task of manufacturing vaccines “to save the world” was another barrier to success. However, Dr Balachandran believes that intead of slowing the trial down, they were able to “accelerate it to complete it a full year ahead of schedule”.
‘We think this can hopefully speak to the idea that rapid custom cancer vaccination is feasible in the clinic.”
Dr Ira Mellman of Genentech admits that at the start, many people viewed the project as an “over-the-horizon or blue-sky thing”, with little expectation of success.
“Now, from two different sources that are totally independent, both using mRNA vaccines, they seem to have some rather significant glimmers of clinical benefit. Whether it’s the next big thing, I’m not prepared to say, but it could be.”
For more insights into therapeutic vaccine development, head to our therapeutic section to view previous articles.
At last month’s Congress we were lucky to meet Dr Andrew Allen, CEO and Co-Founder of Gritstone bio, for a conversation about cancer vaccines and immunotherapy targets. He joined us at the event for the Cancer and Immunotherapy Vaccines track, and we were glad to sit down with him for more insights into his work and the work of the field. We hope you enjoy the interview!
Gritstone bio
As Dr Allen mentions, he is the CEO and Co-Founder of Gritstone bio, a publicly-traded company based in the US. Their facilities are on both the East and West Coasts. Gritstone describes a commitment to “progressing the field of immunotherapy”, which meant that Dr Allen was in a good position to chair the track!
Neoantigen approaches
One of Dr Allen’s sessions was on neoantigen immunotherapy for solid tumours, so we asked him to share a bit about what this involves. He suggests that this is an “idea that has been around for about 7 or 8 years”. Data published in 2014 indicated that “mutations in genes created altered proteins that could function as antigens for the immune system”. Thus, the neoantigen.
“The achilles heel of cancer seems to be that when those proteins change they can provide targets for the immune system.”
For Dr Allen, there is then an “arms race” between “a cell that’s trying to turn into a tumour cell, proliferating without restraint”, and the host’s adaptive immune response, “trying to identify foreignness, and eliminate it”.
“We’re trying to essentially tilt the battlefield in our favour by driving strong immune responses against those tumour neoantigens.”
Luckily, some pretty “elegant biology” works with us here. The mutations are only found in the tumour and are “foreign to your immune system”. Although this sometimes happens naturally, without attracting attention, T cells can “often” enter the tumour but “something stops them from completely eliminating the tumour”. However, most solid tumours don’t have lots of pre-existing T cells. Therefore, we need to “take a step back” and “generate the T cells”.
“We use vaccines to generate those T cells.”
Vaccines on the scene
Dr Allen mentions that vaccines are used to generate T cells. We asked what a successful cancer vaccine might look like, or what the ultimate goal for vaccine developers might be. For solid tumours, the “goal is to prolong survival”. Explaining the role of “biomarkers” or “surrogate markers”, Dr Allen suggests that the “goal” is to “impact those biomarkers in a very striking fashion”. This often happens in patients with advanced disease, before the platform can be moved backwards into an “earlier stage population”. In this population, the immune response is “better” and the tumour presence lesser, so there is greater opportunity to make a demonstrable difference.
The question of clinical trials
Some of the conversations that took place at the Congress were centred on the issue of improving clinical trials to produce better outcomes. We asked Dr Allen what his views on this issue are. For him, it’s a “really interesting area”. He suggests that in oncology, “we’ve been using the same endpoints for about 20 years now”.
“You’re looking for lesions to get smaller, and if they don’t get smaller, you say ‘that therapy doesn’t work’.”
However, this isn’t appropriate for immunotherapy, in which the goal is T cell proliferation within the lesions. When the T cells enter lesions, they can often get bigger, misinterpreted as “progression of disease – that’s failure”. What might actually be happening is proliferation of T cells causing a temporary enlargement, before the T cells “go to work” and the tumour shrinks. “Pseudo-progession”, says Dr Allen, is a “recognised problem” particularly for melanoma.
With vaccines, for cold tumours, the tumour has no T cell population until vaccination, where the notion of lesion expansion is once again “important”. Additionally, there is “good evidence” that some tumours that are responding to therapy develop mini lymph nodes! Lymph nodes are “fixed structures that are stable over time; they occupy space”.
“The expectation that the tumour has to go away for there to be a good outcome I think is based on these flawed ideas from the past.”
With these concerns in mind, Dr Allen suggests that radiology is “struggling” to “meet our needs of being a predictive biomarker”. His question, then, is “do we have something better”, to which he believes we can answer positively! The answer is “circulating tumour DNA”, which can be measured in the blood.
“You treat a patient and if their CTDNA goes down, they are likely to do well.”
This is a well-established approach, but the field has not yet made the transition.
“I think we’re going to find that CTDNA actually is a much better surrogate for overall survival, with immunotherapy.”
What was happening at the Congress?
We asked Dr Allen about his interests at the event, and he shared what he was most looking forward to. Apart from presentations from BioNTech and Moderna, Gritstone’s “competitors in the space”, there were opportunities to meet with other players in the field.
“It’s going to be an exciting year and I’m looking forward to just chatting about that with all of the experts here at this conference.”
We are grateful to Dr Allen for his time and his useful insights into technical details and wider field ambitions. We look forward to more from Gritstone bio at future events! For more interviews with experts in the cancer space, click here to subscribe. To see a breakdown of the event, click here for the post-event report.
Continuing our series of exclusive Congress interviews we are delighted to share a conversation with Dr Gaurav Gaiha at the Congress this month. Dr Gaiha participated in the HIV workshop on the pre-Congress day, presenting “highly networked” CD8+ T cell vaccines for HIV. In our chat we found out more about the challenges associated with developing vaccines for HIV, and how Dr Gaiha and his team are tackling them. We are grateful for his time, and hope that you enjoy the interview!
Introducing Dr Gaiha
As Dr Gaiha tells us, he runs a research laboratory that is focused on infectious diseases and translating protective T cell response findings into vaccines. Additionally, he sees patients at the general hospital.
“So really trying to both work on research advancements but also kind of serve people in a very direct patient-doctor relationship.”
More on “highly networked” approaches
As we know, Dr Gaiha was at the Congress to present on “highly networked” CD8+ T cell vaccines. We therefore asked him to give us a little insight into this approach. He explains that this is an approach that acknowledges the “immense diversity” of HIV and its “incredible” capacity to mutate in response to immune pressure. It uses insights from computational biology and network theory to identify the “critical parts” of the HIV cells that can’t mutate: vulnerable regions.
“If you imagine a network, like a social network, there’s going to be certain ‘key players’ in that social network, where if you were to remove them it would really be damaging to how that social network stays connected.”
This social network analogy is really helpful in the digital age! So, at the level of the HIV proteins, Dr Gaiha and his team are trying to direct T cells towards those “key players”. If the virus tries to mutate it will have a “consequential effect” on the virus’ capacity to replicate.
“Hit the virus where it hurts.”
Challenges for HIV vaccines
When we spoke to Dr Feinberg a few months ago, he described HIV as one of the most “vexing” challenges that vaccine developers are tackling. We asked Dr Gaiha what challenges he identifies, and how he and his team are approaching them. He identifies “several” challenges, two of which he has already mentioned: diversity and adaptability.
From a T cell perspective, there’s a human challenge – “we as humans are diverse”. Therefore, trying to get a “one size fits all” vaccine is a difficult pursuit. Furthermore, there’s the issue of durability. If the immune response dips, the virus can sometimes “break through”.
What Dr Gaiha’s team is trying to do is “hit at the diversity” and “hit at that ability for the virus to mutate”.
“We’ve made strides.”
Now, they are looking to make the immune responses durable and ensure that they “get to the right sites of the body”.
What about access?
As we know, current HIV therapeutics are a lifelong and often burdensome addition to patients’ lives. Could a vaccine overcome some of these issues? Dr Gaiha recognises that enabling access and subsequently encouraging continued uptake of drugs is a challenge. A preventative vaccine would be “fantastic”, obviously, but in the meantime, a therapeutic vaccine that could “suppress the virus” would be a “huge development”.
“HIV is one of those viruses where vaccine development is very much in line with addressing this issue of access.”
What did we take from COVID-19?
Many of our speakers have been working in their fields since before COVID-19, including Dr Gaiha. We asked him if, in his opinion, there are any lessons that we can transfer from our experience of dealing with the pandemic.
“The biggest has been our experience with the RNA vaccines.”
Dr Gaiha believes that we can translate some of our RNA vaccine lessons from COVID-19 into effective and immunogenic HIV vaccines. Furthermore, “because they can be generated so rapidly”, more “iterative developments” can be facilitated in HIV.
“It’s been such a struggle to find the right pieces.”
Another lesson Dr Gaiha hopes to take forward is the “urgency that made it happen”.
“I think we really should be trying to apply that same urgency to the HIV problem.”
Although every “small, incremental” step forward is a worthy achievement, Dr Gaiha is hoping to take the “same mindset and approach” that will spur vaccine development to the “next level”.
Why WVC?
We asked Dr Gaiha what brings him to the Congress, and he kindly gave us an insight into what he was looking forward to over the few days he was with us. He was enthusiastic about the opportunity to be in-person once again, despite the obvious comfort of remote connections!
“The informal exchange is just such a wonderful thing.”
Another benefit is the range of “different perspectives” and Dr Gaiha was looking forward to engaging with these different perspectives and possibly forging some new collaborations.
We are so grateful to Dr Gaiha for his work and hope that you enjoyed his insights as much as we did! For more information on what went on at the Congress, click here to download the post-Congress report. Finally, make sure you subscribe to stay in the loop for future interviews!
In April 2023 Ultimovacs ASA announced that it has adjusted guidance for communication of top-line data from early 2023 to later in the year. A statement from the company indicated that this was due to slow disease progression in patients. However, it is uncertain to what extent the vaccine was contributing to this delay.
UV1
UV1 is a universal cancer vaccine designed to induce a specific T cell response against human telomerase (hTERT). It comprises long, synthetic peptides, which represent a sequence in the reverse transcriptase subunit hTERT, shown to induce CD4+ T cells. These cells can provide inflammatory signals and support believed to be “critical for triggering a strong anti-tumour” response.
Ultimovacs states that, following intradermal injection, antigen presenting cells (APCs) in the skin are exposed to the 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. Activated vaccine T cells will then enter the circulation and identify cells displaying their cognate antigen in the context of HLA molecules.
The vaccine is administered over 3 months as 8 injections alongside the immune-modulator GM-CSF. It is being investigated in the INITIUM trial, a comparative, randomised Phase II trial for first-line treatment of patients with advanced or metastatic malignant melanoma. Enrolment began in June 2020 and was completed in June 2022 with 156 patients.
An encouraging sign
CEO of Ultimovacs, Dr Carlos de Sousa, is “encouraged”. Disease progression is “slower than anticipated” in comparison with “historical data”.
“This is positive for patients, though we do not know if UV1-related efficacy is responsible for this extended time to expected readout since both Ultimovacs and the investigators remain blinded.”
Dr de Sousa looks forward to “learning to what degree UV1 may have contributed to the clinical outcome for patients”.
Expecting results
INITIUM has an “event-driven design”, resulting in top-line progression free survival results being disclosed after progression or death has been verified in 70 patients. Historical data for a combination of ipilimumab and nivolumab indicated that this progression might occur by the first half of 2023. However, it is taking “longer than anticipated” to observe this progression in the required number of patients. Thus, the top-line results will not be announced before the second half of 2023.
For more on therapeutic vaccine efforts against cancer head to our therapeutic section or subscribe for updates in your inbox each week.
Allergy Therapeutics announced in April 2023 that the first cohort of patients with peanut allergies had “successfully” taken the “innovative short-course peanut allergy vaccine candidate”, VLP Peanut through skin prick testing (SPT). Through the PROTECT trial, the first-in-human study to evaluate VLP Peanut in adult subjects, the company aims to establish safety and tolerability.
Peanut allergies increase
Allergy Therapeutics suggests that peanut allergy is one of the most common types of food allergies, with symptoms ranging from mild to severe or even life threatening. An observed increase in peanut allergies is cause for concern, with around 2% of children in the UK affected. Although it most commonly occurs in early childhood, it can develop later in life, and only an estimated 1 in 5 children outgrow their allergies.
For the US, peanut allergies affect around 1.2% of the total population. The statement from Allergy Therapeutics suggests that 1 in 4 children with a peanut allergy require a hospital visit every year. Manuel Llobet, CEO of Allergy Therapeutics, describes the “increasing prevalence” of this “potentially life-threatening reaction”, calling for solutions “now more than ever”.
“We need better treatment options beyond the current approaches that require repeated and long-lasting exposure, therefore limiting patient adherence, and not providing sustained protection after stopping treatment.”
PROTECT
The open label phase of the PROTECT trial has demonstrated a “strongly reduced skin testing reactivity” of VLP peanut compared to a peanut extract, enabling the team to move to the second part of Phase I. This involves healthy subjects receiving doses of the candidate.
The vaccine candidate uses novel virus-like particle (VLP) technology to enhance the body’s immune response by likening the peanut allergen to an inactive virus. It is based on immunologically optimised cucumber mosaic virus derived VLPs with the major peanut allergen (Arachis hypogaea) displayed on the surface. Allergy Therapeutics states that this is a “step change” in allergy treatment.
“This engineered, plant-based virus, is designed for enhanced safety and provides a platform to induce protective antibodies without replicating or infecting human cells, similar to classic vaccination.”
For the growing number of people who experience a peanut allergy this could be a game changer.
Moderna announced in April 2023 that the mRNA-4157/V940, which had been granted BTD by the US FDA in February 2023, has been awarded Priority Medicines (PRIME) scheme designation by the EMA. The investigational personalised mRNA cancer vaccine is intended for combination use with Merck’s KEYTRUDA, an anti-PD-1 therapy. This combination treats patients with high-risk stage II/IV melanoma after complete resection.
Positive results lead to PRIME designation
As we reported in December 2022, Moderna and Merck shared positive results from a Phase IIb trial. The combination therapy demonstrated a “statistically significant and clinically meaningful improvement” on KEYTRUDA alone. As a result, the FDA granted Breakthrough Therapy Designation in February 2023.
PRIME is a mechanism by the EMA to provide support for medicines that target an unmet medical need. This support is described by Moderna as “early and proactive”, to optimise the generation of “robust data” and “speed up the development” of the medicine. The next steps will be discussions of the data with regulatory authorities and a plan to initiate a Phase III study this year.
Potential promise
Dr Stephen Hoge is Moderna’s President. He described the “high unmet need for therapies in melanoma”, which “can be a life-threatening condition” in which current therapies “may not be sufficiently effective” for many patients.
“PRIME scheme designation for mRNA-4157/V940 in combination with KEYTRUDA highlights the potential promise of individualised cancer treatments in a population with limited alternatives.”
Dr Eric H. Rubin, Senior Vice President, global clinical development, at Merck Research Laboratories, agrees that the “milestone underscores the potential” for “personalised approaches” to contribute to the improvement of outcomes for people with “certain types of melanoma”.
“We look forward to working with the EMA, in collaboration with Moderna, to advance our clinical development programme.”
Join us at the World Vaccine Congress in Europe this year for more on cancer and immunotherapy vaccine approaches.
In March 2023, Vaccitech announced top-line interim data from a Phase Ib/II clinical trial of its VTP-200 vaccine in women with low-grade cervical human papillomavirus (HPV) lesions. The vaccine is intended to treat HPV infections, catching them before the virus causes high-grade lesions. The data was described as a “promising step” with more to come in early 2024.
HPV
Vaccitech states that an estimated 291 million women across the world are “carriers” of HPV DNA. Persistent genital HPV infection is “responsible for almost all cases of cervical pre-cancerous lesions”, which can lead to cervical carcinoma.
“Over 95% of cervical cancers are caused by HPV infection.”
WHO indicates that the two most common “high-risk” genotypes cause around 70% of all cervical cancerrs.
“HPV was estimated to cause almost half a million cases and 250,000 deaths from cervical cancer in 2002.”
Although there are two prophylactic vaccines against HPV, it continues to cause problems globally.
HPV001 and VTP-200
HPV001 is a fully-enrolled, randomised, placebo-controlled multi-centre trial to evaluate the safety, efficacy, and immunogenicity of VTP-200. The study consists of an “open label, non-randomised, dose escalation lead-in phase of 9 participants”. This is followed by a “blinded, randomised main phase of approximately 96 participants with high-risk HPV”.
VTP-200 is a “investigational heterologous prime boost immunotherapy” comprising an initial dose using the ChAdOx vector and a second dose using MVA. Both encode the same HPV antigens to elicit an immune response to HPV.
Promising data
Data from the first 58 women enrolled who reached their 6-month timepoint in the study were reviewed with the trial expected to continue as planned to the 12-month endpoint. Immunogenicity results showed “high responses”. This was defined by Vaccitech as an “average greater than 1,000 spot-forming units per million peripheral blood mononuclear cells in an ELISPOT assay”.
VTP-200 was “generally well-tolerated”. Bill Enright, CEO of Vaccitech, described the data as a “promising step in the right direction”, stating that he looks forward to final data next year”.
“Currently people with persistent HPV infection have no treatment options until they develop high grade lesions.”
Enright referred to repeat cervical screening without a treatment option as a “frustrating and anxiety-provoking” approach.
We look forward to hearing more from Vaccitech at the World Vaccine Congress in Washington. If you would like to join us, get your tickets here.
With just weeks to go until the World Vaccine Congress in Washington this April, we are delighted to share another in our series of exclusive interviews with some of the fantastic speakers lined up for the event. This interview was a zoom conversation with Dr Niranjan Sardesai, founder, President, and CEO of Geneos Therapeutics. Our conversation explored the work that Dr Sardesai and his team and doing in developing personalised cancer vaccines, and how this interacts with research happening in the infectious disease area. A full transcript can be found at the bottom of the page. We hope you enjoy it!
Geneos at a glance
Our first question aims to provide a bit of context to Dr Sardesai’s work and his presence at the Congress. He describes Geneos as a “clinical stage immuno-oncology company” that is developing “exquisitely personalised cancer vaccines” based on its GT-Epic platform and importantly, one that is already seeing dramatic tumour reductions in clinical trials.
How does Geneos approach cancer vaccines?
Dr Sardesai uses the term “exquisitely personalised” in his previous answer, and we were curious about how Geneos is pursuing this goal. For Dr Sardesai, “these are really exciting times for the cancer vaccines field”. Although the understanding of the immune system’s response to tumours is “not a new finding”, the challenge has “always been” encouraging this in more patients.
The approach that Geneos is taking is a “holistic view”. The team wanted to identify the tumour-specific antigens, to develop the right immunity to those antigens, and to understand the “ideal clinical settings”. Thus, the concept of the personalised vaccine, “truly tumour derived from each patient”, was developed. The mutations in tumours are twofold; not only do they enable the cancer to “avoid the immune system”, but they can act as the “Achilles heel of the tumour”, marking the cells to the host immune system.
“So what we’re trying to do is exploit those differences in the cancer cell and because these differences are idiosyncratic, they’re different from each patient to patient. The products that are designed based on these differences necessarily have to be personalised.”
The “core” of the GT-Epic platform is understanding and identifying the unique makeup of each patient’s cancer cell, developing their personalised vaccine, and then treating the patient.
What challenges do these vaccines bring?
From the sounds of it, developing personalised cancer vaccines is not a simple process, so we asked for a bit of a rundown of some of the key challenges that Dr Sardesai and his team encounter. This is a “really fundamental question for the field”, says Dr Sardesai. He suggests that because the technology to identify changes in tumours has been developed through “tremendous improvements in sequencing capabilities”, we are in the “golden age of genomics and bioinformatics”. As such, “external developments” in the wider vaccine space are enabling solutions in the cancer vaccine arena.
“I feel like this is the right time and the right place for cancer vaccines, personalised cancer vaccines, because some of the key technological hurdles around identification have been addressed by the field as a whole. So we’re certainly grateful for that.”
However, for each patient there can be “hundreds of somatic changes”. Consequently, identifying “targetable neoantigens” presents another challenge. Among the community Dr Sardesai identifies “different methods” for identifying these, but for him and his team, the lesson they are taking forward is that “targeting more” of these neoantigens is “going to be preferable”.
“Geneos is taking the approach that we identify all targetable mutations, and we incorporate all of them into our tumour vaccines and let nature make the call.”
Dr Sardesai states that lessons from natural immunity show that the immune system is capable of “driving responses to a large range of immunogens” every day. Thus, the team at Geneos puts the “decision-making process” in the hands of the individual immune system. Another challenge is that “patients and the tumours are certainly not waiting around” for treatments to be developed.
“Speed is of the essence.”
Therefore, a challenge is keeping down the turnaround times from biopsy to treatment. With their DNA-based platform, Dr Sardesai and colleagues have already shrunk this to 6-8 weeks. However, they “know” they can do it in under 4 weeks. This is where a clinical development aspect comes into play, because “sometimes clinical development decisions are made based on the capabilities of the platform”. For example, if a platform has a long turnaround time, it may not be applicable to certain types of cancer or treatment settings.
“What Geneos has done is we’ve shown that we are treating patients with bulky tumours.
So far, results from the field are exciting, showing that personalised cancer vaccines can work in earlier stage cancers to “prevent recurrence.” Perhaps even more dramatic is that Geneos has shown that it can reduce – and even eradicate – bulky tumours and their metastases in patients with advanced cancer. These clinical results have led to the planning of a potentially registrational clinical trial.
Infectious diseases and cancer therapy
For many of our speakers who are not directly engaged in infectious disease research, the field has had implications for their work, whether in terms of COVID-19 disruptions or accelerated technological developments. We asked Dr Sardesai about the interplay between his work and infectious diseases. Interestingly, Dr Sardesai entered the field “from the infectious disease side” and he identifies a “phenomenal impact” on the approach he is taking to cancer vaccines.
A key similarity is the notion of central tolerance. Simply put, years (and years) of evolution have developed an immune system capable of “identifying what is self from foreign”. Although we do experience certain auto-immune diseases, in general, the immune system is fairly confident in making these distinctions. This has been “exploited fundamentally” in infectious disease research, and the cancer field can learn from this by seeing the link between “what is it that drives immunity” and tailoring the immunity to the pathogen.
In cancer, the tumour neoantigens are “non-self”, so Dr Sardesai suggests that “just as we think of viral antigens and bacterial antigens as foreign”, these neoantigens can be perceived as “foreign”. However, for infectious diseases the aim is usually prevention, and in Dr Sardesai’s work the goal is therapy.
As he identifies lessons he has learnt from infectious diseases, Dr Sardesai also hopes to share insights the other way. For example, with recent COVID-19 vaccines, they were “very, very effective” in terms of antibody responses, but “it’s been challenging to do clearance because of lack of T cell immunity”.
“So what we love about the idea is that I think we started out from the infectious disease, we all learnt a lot, what we learnt through developing cancer vaccines is what drives effective cellular immunity, which can then go back into developing better infectious disease vaccines.”
We also like the idea of interaction between the different areas of vaccine development, and this leads us nicely into our final question!
Why the World Vaccine Congress?
We love to understand more from our speakers when it comes to what brings them to the Congress. Dr Sardesai puts it perfectly when he says that it’s been organised to cover “all things vaccines”! This means that “concurrent sessions” will cover every aspect of vaccine development and deployment. In particular, he’s looking forward to the regulatory tracks because “these developments that are going on are happening in real time”.
“I’m looking forward to…being able to interact with colleagues across different silos.”
We really enjoyed this conversation with Dr Sardesai and hope you did too. If you would like to hear more on his work, join us at the World Vaccine Congress this April. To read the full transcript, see below!
In March 2023, RVAC Medicines and the University of Pennsylvania (Penn) announced a collaboration to pursue the development of mRNA vaccines to “modulate the body’s normal immune response as possible treatments” for “certain autoimmune diseases and allergic conditions”. The focus will be on potential vaccines for food allergies and selected autoimmune indications.
Unmet medical needs
A statement from RVAC indicates that autoimmune diseases and allergic reactions or conditions comprise “rising unmet needs” that require “more treatment options” for patients across the globe. Autoimmune diseases occur when the immune system becomes “oversensitive” to harmless proteins and triggers an attack on the body itself.
The US NIH “more than 80 autoimmune diseases”, some of which are well known, and others that are “rare and difficult to diagnose”. Many have “no cure”. RVAC suggests that these diseases have “risen steadily in recent years”. Indeed, an average annual increase of 3% to 9% represents a “growing global health concern”. Allergic reactions or conditions are caused by the immune system being triggered against a “harmless allergen” such as foods or animals.
Addressing these needs
In response to the needs identified above, Dr Drew Weissman of the Perelman School of Medicine at Penn is bringing his team to a collaboration with RVAC to “develop and optimise mRNA vaccine candidates”. The goal is to “induce immune tolerance, thereby reducing the chances of autoimmune responses”.
Dr Weissman describes allergic reactions and “inappropriate autoimmune responses” as “difficult and restrictive” conditions in people’s lives.
“We are excited to begin this collaboration for certain conditions that currently have imperfect and incomplete therapies.”
Dr Sean Fu, CEO of RVAC, is also excited, calling Dr Weissman a “pioneer in the field”.
“With this collaboration, we want to develop mRNA vaccine product candidates with the potential to improve lives of patients who suffer from certain autoimmune diseases and allergies.”
Dr Jason Zhang is RVAC’s Chief Scientific Officer and is “very glad” to work with Dr Weissman for a “broad spectrum” of conditions.
“This collaboration will apply the mRNA technologies to induce antigen-specific immune tolerances, and RVAC is committed to becoming a leader in this field.”
For more detail on the myriad possibilities presented by mRNA approaches, join us at the World Vaccine Congress in Washington this April. Dr Drew Weissman and his lab have been shortlisted for a VIE award at the Congress. To view the lists for each category click here!
Researchers in France published a paper in Nature Communications in March 2023 detailing the results of an investigation into their Lassa fever vaccine candidate. MeV-NP was described in 2021 as providing “sufficient” protection against Lassa fever with just a single dose, between 1 month and 1 year after vaccination.
However, the authors note that due to a “limited dissemination area during outbreaks” and the risks of “nosocomial transmission” it would be useful to develop exposed patients during outbreaks. Thus, in the paper they tested if the “time to protection” could be reduced. Results suggest that although MeV-NP can “induce a rapid protective immune response” against Lassa fever, it “can likely not be used as a therapeutic vaccine”.
Lassa fever
The study recognises that Lassa fever, caused by the arenavirus LASV, is a “major public health issue in West Africa” resulting in “thousands of deaths each year”. Unfortunately, “low specificity of early symptoms” means that most cases are confirmed at an “advanced stage”. Thus, there is an “urgent need” for the development of both an effective vaccine and suitable treatments.
In our post on the recent cases in Accra, Ghana, we noted that there are a few collaborations in place to develop vaccine candidates, with WHO ranking Lassa fever in its top priority list of diseases requiring urgent vaccine development. WHO’s target product profile (TPP) for this vaccine demands that it should be safe for all age groups, an ideally confer lasting immunity after a single immunisation.
The authors of the study acknowledge that a “preventative vaccine is preferred over an emergency vaccine” but suggest that the latter would still be “highly valuable” in reducing community or hospital outbreaks.
MeV-NP
The vaccine candidate is a recombinant measles virus (MEV) expressing LASV GP and NP of the “prototypic Josiah strain”.
“To improve the immunogenicity of the measles backbone, the vaccine was further engineered to abolish the IFN-antagonist activity of NP.”
Previous research demonstrated that a single shot protected cynomolgus monkeys against the disease, conferring cross-protection against “strains from distant lineages II and VII”, and inducing “long-term immunity”. However, a concern about use in the human population is the “pre-existing immunity against MeV”, which could potentially affect the efficacy of the candidate.
The study explores efficacy, suggesting that the vaccine “fully protects MeV pre-immune cynomolgus monkeys” between 16 to 8 days prior to “lethal infection”.
“This is particularly interesting, as most LASV outbreaks are limited to geographical clusters, for which infected rodents are the amin source of viral dissemination in the human population.”
Thus, a vaccine “capable of rapid protection of an exposed population in an outbreak setting would be highly beneficial”.
The authors note that MeV-NP conferred “comparable protection” in animals that were “naive or pre-immune to MEV”, which supports “no effect of the MeV pre-existing immunity” on its efficacy.
Although this reduced time span is a positive outcome, the vaccine “does not demonstrate therapeutic efficacy in animals vaccinated after challenge”.
“Innate or adaptive immune responses against the MeV vector do not help controlling LASV replication, at least in a therapeutic setup”.
The study shows the efficacy of the vaccine with a “short time to protection” despite this the lack of therapeutic benefit, which offers the possibility of vaccination during an outbreak.
For more on Lassa fever and other disease that particularly affect that African continent, join us for a session with Dr Daniel Bausch at the World Vaccine Congress in Washington next month.
Following positive results from a Phase IIb trial in December 2022, Moderna and Merck have announced that their personalised mRNA cancer vaccine, in combination with KEYTRUDA, has been granted Breakthrough Therapy Designation by the FDA. In a statement in February 2023, the companies stated “excitement” at the “potential promise of individualised cancer treatments”.
A new frontier
As we noted in December, the Phase IIb trial, KEYNOTE-942, produced positive data. The trial enrolled 157 patients with stage III/IV melanoma and compared mRNA-4157/V940 and KEYTRUDA therapy with KEYTRDUA alone for one year.
Dr Stephen Hoge, Moderna’s President, described the trial as “the first demonstration of efficacy for an investigational mRNA cancer treatment”, which “potentially represents a new frontier in treating melanoma and other cancers”.
“We look forward to publishing the full data set and sharing the results at an upcoming oncology medical conference, as well as continuing discussions with health authorities. We are grateful to the FDA for this designation.”
Breakthrough Therapy Designation
The FDA’s Breakthrough Therapy Designation is intended to “expedite the development and review” of candidates for serious conditions where “preliminary clinical evidence indicates that the product may demonstrate substantial improvement over available therapies on at least one clinically significant endpoint”.
Both companies will continue working with regulatory authorities and initiate a Phase III study with a view to expanding to additional tumour types.
Dr Eric H. Rubin, Senior Vice President, Global Clinical Development, Merck Research Laboratories, stated that this was an “important milestone” for the project”.
“We look forward to working with the FDA, in collaboration with Moderna, to conduct a rigorous and rapid clinical development programme with a focus on addressing the needs of this important patient population”.
For more from Moderna and Merck and specific tracks devoted to cancer vaccine development, join us at the World Vaccine Congress in Washington this April.
In February 2023 Scancell announced completion of a monotherapy dose finding arm of the Phase I/II ModiFY clinical trial. Data demonstrated that the Modi-1 cancer vaccine was “safe and well tolerated” with “encouraging early efficacy” in a head and neck cancer patient.
Modi-1 in trial
Modi-1 is the first candidate from Scancell’s Moditope platform and targets four different types of cancer: HGSOC, TNBC, head and neck squamous cell carcinoma (SCCHN) and renal cell carcinoma (RCC). The Modi-1 peptides are linked to AMPLIVANT, an adjuvant from ISA Pharmaceuticals.
Modi-1 is intended to stimulate CD4 T cells, which may “directly impact tumour growth”. For some patients, however, these T cells “may need to be protected by CPIs if the tumour environment is highly immunosuppressive”.
The ModiFY trial is an “open-label, multicohort, multicentre, adaptive” trial of Modi-1 in patients with “unresectable HGSOC, SCCHN, TNBC, or RCC”. Patients are treated with Modi-1 or Modi-1 and a CPI. Scancell reports that a total of 23 patients have been vaccinated, with 55 doses administered. All had “skin reactions” at the site of injection “consistent with a delayed-type hypersensitivity (DTH) reaction”. This indicates a T cell response.
The first study cohort confirmed the safety profile and the objective for Cohort 2 was to “assess the safety of the two citrullinated vimentin peptides plus an enolase peptide at a higher dose”. Following safety data from the second cohort, the trial was expanded for Modi-1 monotherapy in all four tumour types.
Encouraging data
Dr David Pinato, Principal Investigator at Imperial College, described advanced ovarian cancer as “aggressive” and “hard to treat”.
“The early efficacy data showing that the Modi-1 vaccine is stabilising this advanced disease is very encouraging.”
Professor Christian Ottensmeier, Chief Investigator at the University of Liverpool, believes that “this therapeutic cancer vaccine could have significant potential”.
“Further studies with Modi-1 monotherapy and in combination with CPIs should tell us in which settings it will have maximum benefit to patients.”
Professor Lindy Durrant, CEO at Scancell, is “highly encouraged with the early efficacy data”.
“These results allow us to proceed with the monotherapy expansion cohorts and into the cohorts in combination with checkpoint inhibitors as planned.”
For more on cancer therapy and different vaccination approaches at the World Vaccine Congress in Washington this April get your tickets today.
In February 2023 Gritstone bio and the National Cancer Institute (NCI) of NIH announced a collaboration to evaluate an “autologous T cell therapy expressing a T cell receptor targeting mutated KRAS in combination with Gritstone’s KRAS-directed vaccine candidate”. The Phase I study will be led by Dr Steven A Rosenberg of the NCI’s Centre for Cancer Research.
Combination therapy
The vaccine candidate, SLATE-KRAS, is an “off the shelf” neoantigen vaccine that “demonstrated early evidence of efficacy” in an ongoing study. Based on these results, Gritstone is initiating a separate, randomised study evaluating SLATE against a KRAS mutation driven tumour type.
Through this agreement, NCI will identify patients with metastatic cancer who are eligible for adoptive cell transfer “based on the presence of a G12V or G12D KRAS mutation”. Gritstone will provide the vaccine for the trial.
Dr Andrew Allen, Co-founder, President, and CEO of Gritstone bio is “privileged to establish this collaboration”.
“To date, cell therapy’s success in treating blood cancers has not translated to the more common solid tumours. There is a mechanistic synergy in having cell therapy and cancer vaccines in combination.”
Dr Allen is “thrilled” to test the programme in patients and looks forward to a “promising study”.
A rational approach
Dr Karin Jooss, Executive Vice President and Head of R&D at Gritstone bio described the “use of neoantigen vaccines to enhance the potency of neoantigen-directed T cell therapy” as an “attractive concept”. The KRAS-directed vaccine has a demonstrated ability to ‘induce and expand KRAS mutation-specific T cells” and “drive them into solid tumours”.
“Combining this modality with autologous KRAS mutation-specific TCR transduced T cells…is a rational approach to augmenting therapeutic efficacy”.
We look forward to hearing more on efforts towards cancer vaccines from Dr Andrew Allen at the World Vaccine Congress this April. To join us there get your tickets today.
In February 2023 VBI Vaccines announced interim data from a Phase II study evaluating a combination treatment of VBI-2601 (BRII-179) and BRII-835 (VIR-2218) in chronically infected HBV patients. The data demonstrates that the therapy was “generally well-tolerated”. It also “restored strong anti-HBsAg antibody responses and led to improved HBsAg-specific T-cell responses, when compared to BRII-835 alone”.
VBI-2601
VBI-2601 is a “novel recombinant, protein-based HBV immunotherapeutic candidate”. VBI states that it “builds upon the 3-antigen conformation of VBI’s prophylactic 3-antigen HBV vaccine candidate” and is intended to treat enhanced B-cell and T-cell immunity.
The trial
The Phase II study is a randomised, multi-centre trial across sites in Australia, Taiwan, Hong Kong, South Korea, New Zealand, Singapore, and Thailand. It is sponsored by VBI’s partner Brii Biosciences.
Interim data were generated from 50 adult, non-cirrhotic patients who received “nucleos(t)ide reverse transcriptase inhibitor (NRTI) therapy” for at least 12 months. They were randomised and dosed across three cohorts:
BRII-835 Alone Regimen – Nine subcutaneous 100mg doses of BRII-835, dosed every four (4) weeks through Week 32
BRII-835 Alone Regimen + nine 40µg intramuscular doses of VBI-2601 admixed with interferon-alpha (IFN-α) as co-adjuvant every four weeks from Week 8 through Week 40
BRII-835 Alone Regimen + nine 40µg intramuscular doses of VBI-2601 without IFN-α every four weeks from Week 8 through Week 40
Novel combinations
Dr Francisco Diaz-Mitoma, VBI’s Chief Medical Officer, stated that “numerous studies” have already assessed the potential of siRNA candidates in HBV patients, but this is the “first time we’ve seen data from the combination of an HBV siRNA with an HBV-specific immunomodulator”.
“We are very encouraged by these interim data, which suggest that the combination…has the potential to be a meaningful part of a functional cure regimen.”
Further data are expected “later this year”. For more on the challenges associated with the development of HBV therapies, read our interview with Dr Andrew Vaillant here.
We will hear more about HBV approaches at the World Vaccine Congress in Washington this April. Join us there by getting your tickets now!
In research published in Nature biomedical engineering a team of scientists at Northwestern University’s International Institute for Nanotechnology (IIN) explored the effects of structural changes to cancer vaccines. Using chemistry and nanotechnology they changed the location of adjuvants and antigens on and within a nanoscale vaccine with positive consequences.
The team used spherical nucleic acid (SNA) nanoparticles to “investigate how the spatial distribution and placement of two antigen classes affect antigen processing, cytokine production, and the induction of memory”. Their conclusion is that “the structural design of multi-antigen vaccines substantially impacts their efficacy”.
Current vaccine approaches
News Medical describes the “conventional” vaccine approach as a blend of antigen and adjuvant, which is then injected into the patient. As there is “no control over the vaccine structure” there is “limited control over the trafficking and processing of the vaccine components”. Thus, we can’t control the efficacy of the vaccine.
Dr Michelle Teplensky, one of the study authors, suggests that a “challenge” associated with this “blended mish mosh” approach is that “an immune cell might pick up 50 antigens and 1 adjuvant or 1 antigen and 50 adjuvants”. However, there “must be an optimum ratio of each that would maximise the vaccine’s effectiveness”.
The study indicates that “increasing efforts have been made to develop vaccines targeting identified tumour-associated proteins”. However, although there are “some benefits” to these, “many are designed to primarily activate cytotoxic T cells”.
“Tumour can have considerable heterogeneity and high mutational burdens that allow for easy escape of immune surveillance.”
With cytotoxic T cell activity reliance, current vaccines are “inadequate” and necessitate “vaccines containing antigens targeting multiple immune cell types to induce enhance tumour remission”. Dr Teplensky emphasises that the “more types of cells the immune system has to go after tumours, the better”.
What are they changing?
SNAs, a structural platform developed by Professor Chad Mirkin, Director of the IIN, enable scientists to identify the specific quantities of antigens and adjuvants being delivered to cells, as well as how they are being presented and processed. This novel approach, “rational vaccinology” as Professor Mirkin calls it, recognises that the structural presentation of a vaccine is just as important as its contents.
Professor Mirkin suggests that rational vaccinology allows vaccines to “deliver the precise dose of antigen and adjuvant to every immune cell” so that they are “all equally primed to attack cancer cells”.
“If your immune cells are soldiers, a traditional vaccine leaves some unarmed; our vaccine arms them all with a powerful weapon with which to kill cancer.”
In the study, the authors explore the “vaccine-design space involving multiple cell-targeting antigens.” The vaccines they investigated respond to specific structural placements of antigen targets to “prime the immune system most effectively”. The most potent approach for a cancer vaccine structure in this work involved attaching two different antigens to an SNA comprising a shell of adjuvant. This resulted in a 30% increase in antigen-specific T cell activation. In several animal models the nanostructures stalled tumour growth.
What will this mean for the future?
The authors state that the power to “optimise antigen presentation” to meet the “desired signalling profile” will be “critical” to the future of powerful vaccines. They hope that the developments in their study will offer a “path forward to rethink the design of vaccines for cancer and other diseases”.
With “remarkable” data, they produced a potent vaccine with the same compositional features as a less effective vaccine. However, their success may not be limited to cancer. Another possible advantage to rational vaccinology is the ability to change the vaccine to apply to a different disease. Dr Teplensky hopes that their work affords potential for “almost any type of cancer” and “vaccines across the board”.
We look forward to hearing more updates on cancer vaccine progress at the World Vaccine Congress in Washington later this year, and more positive stories from our vaccine community in the meantime.
Swiss based AC Immune reported in January 2023 that ACI-24.060, its anti-amyloid-beta (Abeta) vaccine, had “elicited an anti-Abeta antibody response” and was “well tolerated” in patients with prodromal Alzheimer’s disease (AD). It will therefore move to a second cohort in the ABATE trial.
ABATE
The trial is a Phase Ib/II multicentre, adaptive, double-blind, randomised, placebo-controlled study to assess the “safety, tolerability, immunogenicity, and pharmacodynamic effects” of the vaccine candidate ACI-24.060 in subjects “with prodromal Alzheimer’s disease and in adults with Down syndrome”. Participants were required to have brain Abeta pathology confirmed by a positron emission tomography (PET) scan.
The trial will now be “expanded, as planned” to include individuals with Down syndrome and to “evaluate higher doses in Alzheimer’s patients”. Early results showed that a low dose of the vaccine could elicit an anti-Abeta antibody response “as soon as week 6”, which is 2 weeks after the second injection.
ACI-24.060
ACI-24.060 is “derived from AC Immune’s SupraAntigen platform” and has already demonstrated an ability to “induce a strong polyclonal antibody response that matures and is maintained against both oligomeric and pyroglutamate-Abeta species”. These are “key pathological forms of Abeta”, associated with Abeta plaque formation and disease progression.
The vaccine is designed to “enhance the formation of broad-spectrum protective antibodies” with the “same safety and tolerability previously demonstrated” in the ACI-24 programme.
“This investigational candidate has the potential to efficiently inhibit plaque formation and increase plaque clearance, and thereby may reduce or prevent disease progression.”
An approved approach
AC Immune states that “targeting Abeta using antibodies has recently been validated with FDA approvals of new monoclonal antibody treatments for patients with AD”. The vaccine programme is intended to “ultimately deliver significant benefits to patients, their caregivers, and healthcare systems”. With “safety and tolerability” meeting “low frequency dosing, low overall costs, and durable responses” it is hoped that this could become a reality.
Dr Andrea Pfeifer, CEO of AC Immune SA is “delighted with the encouraging initial safety and immunogenicity findings”.
“We believe ACI-24.060’s successful development could provide patients with a novel therapeutic option offering numerous potential advantages in treatment, maintenance, and prevention settings.”
Dr Johannes Streffer, CMO of AC Immune SA, suggested that the “innovative” design of the study with provide an opportunity for “early de-risking”.
“Moreover, the inclusion of cohorts of participants with DS in the trial positions us to potentially address the needs of a vastly underserved vulnerable population, virtually all of whom will develop amyloid plaques and AD.”
He thanked trial participants and investigators for their continued efforts.
For more on vaccines against dementia read our previous post here. To learn more about potential vaccine therapies and technologies and the World Vaccine Congress in Washington get your tickets now.
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