Rilimogene galvacirepvec(National Cancer Institute)

Genentech's Ira Mellman, Ph.D., (second from right) argued that the company's mRNA cancer vaccine could potentially become a backbone therapy in the adjuvant setting after surgical removal of tumors. The rest of the panel, from left to right, are Immune-Onc's Paul Woodard, M.D.; BeiGene's Mark Lanasa, M.D., Ph.D.; Regeneron's Israel Lowy, M.D., Ph.D.; and Gilead's Bill Grossman, M.D., Ph.D. Moderna and BioNTech recently reported positive early clinical data for their mRNA cancer vaccines in partnership with PD-1/L1 inhibitors. But as over a decade of research has failed to transpire into approved therapies, several biopharma executives remain on the fence about the future for cancer vaccines, while others believe the field is getting closer to finding its sweet spot. “These are good data that we have to look at and see and understand,” Bristol Myers Squibb Chief Medical Officer Samit Hirawat, M.D., said in an interview on the sidelines of the J.P. Morgan Healthcare Conference earlier this month. Hirawat was referring to Moderna and Merck’s December announcement of positive results from a 157-patient phase 2b trial dubbed KEYNOTE-942. The pair said a combination of their personalized mRNA cancer vaccine, coded mRNA-4157 or V940, and the PD-1 inhibitor Keytruda slashed the risk of tumor recurrence or death by 44% compared with Keytruda alone when used as an adjuvant therapy in stage 3/4 melanoma following complete surgical resection. Industry watchers cheered the KEYNOTE-942 melanoma trial as a milestone for the cancer vaccine field, but it may be too early to call the Moderna shot a success. Unanswered questions   “How does one interpret 157 patients’ worth of adjuvant data for a vaccine in melanoma? One has to obviously get to … look at the data and interpret,” Hirawat said. While detailed analyses remain under wraps, Moderna and Merck said they plan to move the regimen into phase 3 testing this year. The KEYNOTE-942 data, while encouraging, were indeed preliminary. BMS’ Opdivo got its FDA approval as an adjuvant treatment for melanoma late 2017 based on recurrence-free survival (RFS) data from a phase 3 trial of over 900 patients. Keytruda won its own adjuvant melanoma nod after showing an RFS benefit against placebo in a study of about 1,000 patients. Hirawat labeled cancer vaccines as a “great platform to continue to investigate” and said that BMS is “always going to be supportive of any innovation.” But some questions, such as patient profiles, can only be answered when more data become available from KEYNOTE-942, he said.  Besides, why mRNA-4157 had previously failed in colorectal cancer but appears to work in melanoma also deserves investigation. For now, in immuno-oncology, the BMS CMO chose to highlight his company’s three checkpoint inhibitors—namely, Opdivo, CTLA-4 inhibitor Yervoy and LAG-3 antibody relatlimab. Hirawat has every reason to remain skeptical; after all, no new cancer vaccine has reached the market for over a decade now following the FDA’s 2010 approval of Dendreon’s Provenge to treat metastatic castration-resistant prostate cancer (mCRPC). BMS itself swallowed a bitter pill in the field back in 2017 when its Bavarian Nordic-partnered cancer vaccine candidate Prostvac flopped in a phase 3 mCRPC trial. And Hirawat isn’t the only one who has reservations about cancer vaccines. Cost and access   Moderna’s candidate is a personalized vaccine, which is made with an mRNA coding for neoantigens selected based on the genetic mutation profile of each patient’s tumor. The idea is to increase the exposure of those antigens so that the immune system can better target them. The complex steps and individualized nature draws comparison to pricey CAR-T cell therapies and naturally raises the question of patient access. “My questions around this are more in the timing, the frequency of delivery, the manufacturability, and how do you deliver this to patients,” Paul Woodard, M.D., chief medical officer of Immune-Onc Therapeutics, said during a panel discussion at Fierce JPM Week. BeiGene’s chief medical officer of solid tumors, Mark Lanasa, M.D., Ph.D., concurred in questioning the scalability and accessibility of personalized cancer vaccines, especially in emerging markets. Manufacturing and delivery are valid questions for any potential cancer vaccine contenders. Provenge was never widely adopted partly because of its complicated treatment process. But Ira Mellman, Ph.D., vice president of cancer immunology at Roche’s Genentech, argued that personalized cancer vaccines’ turnaround time is already “less of an issue,” especially in a non-metastatic treatment setting. Affordability will continue to be a challenge, Mellman acknowledged, but he predicted cancer vaccines will cost less than existing CAR-T therapies. Thanks to advancements spurred by COVID-19 vaccines, personalized mRNA cancer vaccines' needle-to-needle production time—from obtaining a patient’s tumor sample to giving the vaccine—is about four weeks, Mellman said. That window is similar to or shorter than existing CAR-T cell therapies for blood cancers. And Mellman is hopeful that further improvements could come down the line. “These first hints of efficacy, I’m predicting, will generate a new round of innovation in RNA biology,” he said. Regeneron’s cancer immunotherapy chief Israel Lowy, M.D., Ph.D., also argued that access solutions will follow if the science of cancer vaccines pans out. “I think the concerns about the complexity of manufacturing neoantigens, things like that, those are technical issues,” Lowy said during the panel discussion. He pointed to how DNA sequencing has become much more affordable than it was 20 years ago. “You’re not violating the second law of thermodynamics to try to get this to work properly,” Lowy said. “It’s really a question of technical innovation. So, I’m confident that as we go forward with this, those solutions will emerge.” Regeneron isn’t following the personalized vaccine path, though. The Big Biotech partnered with BioNTech on the mRNA specialist’s FixVac platform. Shots developed with the platform include fixed combinations of antigens that are frequently expressed and shared across patients of a cancer type. Regeneron is pairing its PD-1 inhibitor Libtayo with BioNTech’s FixVac vaccines in PD-1-progressed melanoma, mCRPC and advanced non-small cell lung cancer. Advanced tumor versus early disease   Then the question is: Which treatment setting would cancer vaccines work best in? In other words, can the vaccines help debulk resistant, metastatic tumors as Regeneron is pursuing, or would they be more efficient in early-stage disease to help prevent cancer from returning, as Moderna and Merck are doing? Some experts believe it’s the latter. “I think some of the smart moves and how those trials are being performed is moving into the earlier-stage disease, where you have a more effective immune system to work with,” Bill Grossman, M.D., Ph.D., Gilead Sciences’ oncology therapeutic area head, said during the panel. “You don’t have all the tumor microenvironment, mechanisms of resistance, etc., that have been developed in the tumor.” Genentech’s Mellman said he’s enthusiastic about early disease, potentially even before a malignant tumor forms. The obvious problem with that ambition is uncertainties around the expression of antigens—you wouldn’t know what antigens to target because the tumor isn’t there yet. But Mellman suggested a solution may not be too far away. “I think with the advances that are being made in looking at [circulating tumor DNA] and deep sequencing of them, we may reach a point where we’ll be able to detect what neoantigens or conserved antigens or whatever are actually being made long before there’s a discernible radiologic tumor,” Mellman said. Before that obstacle can be overcome, the post-surgery adjuvant setting represents the closest to a precancerous treatment scenario and at the moment is “the most accessible place” to introduce a cancer vaccine, Mellman said. That’s because the systemic immunosuppression induced by a large tumor burden is lower or absent when the tumor is removed, he explained. There, a cancer vaccine would still work more like a traditional prophylactic, with the only difference being it would prevent tumor recurrence rather than initial occurrence. Roche has also partnered with BioNTech but on the German biotech’s individualized mRNA vaccine platform, iNeST. After posting very low tumor response data in a treatment-experienced group of cancer patients back in 2020, the two companies returned last year with encouraging results for their mRNA shot, known as RO7198457 or BNT122, this time in combination with Roche’s PD-L1 inhibitor Tecentriq and chemotherapy in adjuvant treatment of pancreatic cancer. Preliminary phase 1 data showed eight of 16 patients vaccinated with the personalized vaccine developed new neoantigen-specific T-cell responses. At a median follow-up of 18 months, those patients with a new immune response had a significantly longer recurrence-free survival compared to those without vaccine-induced responses. Based on the early-stage data, BioNTech and Genentech are planning a randomized clinical trial of the combo regimen in patients with resected pancreatic cancer. Mellman argued that cancer vaccines like RO7198457 could potentially become a backbone therapy in any adjuvant setting once the resected tissue is carefully examined. “You can imagine after any successful therapy, you’ll have a lot of information about the tumor, its antigenic profile, whatnot,” Mellman said. “I can imagine a situation where [a cancer vaccine] then becomes an adjunct to anything that you do. You vaccinate somebody to prevent the tumor from coming back.”