Cancer Vaccines Approach New Horizons in Melanoma and Other Solid Tumors

The personalized cancer vaccine research paradigm is expanding, with particular advancements occurring in patients with high-risk melanoma, in whom vaccines have been shown to induce and strengthen responses to immunotherapy, according to Patrick Ott, MD, PhD.¹

“The idea is to induce active immunity that’s durable,” Ott said of cancer vaccines during a presentation at The New York Academy of Sciences Frontiers in Cancer Immunotherapy Symposium 2024. “I would argue that one of the big advantages of T-cell vaccines are that the type of T cells that they can generate are potentially long lasting and effective… [These T cells] will be exclusively present in the tumor and novel to the immune system.”

In the presentation, Ott highlighted several examples of studies that have displayed early efficacy signals with cancer vaccines, the potential clinical implications of this treatment modality in patients with melanoma, and future directions for research in randomized trials for this patient population.

Ott is the clinical director of the Melanoma Disease Center, the director of Clinical Sciences at the Center for Immuno-Oncology, and a senior physician at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both of which are located in in Boston, Massachusetts.

Assessing the Efficacy of Poly-ICLC Vaccines in Melanoma

Findings from a phase 1 trial (NCT01970358) evaluated the use of NeoVax, a long peptide poly-ICLC vaccine consisting of 20 predicted personal tumor neoantigens, in patients with melanoma. Of the 6 patients who were initially vaccinated, all exhibited robust ex vivo responses, and most of the vaccinating epitopes had vaccine-induced immune responses, Ott explained.² However, not all of the immune responses were ex vivo. No ex vivo CD8-positive responses were observed; only CD4-positive responses were seen ex vivo. Additionally, 60% of the CD4-positive and 16% of the CD8-positive responses required in vitro stimulation. Investigators also found that the vaccine-induced T-cell responses they observed were specific for the mutant epitopes of CD4 and CD8.

Two of the 6 patients achieved complete responses (CRs) to post-vaccination PD-1 inhibition that they received due to disease recurrence in the lungs.

“That was interpreted as an early signal of efficacy,” Ott noted.¹

A longer follow-up analysis in the original 6 patients plus 2 additional patients showed that most immunizing epitopes that had induced responses after 16 weeks exhibited persistence at a median follow-up of 55 months after surgery.³ Since all observed responses were ex vivo, investigators generated CD4-positive tetrameters to conduct single-cell RNA and T-cell receptor (TCR) sequencing and evaluate the transcriptional profiles of the T-cell responses.

In the tetrameter CD4-positive T cells, rates of cytotoxicities increased then decreased over time, and memory rates increased over time, which Ott said was consistent with the responses seen in these patients. Additionally, single-cell sequencing revealed that after vaccination, the TCR repertoire diversified over time as new TCR clonotypes joined the response.

Extending Vaccination Research to Lung and Bladder Cancer

Ott continued by describing findings from the phase 1b NT-001 study (NCT02897765), which evaluated the efficacy of NEO-PV-01, a personalized long peptide poly-ICLC vaccine, in combination with nivolumab (Opdivo) in patients with metastatic melanoma, non–small cell lung cancer (NSCLC), or urothelial cancer.⁴ In this study, during vaccine manufacturing, patients received PD-1 inhibition followed by vaccination beginning at week 12. Tumor biopsies were collected prior to treatment with nivolumab, after treatment with nivolumab but prior to vaccination, and post-vaccination. Investigators hypothesized that patients who did not respond to nivolumab would experience a clinical response to the agent after receiving the vaccine.

“We did see nice responses; particularly in melanomas, the overall response [rate] was [59%], where we typically would expect 40%,” Ott emphasized, noting that robust clinical response rates were also observed in the NSCLC and bladder cancer cohorts.¹

Across all cohorts, among patients who initially had stable disease or progressive disease with nivolumab, the response conversion rate with the vaccine was 13%.⁴

“You could interpret this as potentially a vaccine effect, but obviously, it could also be the long-term effect of the PD-1 inhibition,” Ott cautioned.¹

Furthermore, investigators conducted an analysis of epitopes that patients had not been vaccinated with that were identified in their tumors after vaccination.⁴ Epitope spreading occurred in patients across all 3 cohorts, and, Ott explained, was indicative of vaccine-induced tumor cell killing, which correlated with improved progression-free survival (PFS) outcomes.

Additionally, an analysis of serial tumor biopsies in 19 patients from the melanoma cohort showed that at 12 weeks post-nivolumab initiation, 5 patients experienced major pathological response (MPR) and 9 patients who did not have MPRs after nivolumab treatment alone achieved CRs after vaccination. This finding also correlated with improved PFS outcomes.

“These are not surgical pathologic responses or pathologic responses in core biopsies, but nevertheless, [they may be] suggestive of a vaccine effect,” Ott emphasized, saying that this study was “a nice confirmation of vaccine immunogenicity and…some clinical early signals of efficacy.”¹

Deepening Immune Responses Through Multiple Vaccines

A phase 1/2 study (NCT02126579) investigated the efficacy of a long peptide poly-ICLC vaccine in combination with the incomplete Freund’s adjuvant (IFA) Montanide ISA-51 in patients with high-risk melanoma.⁵ This study showed that the CD8-positive T-cell immune response rate to minimal epitope peptides (MEPs) in combination with toll-like receptor (TLR) agonists and IFAs was 24% vs 6% with MEPs plus TLR agonists without IFAs.

These findings validated the use of Montanide plus a long peptide vaccine and localized ipilimumab [Yervoy] in this patient population, which is the focus of an ongoing study at Dana-Farber, Ott said.¹

“These are early data, not quite fully vetted and validated,” Ott said. “But we see differences in profiles, like exhausted CD8-positive phenotypes and exhausted CD4-positive phenotypes. We’re refining this over the next couple months; it’s been interesting to be able to follow these clones with different types of treatments over time.”

Further Validating Vaccine-Induced Responses

Ott also spotlighted the use of cancer vaccines in a study that enrolled 16 patients with pancreatic cancer, all of whom underwent resection and subsequently received PD-L1 inhibition with atezolizumab (Tecentriq). These patients were vaccinated with autogene cevumeran, an RNA-based personalized vaccine, 15 of whom then received standard-of-care mFOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). Of the 16 patients, 8 achieved immunogenic responses induced by the vaccine and 8 did not respond.⁶ All 8 responders and 1 non-responder also had clonal expansion.

The primary analysis of this study showed that T-cell immunity induced through the personalized RNA vaccine in combination with atezolizumab and mFOLFIRINOX correlated with delayed recurrence. The median recurrence-free survival (RFS) was not reached among the responders vs 13.4 months among the non-responders (HR, 0.08; 95% CI, 0.01-0.4; P = .003).

“There’s a lot of excitement in the field about…studies that show clinical activity in a…randomized fashion,” Ott noted.¹

He highlighted findings from the randomized, phase 2 KEYNOTE-942 trial (NCT03897881) of pembrolizumab (Keytruda) plus the personalized RNA vaccine mRNA-4157 (n = 107) vs pembrolizumab alone (n = 50) in patients with high-risk melanoma.⁷ At a median follow-up of 23 months in the vaccine arm and 24 months in the pembrolizumab monotherapy arm, the RFS outcomes favored the vaccine arm (HR, 0.561; 95% CI, 0.309-1.017; 2-sided P = .053). In the vaccine arm, the 18-month RFS rate was 79% (95% CI, 69.0%-85.6%) vs 62% (95% CI, 46.9%-74.3%) in the pembrolizumab monotherapy arm.

“This is meaningful and important because it shows clearly that there was [achievement of] a clinical end point,” Ott said.1 “It’s important to know about the immune responses in these patients, but ultimately, it’s the clinical responses that we should be paying attention to.”

Outlining the Future of Personalized Cancer Vaccines

Ott called attention to the numerous clinical trials investigating vaccines in melanoma, as well as in cutaneous squamous cell carcinoma, renal cell carcinoma, bladder cancer, NSCLC, and pancreatic ductal adenocarcinoma, emphasizing that several of these trials are registrational studies. He also noted the variety of vaccine platforms under evaluation, including RNA-based and DNA-based vaccines.

“It’s nice to see that we can [give cancer vaccines] safely. Vaccines are typically safe therapies; we don’t have a lot of the issues that we have with a lot of other cancer immunotherapy drugs, which, of course, [stems from] the specificity of that approach. We see there’s durable immunity; we see the evolution over time, which is exactly consistent with the mechanism [of action]; we see that these T cells can traffic into the tumor. We have a lot more to learn…and we’ll have a lot more data to look at over the next 5 years,” Ott concluded.

References

1. Ott PA. Personalized cancer vaccines: ready for the clinic? Presented at: Frontiers in Cancer Immunotherapy 2024; May 21-22, 2024; New York, New York. 
2. Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217-221. doi:10.1038/nature22991
3. Hu Z, Leet DE, Allesøe RL, et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat Med. 2021;27(3):515-525. doi:10.1038/s41591-020-01206-4
4. Ott PA, Hu-Lieskovan S, Chmielowski B, et al. A Phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell. 2020;183(2):347-362.e24. doi:10.1016/j.cell.2020.08.053
5. Patel SP, Petroni GR, Roszik J, et al. Phase I/II trial of a long peptide vaccine (LPV7) plus toll-like receptor (TLR) agonists with or without incomplete Freund's adjuvant (IFA) for resected high-risk melanoma. J Immunother Cancer. 2021;9(8):e003220. doi:10.1136/jitc-2021-003220
6. Rojas LA, Sethna Z, Soares KC, Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):144-150. doi:10.1038/s41586-023-06063-y
7. Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024;403(10427):632-644. doi:10.1016/S0140-6736(23)02268-7