Personalized vaccine shows potential benefit across cancer types
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A personalized genomic vaccine administered after standard-of-care adjuvant therapy appeared safe and induced immunogenicity among patients with different cancers at high risk for recurrence, according to results of a phase 1 trial.
The findings, presented at the virtual American Association for Cancer Research Annual Meeting, also showed feasibility of developing the neoantigen cancer vaccine, PGV-001, using Mount Sinai’s computational platform, OpenVax.
“This was the first [cancer vaccine] trial that enrolled a heterogeneous mix of tumors, all of which had a very high chance of recurrence,” Thomas Marron, MD, PhD, assistant director of immunotherapy and early-phase trials at Tisch Cancer Institute and assistant professor of medicine, hematology and medical oncology at Icahn School of Medicine at Mount Sinai, told Healio.
“[Patients in the cohort] had already recurred and they were having a second or third surgery,” he continued. “Three of the patients had multiple myeloma and were undergoing a stem cell transplant. It was a very high-risk population and a population that can definitely use some help.”
Patients who do not respond to immunotherapy are believed to lack adequate priming of T cells to tumor-specific neoantigens. To address this challenge, Marron and colleagues developed PGV-001 with patient-specific synthetic neoantigen peptides (25 mer).
To create the vaccine, researchers sequenced tumor and germline DNA and tumor RNA of 15 patients who had undergone curative-intent surgery for solid tumors or autologous stem cell transplant for multiple myeloma and had at least a 30% chance of recurrence. The OpenVax pipeline then used that data to identify and prioritize candidate immunogenic neoantigens that could be synthesized and incorporated into the vaccine, using up to 10 neoantigen peptides — which were specific to the patient’s HLA type to help predict the potential for their immune recognition — per patient.
The OpenVax pipeline identified an average of 67.1 neoantigens (range, 8-193) per patient and only failed to identify enough neoantigens to synthesize 10 peptides for two patients, demonstrating feasibility of the approach, according to researchers.
The remaining 13 patients — including 10 with solid tumor diagnoses and three with multiple myeloma — received at least seven doses of vaccine. Eleven of the patients received all 10 planned doses of the vaccine over 6 months. Patients also received the immunostimulant poly-ICLC and a tetanus helper peptide, which helps to further activate the immune response against the vaccine’s neoantigens.
Mean follow-up was 925 days.
After excluding one patient lost to follow-up, median PFS from the time of surgery or HSCT was 618 days.
Four patients remained without evidence of disease — including one patient each with myeloma, lung cancer, breast cancer and urothelial cancer — four patients were receiving subsequent lines of therapy and four patients died, two due to disease recurrence.
Initial analysis of patient samples confirmed immunogenicity, with T-cell responses and intracellular cytokine staining showing induction of interferon-gamma, tumor necrosis factor-alpha and interleukin-2.
“We looked at the blood straight away, not manipulating it at all, after the first six injections and we actually barely could detect any response to the vaccine,” Marron said. “But, 27 weeks later, after all 10 vaccines, we saw this amazing, robust response against the majority of antigens that the first patient received.”
Researchers also conducted immune monitoring by collecting serial blood samples.
“In the first patient, we saw that we successfully induced not only CD4 but CD8 T-cell response against their tumors,” Marron said. “So, basically both sides of the immune system recognized the peptides that we were vaccinating them with, which was obviously the goal.”
The vaccine appeared well-tolerated, with grade 1 injection-site reactions occurring among about one-third of patients.
Marron said he sees potential in future research aimed to optimize creation and use of the personalize vaccines, as well as research into creating an off-the-shelf product with shared new antigens that would allow patients to be vaccinated against all common mutations.
“As soon as we find the tumor, we could start vaccinating [the patient],” Marron said. “That would, potentially, significantly increase the response rates to these immune therapies, because you would give patients that much more potential to have a T-cell response that’s able to recognize their cancer and kill it.”
Perspective
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Dmitriy Zamarin, MD, PhD
There are two main takeaways from the study. The first takeaway highlights that it is feasible to collect tumor samples from patients during surgery, process them to bioinformatically identify the potential neoantigens, synthesize the vaccine, and give them back to patients in a personalized fashion. Secondly, the vaccine appears to be safe and have early evidence of being able to induce an immune response, at least in the first patient tested.
This is not the first neoantigen vaccine study that has been presented or published; however, it is one of the first studies taking the neoantigen vaccine approach into an adjuvant setting, where the vaccine serves as a prophylactic strategy to prevent or delay cancer recurrence. There is a strong rationale for adjuvant vaccine therapy: in the early disease setting, the immune system has not yet been compromised by multiple lines of chemotherapy and, thus, may have a stronger ability to respond to vaccination. Further, the immune response to vaccination may be more effective in targeting microscopic tumors rather than large established tumors and carries a potential to eliminate residual cancer cells and prevent cancer from coming back.
Because these are early data, we don’t have conclusive evidence of the clinical impact that the vaccine will have on patients. Immunogenicity data from the first patient certainly looks very encouraging, demonstrating that the patient responded to all of the peptides received. This is a good validation that the vaccine generates a T-cell response. It will be interesting to see if this is the case for all patients.
Also, additional testing will be required to demonstrate whether this vaccine response is maintained. Do these T cells just appear and disappear after the vaccine, or are responses durable? Moreover, in patients who maintain a response but whose cancer relapses, does that relapse correspond to the loss of a response to the vaccine? These kinds of studies will be important in the future to understand how much this vaccine played a role in the trajectory of the patient’s disease.
Another potential area of future investigation would be to administer this vaccine in combination with a drug like another immunotherapy drug like an immune checkpoint inhibitor. The researchers commented that some patients who had disease recurrence on this vaccine study and subsequently received an immune checkpoint inhibitor had a very profound response. We have seen in past studies with different vaccines that prior immunotherapy may sensitize the patients’ cancers to subsequent therapies. So, even if the vaccine doesn’t prevent disease recurrence, it can still be impactful for the patients in the long run.
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Marron TU, et al. Abstract LB048. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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