Cancer vaccine research may have reached ‘tipping point’
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The concept of cancer vaccination has generated excitement in the scientific community for decades.
Preventive vaccines, such as those against HPV and hepatitis B virus, have helped to reduce rates of virus-associated malignancies, such as cervical and liver cancer. In January, American Cancer Society researchers credited HPV vaccination with a 65% decline in cervical cancer incidence among women aged 20 to 24 years between 2012 and 2019.
Image: Sharon Berzofsky
Meanwhile, the development of therapeutic vaccines against nonviral cancers has been fraught with setbacks.
To date, only a few vaccines have received FDA approval. In 2010, the agency approved sipuleucel-T (Provenge, Dendreon Pharmaceuticals), a dendritic cell-based vaccine for prostate cancer. Five years later, the oncolytic viral therapy talimogene laherparepvec, or T-VEC (Imlygic, Amgen), received FDA approval for certain patients with advanced melanoma. Many other vaccines remain under investigation in clinical trials.
“People have been skeptical about cancer vaccines because historically they haven’t really worked in advanced cancer,” Neeha Zaidi, MD, assistant professor of oncology at Johns Hopkins University, told Healio | HemOnc Today.
The success of COVID-19 vaccines, however, has helped draw attention to the potential of mRNA vaccines against cancer.
Among them is the investigational personalized cancer vaccine mRNA-4157/V940, co-developed by Moderna and Merck. A combination of the vaccine and anti-PD-1 therapy pembrolizumab (Keytruda, Merck) conferred a statistically significant and clinically meaningful improvement in RFS among patients with stage III or stage IV melanoma who underwent surgical resection, according to topline data from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial released in December. The data, which showed a reduction in the risk for recurrence or death of 44% (HR = 0.56; 95% CI, 0.31-1.08), represent “the first demonstration of efficacy for an investigational mRNA cancer treatment in a randomized clinical trial,” the manufacturers stated in a news release.
In June, results of a phase 1 study by Balachandran and colleagues presented at ASCO Annual Meeting showed autogene cevumeran (BioNTech, Genentech), an mRNA-based individualized neoantigen-specific immunotherapy vaccine, activated T cells that recognized pancreatic cancer in eight of 16 patients with resected disease. Responders to the vaccine also had longer RFS than nonresponders (median, not reached vs. 13.7 months; HR = 0.08; 95% CI, 0.01-0.5).
“There has been renewed interest in cancer vaccines, partly due to mRNA technology but also the fact that we can identify unique, patient-specific antigens to develop personalized vaccines and treatments,” Zaidi said. “The mRNA technology allows for more flexibility in the types of antigens or targets we can encode, and vaccines can be developed more rapidly in real time.”
Healio | HemOnc Today spoke with experts about the various types of cancer vaccines, ongoing challenges and recent advances in their development, and potential directions for future research.
Types of vaccines
In a paper published in Vaccines, Lollini and colleagues described three broad categories of cancer vaccines: cell-based, protein/peptide based and gene-based (DNA/RNA). Although some vaccines aim for primary cancer prevention, many are designed for secondary prevention of progression or tertiary prevention of cancer recurrence. These vaccines activate the immune system to attack tumor cells through delivery of tumor-associated or tumor-specific antigens.
“At least until now, cancer vaccines have been intended to be therapeutic rather than prophylactic, but they are still vaccines,” Jay A. Berzofsky, MD, PhD, head of the Vaccine Branch at NCI’s Center for Cancer Research, told Healio | HemOnc Today. “A vaccine is something that induces the immune system to make a response against a specific target. In this case, that target would be a tumor antigen, but one doesn’t necessarily want to risk adverse events by immunizing a whole population against one specific type of cancer. So, what they were originally designed to do was to eradicate a cancer that already exists.”
Exposure to tumor-associated and tumor-specific antigens stimulates the immune system to recognize these antigens as foreign and distinct from the body’s native cells.
“The immune system is very good at rejecting foreign organisms, and we believe there are many cancers that start to develop but are sufficiently different from the host that they get rejected before they are ever detected,” he said. “It’s only the ones that escape this rejection that become clinically evident cancers.”
Development challenges
Unlike treatments such as chemotherapy and radiation that are associated with off-target adverse effects, therapies that trigger immune response are capable of targeting only the tumor while sparing the adjacent normal tissue, Berzofsky said.
Although early cancer vaccines successfully induced an immune response measurable in an immunologic assay, they nevertheless failed to kill the cancer, he said.
“People didn’t know why they weren’t succeeding, because the immune response was being developed — this was true in mice, as well as people,” he said. “Researchers could even make a vaccine, immunize mice and transplant the cancer, and the immune system would reject it. However, you couldn’t treat them once they had the cancer. So, you couldn’t treat an established cancer.”
Cancers have evolved to exploit immune mechanisms designed to control overreactions such as cytokine storms that lead to autoimmune disease, Berzofsky said.
“The immune system has mechanisms to keep itself under control, such as checkpoint molecules, but there are many other mechanisms,” he said. “There are also regulatory T cells and natural killer T cells that suppress, as well as cancer-associated macrophages and other suppressive myeloid cells, and then there are cytokines that suppress, like TGF-beta or interleukin-13. All of those can be exploited by the cancer to turn off those T cells before they can reject the cancer.”
This immunosuppressive tumor microenvironment is so hostile to T cells that even when a vaccine triggers an immune response, the T cells are not always able to effectively destroy the cancer.
“What we’ve learned over the past 5 to 10 years is that you need not only to have the vaccine to induce the immune response, but you also need to block these negative regulatory mechanisms that are suppressing the immune system,” he said. “Ideally, you want to block all of these mechanisms, and each one has different subsets.”
Eliminating these suppressive mechanisms enables the T cells to work and reject the cancer. This is why anti-CTLA-4 and anti-PD-1 drugs have shown efficacy in melanoma and in a subset of patients with lung cancer.
“Then there are other tumors, like prostate cancer, where you don’t see any T cells in the first place,” Berzofsky said. “Even if you use, say, anti-PD-1, it doesn’t help because the T cells aren’t there to work. So, now you need the vaccine to induce a T-cell response, which the tumor itself wasn’t capable of inducing.”
Personalized vaccines
Berzofsky and colleagues demonstrated the feasibility and safety of custom-made peptide vaccination for patients with cancer in a study published in 2005 in Journal of Clinical Oncology.
“We found that if we immunized against KRAS and p53 mutations with the peptides corresponding to the patient’s own mutation, the patients who made a good T-cell response tended to live more than a year longer than those who didn’t make an immune response to the vaccine,” he said.
However, the correlation did not prove causation, and the patients who made a strong immune response may have been healthier in the first place, he noted.
“More recently, in the past 5 years, we’ve discovered that there are many mutant genes and that many tumors have somatic mutations,” Berzofsky said. “Tumors that have a lot of mutations that are unique to the tumor are more likely be immunogenic and are therefore more likely to respond to checkpoint inhibitors such as PD-1, even without a vaccine.”
From this, researchers have extrapolated that these mutations could create epitopes that could be targeted with a cancer vaccine.
“So, there has been a flurry of activity toward making cancer vaccines against neoepitopes,” he said. “Now, it’s 17 years after we published our study, and everyone is trying to do this type of thing. It was an idea before its time.”
Zaidi said her group is among those working on development of personalized vaccines in the lab.
“Each patient gets a biopsy, and a small amount of tissue is retrieved that gets sent for sequencing,” she said. “Computerized algorithms can predict which mutations are more likely to generate an immune response. Based on this information, a vaccine is designed.”
Zaidi said her research group is also currently investigating “off-the-shelf” vaccines, which differ from vaccines that are tailored specifically to the patient’s tumor.
“In the off-the-shelf approach, each patient gets the same vaccine but we’re targeting common mutations that result from driver genes,” she said, “There are certain genes, such as KRAS, that drive the growth of the cancer and occur very early on in the development of the cancer. We are targeting those mutations because they are so critical for cancer cell growth and development, as a way to teach the immune system to recognize these mutations and mount a response against the cancer.”
Zaidi and colleagues have developed a long peptide vaccine targeting the six most prevalent KRAS mutation proteins in patients with pancreatic ductal adenocarcinoma. They have evaluated the initial safety and immunogenicity of the vaccine in 11 patients so far in a phase 1 clinical trial. The patients, who underwent surgery and chemotherapy, received the vaccine in combination with checkpoint blockade.
“We’re measuring the immune response in the blood after these patients get the vaccine and looking for T cells that are responding to the targets we’re vaccinating against,” she said. “This is a very small study, but we do have several patients enrolled and many of them are generating immune responses in the blood. However, in terms of efficacy and outcomes, it’s just too early to say.”
Based on their findings, Zaidi and her colleagues have begun enrolling a second clinical trial testing their KRAS peptide vaccine in those at high risk for developing pancreatic cancer.
“These are patients who already have a known risk because of a strong family history or genetic mutation,” she said. “Pancreatic cancer is an ideal cancer [for vaccines] because most of the time it presents when the disease is so far advanced, there are no curative options. Catching it in the earliest stages, even in the precancer stage, is key.”
Promising research
Research into vaccines against breast, ovarian, lung, prostate, colon and bladder cancers has shown a great deal of promise, according to Mary L. “Nora” Disis, MD, director of University of Washington’s Cancer Vaccine Institute.
“We’ve been working on cancer vaccines for probably the past 25 years, and our most advanced programs are in breast cancer and ovarian cancer,” Disis told Healio. “We’re in randomized phase 2 clinical trials, and both of these programs are looking at single-antigen vaccines. We’re trying to target driver proteins in a subtype of malignancy. Our new vaccines, which encode multiple antigens and target biologic pathways that define a cancer subtype, are in early-stage clinical trials.”
Disis and colleagues evaluated the long-term safety of a plasmid-based breast cancer vaccine that encodes the ERBB2 cellular domain in a phase 1 trial of 66 patients with advanced ERBB2-positive breast cancer. At a follow-up of 10 years, the DNA-based vaccine appeared safe and associated with generation of ERBB2-specific type 1 T cells in most patients, prompting the researchers to initiate phase 2 trials.
In a separate phase 1 study, Disis and colleagues assessed the safety of T-helper 1 selective insulin-like growth factor binding protein-2 (IGFBP-2) vaccination among 25 women with advanced ovarian cancer. Researchers administered the plasmid-based vaccine monthly for 3 months and assessed toxicity using NCI criteria. Results showed the vaccine appeared well-tolerated and induced high levels of IGFBP-2-specific interferon gamma-secreting T cells among half of the women.
“The early results of those phase 1 and single-arm phase 2 studies are very promising and showed a progression-free survival and overall survival benefit, although they weren’t powered for those endpoints,” Disis said. “That has now led to large, randomized clinical trials looking at preventing disease recurrence in those patients.”
Looking ahead
Future vaccine research will likely focus on interrupting the development of cancer for people at high risk, particularly for malignancies such as pancreatic cancer, Zaidi said.
“I think moving earlier and earlier, even to a premalignant setting, is where we believe vaccines may be important in intercepting the development of cancer in high-risk individuals,” Zaidi said.
Advances in technology have helped to brighten the future for cancer vaccines, according to Berzofsky.
“The technology to sequence and look for mutations in the patient’s tumor has improved by many orders of magnitude,” he said. “Back in 2005, it was very laborious to sequence RAS and p53 in a patient’s tumor. It took weeks to get the sequence and then months to make the synthetic peptide. Now, the technology is so much better, and you can do it much faster, more easily and more cheaply. So, it’s become more practical to do.”
Zaidi agreed that the science and the technology are steadily catching up to the promise of developing an effective cancer vaccine.
“Not only do we know what to target better in each patient’s tumor, we also are getting better at knowing how to deliver these vaccines with mRNA technologies, with nanoparticles,” she said. “Now, we can take the patient’s tumor and sequence it in a matter of days, and it’s not that expensive. We can use that information to develop personalized vaccines. So, all this technology is helping to drive better cancer vaccines and strategies.”
Disis said she believes cancer vaccine development has reached “a tipping point” for three reasons.
“The first reason is that we now know the type of immune response we need to stimulate,” Disis said. “The second is we now know many proteins are immunogenic in specific types of cancers, so we’re able to put together vaccines quickly that will train the immune system to recognize those proteins. Finally, vaccine technologies have advanced dramatically and nucleic acid vaccines, such as mRNA and DNA vaccines, have shown to be superior in terms of generating high levels of immunity very safely. Considering all of this together, I think we’re there in terms of being able to move ahead extremely quickly.”
References:
- Balachandran VP, et al. J Clin Oncol. 2022;10.1200/JCO.2022.40.16_suppl.2516.
- Carbone DP, et al. J Clin Oncol. 2005;doi:10.1200/JCO.2005.03.158.
- Cecil DL, et al. Clin Cancer Res. 2021;doi:10.1158/1078-0432.CCR-21-1579.
- Lollini PL, et al. Vaccines. 2015;doi:10.3390/vaccines3020467.
- MSK mRNA pancreatic cancer vaccine trial shows promising results (press release). Available at: https://www.mskcc.org/news/can-mrna-vaccines-fight-pancreatic-cancer-msk-clinical-researchers-are-trying-find-out. Published May 31, 2022. Accessed Dec. 12, 2022.
- Moderna and Merck announce mRNA-4157/V940, an investigational personalized mRNA cancer vaccine, in combination with Keytruda (pembrolizumab), met primary efficacy endpoint in phase 2b KEYNOTE-942 trial (press release). Available at: investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx. Published Dec. 13, 2022. Accessed Feb. 6, 2023.
- Siegel RL, et al. CA Cancer J Clin. 2023;doi.10.3322/caac.21763.
- Tosch C, et al. J Immunother Cancer. 2017;doi:10.1186/s40425-017-0274-x.
- Zaidi N, et al. Cancer Res. 2022;doi:10.1158/1538-7445.PANCA22-IA013.
For more information:
Jay A. Berzofsky, MD, PhD, can be reached at Center for Cancer Research, National Cancer Institute, Building 41, Room D702D, Bethesda, MD 20892; email: berzofsj@mail.nih.gov.
Mary L. “Nora” Disis, MD, can be reached at University of Washington and Fred Hutchinson Cancer Center, 850 Republican St., Brotman 221, Box 358050, Seattle, WA 98109-4725; email: ndisis@uw.edu.
Neeha Zaidi, MD, can be reached at 600 N. Wolfe St., Baltimore, MD 21287; email: nzaidi1@jhmi.edu.
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