New Vaccine Harnesses Power Of the Lymph Nodes

Recurrence of pancreatic cancer after surgery to remove the tumor is every patient’s fear, and rightly so.

Even with chemotherapy after surgery, patients have a significant chance of the cancer coming back. This is because microscopic disease may lurk in the body, and it cannot be detected on scans. Undetected microscopic disease is the reason pancreatic cancer remains one of the most lethal of all malignancies.

Although combination chemotherapy regimens and a drug class known as KRAS inhibitors are showing some promise for patients, immunotherapies, which have revolutionized treatment for some other cancers, are lagging behind in pancreatic cancer. But science is making progress.

Researchers are now creating classes of vaccines that may be able to train the immune system to target pancreatic cancer. A case in point: Scientists are testing a peptide-based vaccine targeting KRAS G12D and KRAS G12R, two common pancreatic cancer mutations that drive tumor growth. The vaccine is dubbed ELI-002 2P and it’s been tested in patients with pancreatic or colorectal cancer in a phase I clinical trial called AMPLIFY-201.

How the Vaccine Works

Cancers with RAS mutations account for 25 percent of human solid tumors. Between 90 and 95 percent of pancreatic cancer patients have KRAS mutations. In the phase I AMPLIFY-201 study, ELI-002 2P targeted two of the KRAS mutations, G12R and G12D, the most commonly occurring variant in pancreatic, colorectal, non-small cell lung, ovarian, biliary, and gallbladder cancers.

The technology basically allows the ELI-002 2P  vaccine to train the immune system’s T cells to recognize the G12R and G12D KRAS mutations. Once they are recognized, the T cells, along with helper T cells, zeroes in and targets the mutations for elimination.

The fact the vaccine gets to the lymph nodes by latching on to the protein albumin, which is found in the bloodstream, makes this approach unique and potentially very powerful, says investigator Shubham Pant, M.D., M.B.B.S, Professor in the Department of Gastrointestinal Medical Oncology and Investigational Cancer Therapeutics in the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center (Houston). Lymph nodes are one of the key secondary lymphoid tissues where immune cells congregate and where adaptive immune responses are initiated.

“They call the lymph system the command center or the brains of the immune system,” he explains. “The lymph nodes are where there is this complex coordination occurring between the antigen-presenting cells and the T cells. The T cells go out from the lymph nodes and then find their way into the cancer. Hopefully, they do their job then of targeting and then eliminating the cancer cells.”

More About the Trial

The trial was for patients whose pancreatic tumors had been surgically removed and who had finished their chemotherapy. These patients had no evidence of disease, but were at high risk for recurrence because they had circulating tumor DNA (ctDNA) or an increase in the cancer biomarkers (CA19-9 or CEA) in their blood after treatment. Twenty patients with pancreatic cancer and five patients with colorectal cancer received up to six priming doses and four booster doses of ELI-002 2P. Various doses of a vaccine adjuvant designed to boost T cell expansion were included and tested. 

• T cells targeting the mutant KRAS neoantigens were detected in 20 of 23 patients that could be evaluated, including all nine patients treated with the two highest doses of the vaccine adjuvant.
• A six-month vaccine course resulted in 77 percent of patients having reduced tumor markers, with six patients achieving complete responses. Notably, the technology induced both helper and killer T cells in over half the patients, offering a balanced response.
• Long-term follow-up revealed sustained memory T cells in 75 percent of those included post-boosters. Moreover, a strong correlation emerged between above-median T cell responses and reduced relapse, aligning with the therapy’s goal.

“Minimal residual disease is really a concept that’s been more associated with leukemia and other hematologic malignancies but not so much in solid tumors,” explains Pant. “So what we did in this trial was examine patients who underwent surgery for colon or pancreas cancer who have absolutely no evidence of disease after surgery when we did a scan.”

But when doctors tested blood samples they noted that ctDNA or tumor markers were rising. “At that point, the patient could get this experimental vaccine targeted against the KRAS mutations,” he adds.

The Future of ELI-002

Although he is excited about this trial, Pant cautions that more work needs to be done. “We are getting biomarker responses, we need to study this more. We need more research and obviously bigger trials. However, I am excited because I believe this is the right population to study.” Patients with pancreatic cancer who undergo surgery still run a significant risk of recurrence due to micrometastatic disease. “Surgery offers the only real chance of a cure at this point, and certainly things are improving with adjuvant therapy,” he says. “But still far too many patients succumb to the disease, so this may be one way we improve the odds.”

One of the attributes of the vaccine that particular excites Pant is the vaccine is literally  “off the shelf … and can be given to a patient quickly if they meet certain requirements and have the relevant RAS mutations. But, again, these are early days, so we need to be patient to see what we can learn through more ongoing trials.”

Based on this early data, researchers are running another trial called AMPLIFY-7P. This phase II multisite randomized trial targets seven mutations, specifically G12D, G12V, G12R, G12C, G12S, G12A, and G13D, in patients with high relapse risk, KRAS-driven cancers who have minimal residual disease following surgery and chemotherapy. Researchers hope to recruit 156 participants.