As we gear up towards the World Vaccine and Immunotherapy Congress in San Diego later this month we have been meeting a few of our speakers to get some exclusive insights before their sessions. Dr Stephen Johnston will be representing Calviri Inc. as founding CEO. With almost 200 peer-reviewed papers and 45 patents, as well as teaching positions, his time is precious, so we were very lucky to secure a moment for a zoom interview.
Introducing Dr Johnston
Dr Johnston kindly gave us an overview of Calviri’s work, developing vaccines and diagnostics for cancer.
What can we expect at the Congress?
Although we want to save the best for the Congress, we asked Dr Johnston for a quick preview of some of the content. He explained that he will be trying to encourage his colleagues to accept a “different perspective” on cancer vaccines. He believes they can be “simpler”, less “complicated”, and “less expensive”.
What changes does Calviri Inc. hope to bring to the field?
Anyone who might be familiar with Calviri’s website will know that “outdated” isn’t the strongest term used to describe current approaches to cancer. Dr Johnston acknowledges that this might be a bit “incendiary” but suggests that it’s how he sees it. With “50 years” and “2 Moon Shots“, there “isn’t much to show” for the hard work that has been done. Furthermore, the progress that has been made is inaccessible to people who need it most.
“People sometimes forget that of the 10 million cancer deaths a year, about 7 million of those occur in the developing countries”.
For Dr Johnston and his team, the first key strategy is “early detection”, which leads to higher cure and longer survival rates. Next, they hope to pair this with a “simple, safe, systemic” treatment – a vaccine in their case. Targeting the major cancers, they are creating off-the-shelf solutions.
In a lot of our previous posts we have explored some of the challenges associated with cancer vaccine development. For Dr Johnston, the main issue is targeting key “components” in the make-up of the cancer. He suggests that until now the “community thought that that wasn’t possible” because they were looking at DNA, instead of RNA. Thus, Calviri’s new approach takes on the RNA components that are shared across patients and even tumour types.
How do you keep people motivated?
Our next question reflects the longevity of cancer and the difficulty we have had in developing therapies and preventative measures so far. Dr Johnston suggests that instead of accepting the idea that it is impossible, his team are investigating whether their technology can be applied to cancer prevention.
“Could you design a vaccine to give to people, so that they don’t get it in the first place?”
They have shown in a study in 800 dogs that it is possible to prevent cancer, and so they hope to take this to the next stage in human prevention. The trial in dogs was the “largest” trial in dogs that has ever run, and Dr Johnston believes that after this challenge, humans are “probably easier”.
Accessibility in mind
Dr Johnston mentioned earlier in the interview that accessibility has a huge influence on his work. When we asked more about this, he stated that the team had set goals to meet in terms of production costs, in order to keep the vaccine affordable. They are “quite confident” that this can be done; Dr Johnston emphasises this by suggesting that if dogs can be easily vaccinated then the vaccine can be administered in developing areas. Not only that, but he expects it do be done “profitably”.
Looking forward to the Congress
Our final question gets to the bottom of Dr Johnston’s attendance at the Congress later this month, apart from the importance of sharing his work with others! He explained that he is “open” to hearing from people with platforms that he and his team could use. Having spoken to a few colleagues already, he is looking forward to meeting in person to further the conversation. Finally, he is testing the waters of the cancer community. Previously it has been “rutted” and “stovepiped” so this will be an opportunity to see how imaginative people are prepared to be in the future!
We are grateful for Dr Johnston’s time, particularly so close to the Thanksgiving holiday. If you are curious about his work and want to learn more at the Congress, get your tickets now.
In November 2022 the results of the AELIX-002 trial were published in Nature by collaborators from Aelix Therapeutics and Gilead Sciences. This is the trial that Dr Christian Brander, Co-founder and Chief Scientific Officer at Aelix Therapeutics, hinted at in our exclusive interview during the World Vaccine Congress in Barcelona 2022. Dr Brander is reportedly “excited” to have his team’s results recorded in a “prestigious journal” with a global reach.
The trial in context
The WHO reported that in 2021 38.4 million people were living with HIV. WHO’s strategy for 2022-2030 aims to “reduce HIV infections from 1.5 million in 2020 to 335,000 by 2030”. UNAIDS reports that 28.7 million people were accessing antiretroviral therapy in 2021.
The authors of the study note that therapeutic vaccines targeted to HIV-specific immunity have been “postulated to be a key component of any HIV cure strategy”. Despite the safety and immunogenicity of different candidates in trials, “no reduction in HIV-1 viral reservoirs, prevention of viral rebound, or suppressed viremia off ART have been reported” in trials such as this one.
A “potential reason” for previous “suboptimal trials outcomes” might be “T-cell immunogen designs and the induction of virus-specific T-cell responses with ineffective or insufficient antiviral activity”. In order to overcome this issue, HTI (HIVACAT T-cell immunogen)-based vaccines were designed to “induce functional HIV-1-specific T-cell responses that were associated with better viral control”.
The trial meets endpoints
The trial was a “double-blind, randomised, placebo-controlled trial” with the primary objective of safety evaluation. The secondary objectives “included T-cell immunogenicity, the effect on viral rebound, and the safety of an antiretroviral treatment interruption” (ATI). The study “demonstrated that HTI vaccines were safe, well-tolerated, and able to induce strong, polyfunctional, and broad CD4 and CD8 T-cell responses focused on the HTI immunogen sequence”.
“The AELIX-002 trial results support the idea that the induction of HIV-specific T-cells is a key factor in improving post-rebound viral suppression during an ATI, while validating the design of the HTI immunogen to induce functional T-cell responses to vulnerable sites of the virus”.
The authors believe that their findings “strongly support” the further use of HTI vaccines in “simpler regimens, given alone, or in combination”. A second study is also being conducted in collaboration with Gilead, according to Pipelinereview.com. Dr Brander remarked that the “T-cell vaccine approach has the potential to play a critical role in strategies to cure HIV infection”.
“AELIX is a leader in developing vaccine-based solutions for an HIV cure.”
For more on HIV strategies at the World Vaccine and Immunotherapy Congress get your tickets now.
As we look back on the Congress in Europe and forward to future events, a conversation with Dr Andrew Vaillant of Replicor links our event in Barcelona to the World Vaccine and Immunotherapy Congress in San Diego. As Chief Scientific Officer with 20 years’ experience, he has pioneered Replicor’s nucleic acid polymer (NAP) technology. With a focus on hepatitis B (HBV), his insight into therapeutic development is particularly interesting.
Unique challenges for HBV
We asked Dr Vaillant about the considerations that are required for HBV therapies, and he outlined several “unique challenges” for us. Firstly, the “production of a very large excess of non-infectious subviral particles (HBsAg)” hinders the immune response to HBV. Therefore, the processes involved in vaccine responses are also affected. A successful approach must “occur with the clearance of these particles”. The next challenge is that HBV “exists as a population of thousands of quasispecies all with varying immunoreactivities” as well as “immune escape potential”. Thus, vaccine candidates must “focus on engendering multiple different HBsAg-reactive T-cell species”.
As Replicor will be presenting at the World Vaccine and Immunotherapy Congress later this month, we asked for a sneak preview of what that might involve. Dr Vaillant graciously gave us an insight! He indicated that we can expected to learn more about “how the industry is faring in achieving” therapy milestones. On top of this, we will hear updates from Replicor’s access programme for REP 2139-Mg in “patients with chronic hepatitis B and D infection with very advanced liver disease”.
REP 2139-Mg may have caught your attention, and we heard it is “unique and industry-leading” so we wanted to find out why. It’s Replicor’s “lead drug in development for the treatment of chronic HBV and HDV infection”. It is unique in its ability to “directly” target non-infectious subviral particles.
“When combined with immunotherapy, REP 2139-Mg is achieving high rates of HBsAg loss and functional cure of both HBV and HDV infection. These are outcomes not achievable with currently approved therapies or with any other technologies currently in development.”
A wider lens
After we had asked Dr Vaillant to explain some of the finer points of Replicor’s work we took a broader approach. We asked about challenges that therapeutic developers are facing, and how they can be overcome. Dr Vaillant recognises that although Replicor is “not directly focused” on an HBV vaccine, a “properly designed therapeutic vaccine” would play an important role in “achieving functional cure of HBV”.
“With its unique platform of nucleic acid polymers (NAPs) such as REP 2139-Mg, Replicor is in a unique position to remove the immunoinhibitory HBsAg from patients to potentiate a vaccine response.”
In collaboration with vaccine companies, Replicor is pursuing suitable candidates to work “in combination” with REP 2139-Mg for “high rates of functional cure”. Technology evidently plays a huge role in Replicor’s work, but interestingly Dr Vaillant believes “all the technology needed is in place” already.
“We are focused on educating the field about how to use this technology to develop appropriately broadly HBsAg specific vaccines essential for functional cure of HBV.”
Disruptions and distractions
Our final question was on the issue of COVID-19, which has influenced the work of many of our speakers, whether direct or indirect. For Dr Vaillant, the pandemic “has taken the focus away from many diseases which also take millions of lives each year”.
“Chronic HBV infection is a disease which affects more than 300 million people worldwide and kills more than 1 million people each year. This death rate is rising due to the important and unmet medical need in this disease.”
Looking forward, Dr Vaillant hopes that “appropriate attention” will return to “other infectious diseases” like HBV and HDV, to “allow faster progress in the field”.
We are very grateful that Dr Vaillant took the time to answer some of our questions and to give us a preview of Replicor’s presentations at the World Vaccine and Immunotherapy Congress in November. We look forward to hearing more then and hope you will join us!
In a study published in JAMA Oncology in November 2022, researchers from America and Europe collaborated to demonstrate “clinically meaningful and statistically significant extension of survival” for patients with glioblastoma. The results are described as “astonishing” by Professor Keyoumars Ashkan, of King’s College Hospital in London. The team aim to “offer fresh hope to patients battling with glioblastoma”.
A deadly threat
The Brain Tumour Charitydescribes glioblastoma as the “most common high grade primary brain tumour in adults”. They are grade 4 brain tumours that are fast growing and likely to spread, and often return despite treatment. Brain Tumour Research suggests that they “almost never spread outside of the brain, spine, or central nervous system to other parts of the body”. They are also “complex”, making them harder to treat.
“The average survival time is devastatingly short.”
However, some patients survive longer than a year or up to 5 years, and the reasons for this are unknown. Current treatment options include surgery, radiotherapy, and chemotherapy. Unfortunately, the reported recurrence rate is nearly 100% and the study describes “dismal patient survival”.
A “fresh hope”
The study objective was to investigate whether adding the autologous tumour lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) results in extended survival among patients. It was a phase III, prospective, externally controlled nonrandomised trial that compared “overall survival” (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) with “contemporaneous matched external control patients treated with SOC.”
Conducted at 94 sites in 4 countries, the trial took place between August 2007 and November 2015, with data analysis in 2020/2021. 331 patients between the ages of 18 and 70 years were enrolled. Following surgery and a collection of tumour tissue for the vaccine manufacturing, patients received the vaccine or a placebo on days 0, 10, and 20, and then in months 2, 4, 8, 12, 18, 24, and 30 as well as “monthly temozolomide as SOC”.
“Each DCVax-L dose comprised 2.5 million DCs injected intradermally in the upper arm, alternating arms between treatment visits”.
The data suggest a “20% relative reduction in risk of death at any point in time for patients with nGBM” who are receiving the vaccine, and this benefit “increased over time”. Furthermore, for rGBM a 42% relative reduction is risk was indicated, with the benefit once again continuing over time.
Delivering the vaccine
Professor Ashkan describes the vaccine as a “personalised solution, working with the patient’s immune system, which is the most intelligent system known to man”. Although the vaccine is not yet available to patients on the NHS, the US company that manufactures it, Northwest Biotherapeutics, intends to seek approval.
Dr Karen Noble is Brain Tumour Research’s director of research, policy, and innovation. She states that this is the “first emerging therapy proven effective in treating glioblastoma since temozolomide chemotherapy in 2005”.
“What the brain tumour community hopes is for it to become affordable, possibly becoming standard of care – so available on the NHS.”
For Dr Henry Stennett of Cancer Research UK, this is “particularly exciting” because it can “improve outcomes for people who don’t usually respond well to therapy.” Although “stringent regulatory” steps need to be taken, it is a “big step forward”.
We expect to hear more about other updates in developing a glioblastoma therapeutic vaccine at the World Vaccine and Immunotherapy Congress in San Diego later this month. To join us there, get your tickets now.
A study by researchers led by the University of Houston demonstrates potential to eliminate the high caused by the synthetic opioid fentanyl. The hope that it will block its ability to enter the brain has positive implications for tackling a widespread opioid epidemic. Although Opioid Use Disorder (OUD) is treatable, up to 80% of patients with a dependency on the drug experience a relapse. The publication in Pharmaceutics states that the data support “further clinical development of [the] vaccine to address OUD in humans”.
An opioid epidemic
The authors reflect in their publication that a “significant public health crisis” has been caused by “illicit synthetic opioid use”. Between 2019 and 2020 overdose deaths in the US increased to the “highest ever recorded” at 81,000, and more recent statistics are “even higher”. So, what is driving this?
“Fentanyl (FEN) is a synthetic opioid agonist that is approximately 100 times more potent than morphine.”
It is “decidedly lipophilic” and quickly enters the central nervous system, activating mesocorticolimbic circuitry to produce “highly reinforcing euphoria”. The study reports that in the early 2000s there was a significant rise in overdose deaths. This showed that “FEN and its derivatives adulterated other misused substances that led to increased lethality”. Furthermore, between 2010 and 2016 more than 50% of stimulant-related overdose deaths involved it.
Current treatments are effective based on formulation, compliance, access, and the opioid in question; FEN is a “particular treatment challenge” because of its “pharmacodynamics”. This challenge can be addressed with immunotherapies that prevent FEN from entering the brain, thus “pre-emptively circumventing its reinforcing and overdose effects”.
With “poor medication compliance” OUD has almost 90% relapse rates. The authors believe that vaccine immunotherapy could address this by demanding a less intense administration schedule.
“Vaccine immunotherapy targets small molecule antigens such as opioid compounds consisting of the antigen (hapten) linked to an immunogenic carrier protein that stimulates the immune system to generate antibodies.”
An adjuvant is often added to increase immunogenicity. Then, post-vaccination, when an opioid is consumed, antibodies “prevent it from getting into the brain or affecting other organs”. This vaccine comprises a “FEN-like hapten containing a linker with a carboxyl moiety suitable for carbodiimide coupling chemistry to form amide bonds to lysine residues on the carrier protein CRM197, a genetically deactivated diphtheria toxin contained in several FDA-approved conjugate vaccines”.
The study in rats
The study involved 60 Sprague Dawley rats. 32 were used for the schedule-controlled responding experiments and 28 were used for the physiology experiment. FEN was then obtained, as well as morphine, and both were dissolved in sterile saline and administered subcutaneously.
The vaccine formulation was prepared “immediately before administration”. Animals were injected at 0, 3, and 6 weeks. Blood samples were then collected during weeks 4, 6, 8, and 10 post-initial vaccination.
The conclusion states that the vaccine “produced significant amounts of anti-FEN antibodies” in both sexes. It also reduced FEN entry into the brain. The results “warrant further development as a potential therapeutic for OUD and overdose in humans”, with minimal side effects expected.
Lead author Dr Colin Haile describes this study as having “significant impact”. The vaccine’s ability to prevent FEN from entering the brain will subsequently prevent “euphoric effects” and promote an easier road to “sobriety”. Furthermore, the anti-FEN antibodies “did not cross-react with other opioids”, meaning a vaccinated person would “still be able to be treated for pain relief with other opioids”. For Dr Therese Kosten, this vaccine could be a “game changer”.
For more on adjuvanted opioid vaccines at the World Vaccine Congress in Washington 2023 get your tickets now.
A study in JAMA Oncology in November 2022 suggests that researchers in the US are making progress with an experimental vaccine against breast cancer. Led by Dr Mary (Nora) L. Disis of the University of Washington Medicine Cancer Vaccine Institute, the team indicate success in Phase I clinical trials.
The WHO states that 2.3 million women were diagnosed with breast cancer in 2020. The NHS estimates that 1 in 8 women are diagnosed with the cancer throughout their lifetime. Many are over the age of 50, but not all. Only 1% of breast cancer diagnoses occur in male patients. Dr Kotryna Temcinaite of Breast Cancer Now told Medical News Today that it is not a “single disease, which makes it more difficult to treat”.
“There are many types of breast cancer and treatments that work well for some people, may not work as well for others.”
Calling for “kinder and smarter” treatments, she indicated the importance of “further research” into the disease. Dr Disis, lead author of the recent study, explained that current treatments often lead to “disease recurrence” when a small amount of cancer remains undetected. Thus, vaccines are required to fill the gap.
“Vaccines will stimulate t-cells which can be programmed to hunt down these last remaining cells in the body and kill them. Stimulating effective immunity is the only way I know we can sterilise the body from all breast cancer cells.”
UW’s Phase I trial
The trial was a nonrandomised clinical trial of 66 patients with “advanced-stage ERBB2-positive breast cancer”. Formally known as HER2, ERBB22 is a key tumour protein. High levels of ERBB2-specific type 1 T cells are “associated with favourable clinical outcomes after trastuzumab therapy”. Unfortunately, only a “minority of patients develop measurable ERBB2 immunity after treatment”.
The researchers determined to assess the safety and immunogenicity of 3 doses of a plasmid-based vaccine, which encoded the ERBB2 intracellular domain. Over two periods, 2012-2013, and 2021-2022, they collected and analysed data. The vaccine was “administered intradermally once a month” with “soluble granulocyte-macrophage colony-stimulating factor as an adjuvant for 3 immunisations”. Medical News Today reports that the most common side effects associated with the injection were flu-like symptoms and fatigue.
“Participants who received the higher vaccine doses of 100 μg and 500 μg demonstrated a stronger immune response than those who received the 10ug dose, but there was no significant difference between the immune responses to the 100ug and 500ug doses.”
The future of vaccines
Dr Disis hopes there is a “good chance” that we will see breast cancer vaccines in about 5 years. Many groups are “working on ‘next-gen’ vaccines with very effective delivery technologies and adjuvants” she says. However, this progress is not limited to breast cancer. A range of possibilities are being explored in Washington alone, with programmes including ovarian cancer, colon cancer, and prostate cancer.
For this vaccine, the next step is to “formally test” the observations of this study to see if it does “prevent disease recurrence”.
Another highlight from this year’s World Vaccine Congress in Europe was the opportunity to speak to Dr Christian Brander in person. Co-founder and Chief Scientific Officer at Aelix Therapeutics; he and his team are based in Spain, focusing on a therapeutic HIV vaccine. His presentation at the Congress explored some of Aelix Therapeutics’ recent results, and we were lucky to steal some of his time for a conversation.
Introducing Aelix Therapeutics
Dr Brander kindly explained who he is and what his current role is for those of us who are unfamiliar with the team at Aelix Therapeutics. He believes that his roles as Chief Scientific Officer and ICREA Research Professor complement each other and contribute to “recent success” in the clinical programme. Aelix Therapeutics is dedicated to the development of a therapeutic HIV vaccine for use in cure/eradication stages.
What did you bring to the Congress?
We asked more about Dr Brander’s showcase at the Congress, and he indicated that he was sharing limited data due to a paper embargo at Nature Medicine. Therefore, he was able to give insights into the safety and efficacy data from the recent 002 clinical trial, a “double blind placebo controlled” trial in patients whose infection was quickly identified and “immediately treated”.
How did you operate during COVID-19?
As ever, we were interested to learn how Aelix Therapeutics fared during the pandemic, and to what extent research was affected. Dr Brander suggested that “at the height of the COVID outbreak in Spain” Aelix Therapeutics conducted 002 and 003. Luckily, thanks to “corrective measures” such as home visits and early vaccinations, no participants were lost. Despite the “severe impact on day-to-day operations” the team pulled through. It is remarkable to hear from so many of our speakers how they were able to rise to the challenges presented by the pandemic.
Although COVID-19 presented a unique set of obstacles to the development of Aelix Therapeutics’ vaccine, T-cell vaccines bring their own challenges. For HIV infection, Dr Brander sees the need for a “combination approach”. This necessitates testing a vaccine alongside “other components that [they] think can complement” it. Thus, large trials are required, with “large cohorts” across “different arms”.
At this stage, Dr Brander and his team have “massively de-risked” the T-cell immunogen platform in order to “go confidently” into combination trials.
Those of you who have been following previous interviews will know that we love to ask about our events. Apart from the ego boost, it is helpful to understand what really draws our world-class speakers to the Congress. Dr Brander served us a slice of humble pie on this occasion, remarking that being “close to home” is ideal! He reflected that getting to “sleep in [his] own bed” after a “day of fantastic talks” is a winning factor. However, he also identified that “contacts and matchmaking” make it a “great place”.
Thank you to Dr Brander for making the time to speak to us, and for giving us an insight into the development of HIV therapies. If you are interested in learning more about HIV programmes you can join us either in San Diego or Washington by getting tickets now.
A publication in the Journal for ImmunoTherapy of Cancer in October 2022 by researchers at the Leiden University Medical Centre (LUMC) investigated the safety and immunogencity of ISA Pharmaceuticals’ Amplivant adjuvant and Synthetic Long Peptide (SLP) therapeutic vaccine technology. ISA stated in November 2022 that it is “delighted” with the publication, which demonstrates a “favourable safety profile”. The study was expanded from initial approval to enrol oropharyngeal squamous cell carcinoma (OPSCC) patients after “treatment with curative intent” to include patients with “an HPV16 positive (pre-)malignant lesion following standard treatment”.
The study in context
The authors of the publication note that “cancer vaccines are a promising strategy for cancer immunotherapy”. Furthermore, SLP based cancer vaccines are “safe, able to induce functional tumour-specific T cells, and show clinical efficacy”. However, they require combination treatments because they have “no intrinsic adjuvant”. Preclinical studies had revealed that “chemically well-defined adjuvants” such as Toll-like receptor (TLR) ligands can improve synthetic peptide cancer vaccines.
ISA’s Amplivant is one such ligand, which is “chemically adapted to optimally interact with the binding domain of the TLR2/TL1 heterodimer receptor to induce improved immunological activity”.
“Molecularly defined, self-adjuvanting peptide vaccines have the potency to cause local innate immune activation, antigen-targeting to dendritic cells (DCs) and DC activation, together leading to efficient T cell activation.”
In order to explore to potency of Amplivant-conjugated SLP vaccines the researchers used SLP derived from the human papilloma virus type 16 (HPV16) E6 oncoprotein amino acid (aa) sequence. Previous studies have demonstrated that spontaneous HPV16-specific T cell responses “occur but are weak” and unable to control tumour outgrowth.
The study is the first in human Phase I trial to establish safety and immunogenicity of Amplivant conjugated to HPV16 E6-SLP. Administered intradermally to take advantage of the “direct loading potency of skin-resident DCs”, the vaccine was injected 3 times in 4 dose cohorts. Between 2015 and 2020, 25 patients were enrolled.
“Patients were eligible for inclusion if they were at least 18 years of age, had previously documented evidence of an HPV16 positive (pre-)malignant lesion following standard curative treatment and were without residual disease based on physical examination between 4 and 16 weeks after therapy.”
Further inclusion criteria were applied. The vaccine comprised two HPV 16 E6 SLOP sequences, and the Amplivant-conjugated SLPs were manufactured and tested in The Netherlands. The trial included 2 weeks of screening, 6 weeks of vaccination treatment, and follow-up visits throughout the 20 weeks after the final dose of the vaccine.
Conclusions and limitations
The authors state that the study shows the vaccine to be “safe with only minimal and mostly local side effects”. In this study, CD4+ T cell responses were “more frequently found compared with CD8+ T cell responses”. This is “consistent” with previous results.
The authors note that “trial set up and patient availability” caused an “unfortunately unbalanced” male-female ratio. Despite this, they believe that the “unintentionally skewed” ratio didn’t influence response outcomes.
Researchers in Europe published results in Cancer Discovery in November 2022 that indicate promising responses to vaccination with senescent cells. The researchers suggest that these cells “combine several features that render them highly efficient in activating dendritic cells (DCs) and antigen-specific CD8 T cells”. Furthermore, the immune response to this study is “superior to the gold standard of immunogenic cell death”.
The Barcelona Institute for Research in Biomedicine (IRB) states that “senescence is a state of latency reached by damaged or aged cells in which they do not reproduce”. They “emit information signals into their environment”, alerting the immune system to their presence, which stimulates an “inflammatory response and tissue regeneration”.
The team used these cells because of these useful characteristics. As they are living, they stimulate the immune system for longer, but as they don’t divide, they can’t “regenerate the tumour”. Ines Marin is a doctoral student and author of the study who believes their findings are “very positive”.
“Our study concludes that the induction of senescence in tumour cells improves the recognition of these cells by the immune system and it also increases the intensity of the response they generate.”
Next level immune responses
Led by Dr Manuel Serrano and Dr Federico Pietrocola the group explored the effectiveness of senescence in immunisation. The IRB describes how this was a two-pronged approach looking at preventing and improving cancer in mice. As a therapeutic option, although limited by the “protective barrier of the tumour”, some “improvements were also observed”. Dr Serrano explained that this could be a positive step in understanding the immune response.
“Our results indicate that senescent cells are a preferred option when it comes to stimulating the immune system against cancer, and they pave the way to considering vaccination with these cells as a possible therapy.”
The study is supported
Using animal models of melanoma and pancreatic cancer, as well as samples from cancer patients, they found that “human cancer cells also have a greater capacity to activate the immune system when they are previously rendered senescent”. The next step is a combined approach of vaccination and immunotherapy.
This study was published in the same journal as another article that IRB describes as “completed in collaboration with IRB Barcelona”. This reaches “complementary conclusions” from a “different approach”. The work reveals that these senescent cells are better able to “receive” signals from their environment, which “amplifies the anti-tumour effects of signals such as interferon, making tumour cells more visible to the immune system”.
These studies present further potential for cancer therapies, which we know to be a huge task for researchers across the globe. To learn more about progress in cancer and immunotherapies at the World Vaccine Congress in Washington next year, get your tickets now.
Speaking to the BBC’s Laura Kuenssberg on the Sunday programme in October 2022, Professors Ugur Sahin and Ozlem Tureci indicated that mRNA treatments against various cancers could be available as soon as 2030. The professors co-founded the German company BioNTech in 2008 with the intention of “using mRNA to activate the immune system against a patient’s individual tumours”. They believe that this approach can be “tailored” against several kinds of diseases.
During the COVID-19 pandemic BioNTech and Pfizer attracted media attention for their collaboration in developing an mRNA vaccine against the disease. BioNTech reports that this vaccine was the “first mRNA drug approved for human use” as well as the “fastest vaccine” that targeted a new pathogen in “the history of medicine”.
Professors Ugur Sahin and Ozlem Tureci were married in 2002, 6 years before the establishment of BioNTech. They, along with their company, gained a public profile thanks to BioNTech’s role in the development of a vaccine during the pandemic. Due to what The Guardian described in 2020 as “scientific rigour, unrelenting work ethic, and appetite for entrepreneurship” the pair joined Germany’s rich list at number 93 after the vaccine success. However, the pandemic was a mere distraction from the main event for the Professors and their researchers, who have several trials in progress.
Addressing the BBC in October, Professor Tureci described mRNA as a “blueprint”.
“When you use mRNA as a vaccine, the mRNA is a blueprint for the ‘wanted poster’ of the enemy – in this case cancer antigens which distinguish cancer cells from normal cells.”
With the proven success of mRNA during the COVID-19 pandemic, BioNTech returns to its roots with renewed energy. Targeting bowel cancer, melanoma, and other cancer types, the research will attempt to get to the bottom of one of the most evasive diseases.
“Every step, every patient we treat in our cancer trials helps us to find out more about what we are against and how to address that.”
However, Professor Tureci emphasised the need to be cautious when describing a “cure for cancer”. Although they have had a “number of breakthroughs”, the company will continue to work on them with the same “rigour” that earned them their notoriety.
Furthermore, BioNTech is facing legal action from another big name in the mRNA game, Moderna. This has the potential to cause further disruptions to the programme. For Professor Sahin, though, the work they did is “original”.
“We have spent 20 years of research in developing these types of treatments and of course we will fight for this, for our intellectual property.”
We look forward to hearing more on the potential that mRNA has against cancer at the World Vaccine Congress in Washington 2023. To join us get your tickets now.
An article in the New York Times in October 2022 reflects that developing a cancer vaccine for high-risk patients seems like an “impossible dream”. However, recent steps suggest that we may be closer to this possibility than previously thought. While these investigations continue, attempts to develop vaccine therapies against cancer also progress. So which area should gain most attention, and which will improve or save more lives?
In previous posts we have investigated current projects for cancer vaccines and found that, despite investment, the challenge is great. Dr Sachet Shukla from the University of Texas told the NYT that the “time has come” for cancer vaccines. For Dr Susan Domchek of the University of Pennsylvania, “it’s super aspirational, but you’ve got to think big”.
Patients with pancreatic cancer have very few options, the article suggests. Removing the pancreas is one that leads to a “realm of severe diabetes and digestive problems”. Leaving lesions alone might allow them to become cancerous, or it might not.
Dr Elizabeth Jaffee of Johns Hopkins University finds potential in this pancreatic problem. The first change in normal cells, she describes, is a mutation in a well-known cancer gene: KRAS. This is followed by other mutations. Knowing this, researchers were able to consider a vaccine to train T cells to target these mutating cells. The initial safety study was in 12 patients with early cancer who had already been treated with surgery. Although this early intervention is effective, there is a 70%-80% chance of a recurrence in the following years. Then it is “metastatic and fatal”. For the 12 patients in the study, this has not been the case, as they have not experienced a recurrence.
Take it back to the beginning
The NYT traces cancer vaccine history back to Dr Olivera Finn of the University of Pittsburgh School of Medicine. In 1993 her initial vaccine targeted the core of a muc1. In ordinary cells it goes undetected by the immune system thanks to its covering of sugar molecules, but in some cancers it can become visible. This made it “seem like a perfect vaccine target”. In a trial of 63 patients with Stage 4 cancer it became clear that the cancers were too advanced for immunisations to be effective. Dr Finn told the NYT that she didn’t want to repeat that.
“It is not the vaccines. We have to look at different patients.”
With a colleague she is now trying to prevent precancerous colon polyps. By focusing on people whose colonoscopies had detected advanced polyps, they aim to stimulate the immune system into preventing further polyps. This was effective in mice, but in a human study did not have the same level of reduction in polyp recurrences.
At the University of Washington, Dr May Disis is hoping to prevent breast cancer in patients with gene variants that put them at high risk. Her aim is to replace surgery, chemotherapy, or radiation as treatments for “pre-cancer” with a vaccine. Starting with breast cancer stem cells, which are resistant to certain therapies, she found several proteins being produced at higher levels than in noncancerous cells.
The NYT reports that the vaccine was tested in women with well-established advanced cancers. Although it did not cure the cancers, it demonstrated an ability to provoke a helpful immune response. Next, she will try vaccinating patients with ductal carcinoma in situ, or another precancerous condition called atypical ductal hyperplasia. Hopefully, the lesions would be made to shrink or disappear before a surgery.
“This would be proof the vaccine has a cleansing effect.”
This presents a positive outlook on the future of cancer therapy and prevention, but as patients continue to receive life-changing diagnoses the question of which we should target remains. There is little time to spare in the race to develop a vaccine that protects against or remedies the effects of cancer. So, which will be the first to appear, and which will be the most effective?
To hear more about cancer vaccine candidates at the World Vaccine Congress get your tickets here.
A German study published in September 2022 in Molecular Therapy supports a clinical trial of “periodic low-dose intramuscular administration” of an mRNA-based therapy against Hereditary tyrosinemia 1. This is a recessive genetic disease of amino acid metabolism, characterised by deficiency of fumarylacetoacetate hydrolase (FAH). HT1 is estimated to affect 1 in 100,000 despite regional differences. It is particularly harmful for untreated children, who “usually do not survive past the age of 10 years”.
At present there are only limited treatment options, with patients following a “strict diet” and facing “complications” such as liver cancer and progressive neurocognitive decline. Thus, the need for therapies to “standardise metabolite levels and promise normal development” is pressing.
The current standard of care for HT1 involves an oral drug and a life-long diet low in phenylalanine and tyrosine. However, the study suggests that some adults do not respond to treatment, and some children following the programme experience developmental difficulties. The novel approach focuses on mRNA-based therapy, described as a “powerful tool with tremendous potential to treat a variety of indications”.
The mouse model
The study describes how “repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA” prompted FAH protein synthesis in deficient mouse livers. Furthermore, it “stabilised body weight, normalised pathologic increases in metabolites after nitisinone withdrawal” as well as reducing the likelihood of early death.
The authors concluded that “very low amounts” of FAH expression in the liver were enough to remedy body weight loss. Additionally, repeated intravenous injections of FAH mRNA-LNPs provided a “valuable therapeutic approach” and repeated intramuscular injections led to the transport of these FAH mRNA-loaded LNPs to the liver via the blood stream.
“These findings provide the potential basis for clinical application of mRNA technology to HT1 treatment”.
To hear more about the potential presented by mRNA come to the World Vaccine Congress in Europe 2022.
Several our recent articles have focused on the role of vaccination in cancer therapies. Initially we considered some of the current options, followed by reports of a positive study from Tufts University. We also explored some of the key players in President Joe Biden’s Cancer Moonshot programme. Finally, we have investigated cervical and prostate cancer therapies. Recently, in the October 2022 issue of The Lancet Oncology, a European study reflects the current landscape.
Why mRNA vaccines?
The authors begin by acknowledging the “worldwide focus” on mRNA, directed by the development and production of vaccines during the COVID-19 pandemic. However, this progress relied on years of research and development of mRNA for cancer therapies. The introduction sets out the benefits of mRNA in vaccine settings.
mRNA vaccines are well tolerated
“Adverse events are generally manageable and transient”
No genome integration
“Eliminates the risk of insertional mutagenesis”
“No pathogenic viral agents are used”
“Reduces risk of toxicity”
Humoral and cellular immunity
“Necessary for activating and sustaining anti-tumour responses”
Fast and inexpensive to produce
“Laboratory-based and cell-free production”
The authors state that “the clinical efficacy and immunogenicity of mRNA vaccines” have been “evaluated across cancer diagnoses and administration methods”. These vaccines are “promising therapeutic candidates”, particularly in combination therapies. Despite this, they report that at the time of publication no Phase III studies were ongoing, and the FDA had not yet approved any candidates. Thus, the paper explores the landscape of therapeutic mRNA-based cancer vaccines.
“The aim of mRNA-based vaccination is to induce or boost an effective anti-tumour immune response.”
The article explores the variety of mRNA options at different clinical stages and concludes with the anticipation of further development.
“with the optimisation of mRNA vaccine structure, stability, and delivery methods, and with the associated advantages of personalised preparations, low manufacturing costs, and the fast and scalable production required for a patient group that often experiences rapid disease progression, mRNA vaccines are reaching their potential as a future crucial strategy for cancer treatment.”
To participate in a day of discussion on immuno-oncology profiling at the World Vaccine Congress in Europe 2022 get your tickets here.
With just a few weeks left until the World Vaccine Congress in Europe 2022 we are looking forward to hearing from a range of incredible speakers. One such speaker is Dr Miguel Sanjuan, SVP Research and Development at Provention Bio. He will be showcasing a vaccine candidate PRV-101. We spoke to him ahead of his showcase to learn a little more about what we can expect, and what work is still to be done.
What is PRV-101?
Without giving too much away, we asked Dr Sanjuan if he could hint at what we might hear in Barcelona. He told us that Provention is “researching the safety and immunogenicty of our investigational candidate, PRV-101 for the prevention of acute CVB infection”. Furthermore, its “potential for preventing autoimmune disorders that are driven by latent CVB infection” is considered. PRV-101 is a “polyvalent inactivated coxsackievirus B (CVB) vaccine candidate”. It targets “all key CVB strains”. So far it has “met its primary endpoint in a Phase I, first in-human trial”.
Clarifying that PRV-101 is “not approved for any use at the present time”, Dr Sanjuan stated that there is “a lot of development” needed before we will see “benefits to the market or to the community”. However, this progress is exciting. Dr Sanjuan outlined the importance of targeting CVB.
“Acute infection can cause myocarditis, meningitis, pericarditis, otitis, and hand-foot-mouth disease. Recent research strongly supports that CVB also damages insulin-producing cells and gut-lining cells causing autoimmunity.”
In his presentation, Dr Sanjuan will discuss data from an initial Phase I study. As well as meeting the safety primary endpoint, this vaccine produced immunogenicity results that suggest it is worth studying in connection with “blocking acute CVB infection” and “the prevention of autoimmune disorders associated with latent CVB infection”.
Dr Sanjuan referred to a “substantial body of evidence” pointing to the role of CVB as a “trigger in the initiation of two common autoimmune diseases”. These are Type 1 Diabetes (T1D) and Coeliac Disease. As well as the “acute consequences of CVB infection, vaccines for CVB may potentially prevent CVB-driven autoimmunity”.
So why PRV-101, and what is next?
When we asked what the vaccine offered that is unique in comparison with other programmes, Dr Sanjuan reflected that PRV-101 is, to his knowledge, the “only vaccine in development against key relevant CVB viruses”. He believes there isn’t another polyvalent CVB vaccine in development.
“That makes PRV-101 unique, fully differentiated from other programmes in development, and provided it proves to be efficacious in the future, a potential first in class.”
The next steps for the vaccine will be “investigating the dose and safety” in children. If the researchers can establish an “acceptable safety profile in a paediatric population” they may be able to advance to a “larger proof of concept trial”. This would explore whether PRV-101 can prevent acute infection and CVB-mediated T1D.
We recognise that public understanding of vaccines for the treatment of autoimmune disorders is limited. Therefore, we asked Dr Sanjuan what he hopes to make clear at the Congress and beyond. He identified the “emerging evidence that latent viral infection can drive autoimmunity”. The connection between EBV and multiple sclerosis has been “known for several years”. Similarly, and “according to literature”, Dr Sanjuan stated that “CVB is the only virus on the human virome whose persistent infection is significantly associated with the development of T1D and coeliac disease on patients with predisposed genetic risk”.
Clinical mouse models “clearly show that vaccination against CVB prevents autoimmune diabetes”. Dr Sanjuan’s message for the public, therefore, is that vaccines play a role in “preventing the acute consequences of viral infections”, but could also play a role in preventing autoimmunity. He recognises that, because of the COVID-19 pandemic, “public awareness of vaccinations as an important part of family and public health has significantly increased”.
“Vaccines can be cost-effective treatments and government and private capital have now a renewed interest on being more strategic and proactive in developing vaccines for the treatment of old and new infective agents.”
Despite this, the importance of researching vaccines “spans beyond fighting infections”. For example, cancer antigens in vaccines have proven “promising” in treatment. Provention Bio is developing autoimmune vaccines. The effect of this treatment, if successful, could be “substantial”. Dr Sanjuan cites the number of more than 300,000 people in the US who are in the early stages of T1D at “any given time”.
“A successful CVB vaccine could potentially prevent CVB infection but also up to ~50% of T1D and ~20% of coeliac disease.”
Challenges and changes
We asked Dr Sanjuan about public health work and the relationship between the scientific community and public opinion. He believes that there is a tension between public recognition that “scientific research supports the advancement of novel treatments” and “reservations about warning of an impending public health crisis”. The key to “breaking through this scepticism” is “education”. He very graciously identified the Congress as a “critical” player in the mission!
“As one of the most well-regarded vaccine meetings, it brings together global experts creating a unique opportunity to discuss the state of research and development of vaccines but also to educate the public on our latest understanding of threats and research on potential treatments.”
When we reflected on technological advancements, Dr Sanjuan pointed out that the past decade has allowed disciplines such as “translation research” to “deliver on the promise of understanding deeply the pathophysiological mechanisms of disease”. He is interested in taking this on board to “develop novel therapies that intercept disease before they lead to irreversible damage and organ failure”. His example of individuals who discover they have T1D “the same day they need to start insulin treatment” emphasised this need.
With the help of genetic biomarkers “we now know that patients can be tested to determine whether they are at increased risk of developing symptomatic disease”. These patients “could benefit from vaccines or therapies for early-stage T1D”. However, this is “different to treating the disease at its chronic stage and when the damage has already occurred”.
“At Provention, we are committed to therapies that intercept and prevent autoimmune disease ahead of irreversible tissue damage.”
For those of us lucky enough to hear Dr Sanjuan’s presentation, we will hear more about the promise of developing a CVB vaccine and the initial safety data for PRV-101 .
Hope for the future
We concluded our interview by looking to the future and public health threats. Dr Sanjuan referred to the WHO’s warning that “noncommunicable diseases, such as diabetes, cancer, and heart disease are collectively responsible for over 70% of all deaths worldwide”. Furthermore, they are “responsible for the premature death of more than 15 million people globally”.
“It is therefore encouraging that vaccines that typically represent safe and cost-effective options are being developed for the treatment of some of those serious diseases.”
We thank Dr Sanjuan for his time and the thought he put into these answers ahead of his appearance at the Congress in October. We look forward to hearing more from him at the showcase! If you would like to join us, make sure you get your tickets here.
In September 2022 LABIOTECH.EU announced that a partnership between European biotech companies had been awarded a €1.06 million grant from EUREKA Eurostars. CimCure BV, a Dutch Biotech, Covalab, a French biotech, Amsterdam UMC, and the University of Zurich have accumulated a total budget of €2.24 million, which includes partner investments.
Eurostars is described by EUREKA as the “largest international funding programme for SMEs wishing to collaborate on R&D projects that create innovative products, processes, or services for commercialisation”. EUREKA is an intergovernmental network across 37 countries.
The winning project
Coordinated by CimCure, this project aims to develop a new treatment against glioblastoma. Glioblastoma (GBM) is a complex, often treatment-resistant cancer, which accounts for up to half of all primary malignant brain tumours.
The project is focused on a combination therapy that comprises CimCures iBoost vaccines and CAR-T cells against GBM. It is called ‘Optimal Synergistic Immunotherapy Strategy (OpSIS)’ and will last around 36 months in the Netherlands and Switzerland, as well as the facilities of Covalab and CimCure.
The aim, according to LABIOTECH.EU is to “deliver preclinical proof of concept” for a “novel combination of immunotherapy treatment” for GBM. The next step will be to “provide validation for translation of this strategy in GBM patients”.
“This project strives to demonstrate the efficacy, long-term persistence, and synergistic ability of combining GMB-targeting CAR-T cells with tumour vasculature-targeting vaccines.”
The project gained encouraging data from an initial study by Amsterdam UMC and the Medical Centre for Animals (MCD). A vaccine against bone cancer was “successful in an efficacy study in client-owned dogs”. Published in Nature Communications in May 2022, the results revealed that it is “safe and effective” in murine animal models and in dogs. With CimCure’s iBoost vaccine-based cancer immunotherapy, the consortium is hoping to replicate these results in humans.
Said El Alaoui, CEO and founder of Covalab said that they are “excited” to bring “extensive expertise in antibody engineering” to the project.
“Additionally, our platforms in molecular biology, immunology, and bioproduction will support the preclinical validation of therapeutic molecules and we can use our know-how in anticancer immunotherapy for this unique combination therapy project in oncology.”
Diedrick Engbersen is CEO at CimCure. He believes this is a “unique opportunity” to tackle a “disease with a dismal clinical outcome”.
“The collaboration with Covalab, the University of Zurich, and Amsterdam UMC is unique and promises major achievements.”
The group will aim to have the combination therapy “ready to enter regulatory procedures for testing patients”.
To hear more about cancer therapies at the World Vaccine Congress in Europe 2022, get tickets at this link.
Published in Nature in September 2022, Ken Garber explores the hopes of mRNA companies who are setting their sights back on therapeutic proteins. Disrupted by the COVID-19 pandemic, these companies are “doubling down on the goal of converting human cells into protein factories to treat disease”.
The recognised success of the COVID-19 vaccines produced by companies such as Moderna and BioNTech/Pfizer has “validated the mRNA technology platform”. Thus, with renewed enthusiasm these companies return to the “growing pipeline” of therapeutics.
The article suggests that, in comparison with gene therapies, mRNA offer “potential safety advantages” because “there is no genome integration or permanent modification”. Furthermore, Garber identifies manufacturing benefits, and the “opportunity to improve drug characteristics”.
“Unlike recombinant proteins, which are confined to the extracellular space, mRNA can reach any subcellular compartment.”
A “major process advantage” is the fact that it doesn’t need living cells, an improvement on recombinant proteins and lots of vaccines. However, “synthetic mRNA is intrinsically unstable in vivo”. Understanding mRNA in order to develop the COVID-19 vaccines “culminated decades of research”. These vaccines use nucleoside modifications to the sequence to “improve stability”. Intracellular delivery is facilitated by “encapsulation in lipid nanoparticles”.
However, the article suggests that we are facing “several technical obstacles” to furthering the progress of therapeutic pursuits. Trials have been terminated for “lack of efficacy”. Moderna’s advanced molecule was dropped by AstraZeneca. Although mRNA therapeutics “are composed of the same basic package” as the vaccines, it’s far easier to make vaccines work.
“As vaccine euphoria gives way to therapeutic reality, drug developers in the field are crafting solutions to the problems – particularly related to delivery, immunogenicity, and duration of protein expression, which present much greater hurdles for mRNA therapeutics than for vaccines.”
The article emphasises the quantity of protein required to treat disease. This, “implying heavier and more frequent dosing”, increases the risk of toxicity. This toxicity is “mainly immunological”. The immune system identifies unmodified mRNA as viral RNA, “triggering pattern recognition receptors”. This leads to “type 1 interferon and inflammatory cytokine production”.
In 2005, researchers at the University of Pennsylvania reported a “key advance”. They incorporated pseudoridine nucleosides to “dampen immunogenicity and boost translation”. Although mRNA vaccines are supported by “some innate immune system activation”, it’s not the same for therapeutic purposes.
“Immunogenicity is an absolute liability for an mRNA therapeutic”.
Solving this has historically taken two routes; companies “incorporate non-natural nucleosides” or use “sequence optimisation”. The former conceals the mRNA from the immune system. The latter “typically involves switching out uridine nucleosides for guanosines and cytidines in specific codons”.
Another toxicity issue identified in the article is the “accumulation of lipid nanoparticle carriers in the liver”. This might have been addressed by more recent lipid nanoparticles, “engineered for rapid degradation”.
Toxicity is not the only hurdle to overcome. mRNA is “inherently short-lived”, representing another challenge for therapeutics. An enhancement can be enabled through “nucleoside modifications” and “sequence optimisation”. A promising development is Circular RNA (circRNA), which is “very long-lived”. Companies are described as “enthusiastic” at the prospect that this could lengthen the duration.
Some, in attempts to “get around” the issue, are targeting diseases with already long-lived protein expression, or where “durable expression” isn’t a requirement. For example, primary ciliary dyskinesia is the object of Sanofi and Ethris’ interest.
To add to the list of obstacles, the article questions whether mRNA therapeutics can “get beyond the liver”. One solution might be to “engineer lipid nanoparticles with affinity for other tissues”. However, rodent models are “unreliable predictors” of how this might work for humans. Another option incorporates microRNA target sites into mRNA UTRs to achieve “some selective expression”.
The article concludes with a question: “how much further can mRNA engineering take the field?”. For John Androsavich of Pfizer, we should be aspiring to “progress, not perfection”.
“I don’t think there is one discovery that will make mRNA rock solid”.
He believes it requires a “combination of innovations” to produce an optimised product.
To learn more about mRNA technologies at the World Vaccine Congress in Europe, get your tickets here. For more on mRNA promise against cancer click here.
In Nature in September 2022 an article by Anthony King identified the difficulties associated with creating an immunotherapy for prostate tumours. The 2010 FDA-approved vaccine, sipuleucel-T, “raised hopes for a surge of cancer treatments”, which the article suggests have not been delivered for the prostate.
The vaccine originally targeted prostate tumours. The process involves extracting antigen-present cells from the patient’s blood and inserting a marker found on prostate tumours, before returning them to the patient. The idea, the article explains, is to direct “other immune cells” to “attack the cancer”.
Dr Lawrence Fong of the University of California is quoted emphasising the “big challenge” of prostate cancer. Although sipuleucel-T “delivered a slight survival benefit”, the American Cancer Society suggests that it “hasn’t been shown to stop prostate cancer from growing”.
Since 2010 there have been several “disappointing” immunotherapy attempts for prostate cancer. There are still gaps in our knowledge, which present a “key obstacle to getting immunotherapy to work”. However, momentum will not be stopped. Researchers are beginning to better understand this cancer, and promising approaches are progressing through trials.
So, what do we know about prostate cancer? Dr Charles Drake of Janssen Pharmaceutical suggests that because prostate cancers mutate less than other cancers, they offer fewer targets: “there’s just not as much fodder for T cells to recognise”. Another issue is that the prostate “has an unusually dialled-down immune environment”.
“Researchers using genetic sequencing to look for immune cells in the prostate will often come away empty-handed.”
The low T cell count means that checkpoint inhibitors encounter problems. When combined with the cancer, which “secretes a chemical messenger that further dampens immunity”, a “tricky environment” is created.
So far, therapeutic candidates have been “a bit of a let-down”. However, some scientists believe that a combination approach could be effective. This would involve a vaccine and a checkpoint inhibitor, working together. This could work based on a study of sipuleucel-T; it revealed that “people who received the treatment contained three times as many activated T cells”.
Trialling this is Dr James Gulley and his group in the US. Using a vaccine called Prostvac (PSA-TRICOM), which “disappointed in a phase III trial”, he hopes to “break the blockade”. Although Prostvac was insufficient alone, Dr Gulley’s group is trialling it alongside a checkpoint inhibitor targeting PD1, which tumours use to dodge detection by the immune system. Early signs a promising; “not a home run, but an interesting early signal”, for Dr Gulley. His “next step”, the article reports, is adding a third element. Interleukin-15 is a cytokine molecule that is involved in immune signalling. Despite positive early responses, this project must “clear tough regulatory hurdles”.
Targeting treatment and looking ahead
In order to achieve the most successful outcome, immunotherapies must be “targeted to the right people”. The article suggests that personalisation is common in other cancers but is “lagging” for prostate cancer. Furthermore, there is a “consensus” that the timing of immunological intervention “could be crucial”. We often see immunotherapy in patients with advanced disease, but the longer the battle with cancer, the “more entrenched it can become”. Considering immunotherapy “immediately after surgery or radiation therapy” is an avenue to explore.
In the face of numerous challenges, there is optimism. Dr Gulley identifies “little signals” that we can achieve “long-term durable responses”. Although “we haven’t quite cracked it” he believes there could be a “path forward”.
Genexine, a Korean biopharmaceutical company, announced in August that its “first-in-class proprietary DNA vaccine” demonstrated efficacy and safety in a Phase II study. The study examined these two qualities of the vaccine in patients with advanced cervical cancer. The vaccine was administered in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy.
The Phase II treatment group involved 60 patients with HPV 16- and/or 18- positive advance cervical cancer who had progressed after standard-of-care therapy. It was an “open-label, single-arm” trial and took place in South Korea. Each patient received intramuscular doses at weeks 1, 2, 4, 7, 13, 19 and an optional dose at week 46. Additionally, they received intravenous pembrolizumab every 3 weeks for up to 2 years.
Genexine reported that top line results showed a Best Overall Response Rate (BORR) of 31.7%. This increased to 38.5% in PD-L1 positive patients with HPV 16+ and Squamous Cell Carcinoma. The statement highlighted that PD-L1 negative patients showed an ORR of 25%. This was “extremely encouraging for this patient population” as it “demonstrates potential improvement in efficacy” on monotherapy of immune checkpoint inhibitors. This suggests a “beneficial effect of the combination therapy”.
“The combination therapy was found to be safe and tolerable with a similar safety profile to that of pembrolizumab monotherapy.”
For Professor Sung-Jong Lee of the Catholic University of Korea, College of Medicine, and investigator in the trial, the data are “very encouraging”. Acknowledging the “urgent need for better therapies” the professor believes that this combination could be a “strong alternative”.
“I am particularly pleased to see a clear efficacy signal in all patients.”
Furthermore, the professor commented on the “mechanistic” appeal of this combination therapy. The approach “appears to result in a strong, beneficial effect”, made clear by the results of the trial. Neil Warma, President and CEO of Genexine, also offered his thoughts. He was “encouraged” by the study and hopes that this combination therapy could “represent a new standard of care for patients”.
“This could open the door to a new therapy for this patient population that previously had limited treatment options available”.
Pfizer announced in September 2022 that its investigational Group B Streptococcus (GBS) vaccine candidate, GBS6, or PF-06760805, had received Breakthrough Therapy Designation from the FDA. The vaccine is intended for the “prevention of invasive GBS disease…by active immunisation of their mothers during pregnancy”.
The decision comes amidst an ongoing study, evaluating the safety and immunogenicity of GBS6 in healthy pregnant women between the ages of 18 and 40, who received vaccination during their second or early third trimesters. This is a placebo-controlled Phase II study, NCT03765073.
What is GBS?
GBS is a bacterium that causes “potentially devastating diseases in infants”, such as sepsis, pneumonia, and meningitis during the first 3 months of life. Pfizer stated that “about 1 in 4 pregnant women carry GBS bacteria in their body” with the potential to pass it on to their infant “during or prior to birth”. The annual global burden is an estimated 410,000 cases worldwide, with more than 147,000 stillbirths and infant deaths.
Breakthrough Therapy Designation
The FDA’s Breakthrough Therapy Designation is “designed to expedite the development and review” of vaccines that are considered better than current therapies. In order to obtain this status, preliminary clinical evidence must demonstrate “substantial improvement” on “clinically significant endpoints”. The attainment of this status follows the FDA’s decision to grant Fast Track status to GBS6 in March 2017.
The vaccine candidate is designed to offer protection against the “6 most prominent GBS serotypes”, which comprise 98% of the disease. The vaccine is an investigational maternal vaccine, hexavalent anti capsular polysaccharide (CPS)/cross reactive material 197 glycoconjugate.
It is undergoing evaluation in a Phase II study across South Africa, the UK, and the US. In April 2022 GBS6 was granted PRIME designation by the EMA’s Committee for Medicinal Products for Human Use (CHMP). This “provides enhanced support for the development of medicines that target an unmet clinical need”. In 2016 Pfizer reported receiving a grant from the Bill and Melinda Gates Foundation towards the ongoing clinical trial and a “parallel non-interventional natural history study”.
Dr Annaliesa Anderson, Senior Vice President and Head of Vaccine Research and Development at Pfizer, stated that GBS infections have “devastating” effects on new-borns and their families. Although she credits prenatal screening and antibiotics during childbirth with providing protection against GBS, she is concerned that this approach is not “fully protective in the first week of life”. Furthermore, it “presents multiple challenges in low- and middle-income countries” and “has not been shown effective” up to the first 3 months of life.
“If approved for pregnant women, GBS6 could help protect new-borns from the serious illnesses caused by this disease like meningitis, pneumonia, and sepsis”.
Dr Anderson is “encouraged” by the FDA’s decision and is prepared to discuss the vaccine candidate with the FDA and other agencies to “potentially reduce neonatal deaths” as well as the “global disease burden of GBS”.
To hear from speakers from Pfizer at the World Vaccine Congress in Europe 2022 get your tickets here.
An article in In Vivo in September 2022 explored the development and therapeutic potential of oncolytic viruses. Crediting a “relatively safe mode of action” and possibility of enhancing existing treatments, the article stated that 1/3 or cancer vaccines in development are now oncolytic viruses. Cancer vaccines continue to gain momentum as “immuno-oncology has validated the immune system’s essential role in maintaining healthy cell division”. Thus, researchers have become interested in designing vaccines against cancerous cells as well as infectious diseases.
In a previous post we explored how oncolytic viruses (OVs) have the “potential to revolutionise standard cancer treatment”. OVs can “selectively infect cancerous cells, with an additional genetic modification step”. This causes oncolysis and releases intracellular antigens. These antigens “can stimulate an innate immune response that eliminates” further cancerous cells. OVs are “highly targeted”, so have a “limited effect on healthy cells”. The result is that, although they sometime prompt the immune system to turn on healthy cells, they lead to “minimal toxicities”.
The article in In Vivo states that there are “currently 162 OV therapies in active development”. Although the majority are not yet at clinical trial stage, 4 have “successfully navigated through clinical development” to receive regulatory approval.
The approved products
Of the 4 that have gone to market, Imylgic (talimogene laherparepvec) is “the most notable as the first genetically modified OV”. Approved in 2015 by the FDA and the EMA, it is an attenuated herpes simplex virus type-1 vaccine.
Further products include Rigvir, approved in 2004 in Eastern Europe for the treatment of melanoma. Oncorine received approval in China “in conjunction with chemotherapy” against nasopharyngeal cancer. Finally, in 2021 Delytact (teserpaturev) was conditionally approved in Japan for the treatment of malignant glioma.
At present, OV therapies “are not currently approved for use in combination with other therapies”, but this possibility is being explored in clinical trials.
“Combining OVs with other immunotherapies is a sensible approach to achieve additive or synergistic anti-tumour responses and to overcome treatment resistance”.
Furthermore, the “nature of the treatment algorithm” promotes this combination approach as the “most practical way to evaluate an investigational drug in clinical trials”.
What is next for OV therapies?
OV therapies are “the ideal therapy type for cancer” because they are so precise, “preserving healthy cells” whilst targeting tumour cells. However, compared to other types of immunotherapy they “perform poorly”. The article questions whether this is down to “lack of investment” or an “inherently weaker clinical profile”.
As we encountered in IDT Biologika’s white paper on OVs, there are several “developmental drawbacks” that must be overcome in order to accelerate the pipeline process. As this article in In Vivo highlights, realising the potential of OV therapies will require developmental optimisation.
“The future success for OVs will depend upon finding the most appropriate patient populations and combination strategies where clinical benefit will be greatest.”
To learn more about therapeutic cancer vaccines come to the World Vaccine Congress in Europe, October 2022. Get your tickets at this link.