A novel cancer vaccine that stimulates T-cell activity in KRAS-driven pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) has shown promise in early testing.
The investigational vaccine, ELI-002, developed by Elicio Therapeutics, is designed to train the immune system to recognize and attack tumor cells harboring mutant KRAS, which is present in roughly 93% of PDAC and 50% of CRC.
While only in phase 1 testing, the vaccine elicited strong T-cell responses in more than 80% of patients with minimal residual mutant KRAS disease following standard locoregional treatment. This strong response correlated with longer recurrence-free and overall survival, the investigators, led by Zev Wainberg, MD, with University of California, Los Angeles, reported online earlier this month in Nature Medicine.
It’s “extremely promising to have a vaccine that seems to stimulate T-cell activity in KRAS-driven tumors,” Magnus Dillon, PhD, clinician scientist at The Institute of Cancer Research, London, England, said in a statement from the UK nonprofit Science Media Center. “These are generally ‘immune cold,’ so therapies which stimulate immune responses in this group of patients are much needed.”
But Dillon and other experts not involved in the research cautioned that the data are preliminary, the study was not powered for efficacy, and no firm conclusions about clinical value can be drawn.
While there is “some interesting science in this study,” said Richard Sullivan, PhD, director, Institute of Cancer Policy, King’s College London, London, England, “this is a long way from proving any sort of clinical utility.”
“We’ve been here before with this sort of approach and not have it translate into tangible efficacy,” Sullivan added.
In the phase 1 AMPLIFY-201 study, 20 patients with PDAC and five with CRC who had minimal residual disease following surgery and chemotherapy received the peptide-based ELI-002 vaccine. Doses included 0.1 mg, 0.5 mg, 2.5 mg, 5 mg, and 10 mg. The researchers identified a T-cell response threshold — a 9.17-fold increase over baseline — that best differentiated patients with better (n = 17, 68%) and worse (n = 8, 32%) outcomes.
Overall, 21 of 25 patients (84%) developed mutant KRAS-specific T-cell responses, including all six patients treated at the two highest doses as well as responses in both CD4+ and CD8+ in 71% of patients. The induction of both CD4+ and CD8+ T cells significantly correlated with overall tumor biomarker response.
Tumor biomarker responses occurred in 21 patients (84%), with complete clearance in six (three PDAC and three CRC), as determined by tumor-informed ctDNA analysis.
With follow-up extended to a median of 19.7 months, median relapse-free survival was 16.3 months and overall survival was 28.9 months.
Median overall survival was not reached in above the threshold responders vs 15.98 months in those below (hazard ratio [HR], 0.23; P = .0099). Median radiographic relapse-free survival was also not reached in above the threshold responders vs 3.02 months in those below (HR, 0.12; P = .0002).
Overall, 11 of 17 patients with T-cell response above the threshold remained free from radiographic progression, whereas all eight patients below the threshold had radiographic progression, seven of whom died.
In addition, in 67% of patients, the immune system expanded its attack to other tumor-specific antigens not included in the vaccine, potentially broadening protection.
No dose-limiting toxicities or severe treatment-related side effects were reported.
Elicio Therapeutics is now testing a 7-peptide formulation of ELI-002 (ELI-002 7P) in 135 patients with mutant KRAS-driven PDAC, with interim data on disease-free survival expected later this year.
The findings are promising but preliminary.
“Many patients have these KRAS mutations, so an off-the-shelf vaccine could benefit lots of people — it saves the cost and time required to make a personalized vaccine,” Dillon commented.
“However, it’s a bit early to definitively tell whether this will work to prevent cancer relapse in this group of patients who have had all disease removed at surgery — larger studies will be needed,” Dillon said.
Sullivan noted that “all this paper really says is that the vaccine generates polyfunctional CD4+ and CD8+ T-cell immunity to mutant KRAS.”
Khurum Khan, MBBS, consultant medical oncologist, University College London Hospitals NHS Foundation Trust, London, England, agreed that, while the immune and clinical signals observed in this phase 1 study are “promising and hypothesis-generating” and “the scientific data presented are robust,” the findings do not yet establish efficacy.
“We cannot assume these findings will translate to benefit in larger phase 2 or phase 3 trials,” Khan said.
This study was sponsored and funded by Elicio Therapeutics. Wainberg reported receiving consultant/advisory fees from Alligator Bioscience, Bayer, Lilly Oncology, AstraZeneca, Merck, Merck KGaA, Daiichi Sankyo, MacroGenics, Amgen, Bristol-Myers Squibb, Astellas, Ipsen, Arcus, Novartis, PureTech, Roche, Seagen, and Pfizer, and reported receiving research funding (institutional) from Elicio Therapeutics, Five Prime Therapeutics, Arcus, Pfizer, Plexxikon, Novartis, and Merck. A full list of disclosures for the study authors is available with the original article. Dillon, Sullivan, and Khan had no disclosures.