KRAS-mutated pancreatic cancer vaccine triggers immune response
90% of pancreatic cancers are linked with mutations in the KRAS gene
A vaccine therapy called ELI-002 2P led to anti-cancer immune responses in a Phase 1 trial and showed potential for preventing disease relapses among people with pancreatic cancer related to KRAS gene mutations.
“This is an exciting advance for patients with KRAS-driven cancers, particularly pancreatic cancer, where recurrence after standard treatment is almost a given and effective therapies are limited,” Zev Wainberg, MD, professor and researcher at the University of California, Los Angeles, and the study’s first author, said in a university news story. “This study shows that the ELI-002 2P vaccine can safely and effectively train the immune system to recognize and fight cancer-driving mutations.”
The study, “Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results,” was published in Nature Medicine. It was funded by Elicio Therapeutics, the vaccine’s developer.
Elicio is developing a next-generation version of the vaccine called ELI-002 7P that’s designed to target a broader set of KRAS mutations. A fully enrolled Phase 2 trial called AMPLIFY-7P (NCT05726864) is testing it in adults with pancreatic cancer and other KRAS-mutated solid tumors.
About 25% of solid tumors, including 90% of pancreatic cancers, are associated with mutations in the KRAS gene that’s involved in cell growth and division. These mutations help tumors grow uncontrolled and are associated with more aggressive cancer that’s less responsive to treatment. For this reason, therapies that target mutant KRAS (mKRAS) proteins are of interest, but this has “long been considered one of the difficult challenges in cancer therapy,” Wainberg said.
What does the ELI-002 vaccine do?
The ELI-002 vaccine is designed to stimulate the immune system to recognize and attack cancer cells that express mKRAS. It contains mKRAS protein fragments (peptides) and another immune-activating substance that are shuttled directly to the lymph nodes. There, the vaccine activates immune T-cells, which subsequently become trained to recognize and attack cancer cells expressing mKRAS.
Unlike other vaccine-based approaches that have to be individually developed for each patient, ELI-002 is an “off-the-shelf,” or ready-to-use option. It could thus represent, “a promising approach to generating precise and durable immune responses without the complexity or cost of fully personalized vaccines,” Wainberg said.
Called AMPLIFY-201 (NCT04853017), the Phase 1 trial was designed to test the safety and efficacy of the ELI-002 2P vaccine in 20 people with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, and five people with colorectal cancer who had KRAS mutations expected to respond to the vaccine. All had undergone surgery to remove their cancer, but were considered to be at a high risk of a relapse because blood tests showed signs that a small amount of cancer cell DNA was remaining. All the participants received the vaccine.
The final results, consistent with previous analyses, showed the vaccine was well tolerated and led to durable treatment responses.
Vaccine causes immune response
Twenty-one of the 25 (84%) developed mKRAS-specific T-cells after receiving the vaccine, with these immune responses often persisting over time. In around a quarter of them, tumor-associated biomarkers were completely gone.
Over a follow-up of 19.7 months, or 1.7 years, the median radiographic relapse-free survival, that is, time spent alive without signs of cancer recurrence on imaging, was 16.3 months (nearly 1.5 years) and the median overall survival was 28.9 months (nearly 2.5 years). These survival rates exceed what’s normally seen with these forms of cancer, according to the scientists.
The greatest benefits were observed in those who developed strong T-cell immune responses to the vaccine.
In the group with higher T-cell responses (those that reached above a certain threshold), the median relapse-free survival was not reached, meaning thatnot enough people had a cancer recurrence to calculate a value. Those with T-cell responses below the threshold had a median relapse-free survival of about three months.
Likewise, median overall survival wasn’t reached for high T-cell responders, compared with median survival of nearly 16 months for the low T-cell group.
Two-thirds of those with above-threshold immune responses — 11 of 17 people — were free from disease progression, including five who remained free of relapses and didn’t receive any subsequent therapy after ELI-002 2P treatment. The other six patients started chemotherapy after their tumor markers went up, but didn’t show any signs of disease progression during the follow-up.
The disease progressed in all eight people below the threshold, and seven of them died.
“We observed that patients who developed strong immune responses to the vaccine remained disease-free and survived for much longer than expected,” Wainberg said.
About two-thirds of those developed immune responses to other tumor-associated proteins not specifically targeted by the vaccine, a phenomenon known as antigen spreading.
“Taken together, the long-term follow-up of the AMPLIFY-201 phase 1 study provides evidence that ELI-002 2P induces potent … T-cell immunity to mKRAS alongside frequent antigen spreading that may delay tumor recurrence,” the researchers wrote.
While ELI-002 2P targeted two specific forms of mKRAS, the next-generation vaccine being tested in the Phase 2 trial targets seven.
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