Innovative Cancer Vaccine Reduces Recurrence in KRAS-Mutated Pancreatic and Colorectal Cancer

According to a recent study by Pant and colleagues published in Nature Medicine on 9 January 2024, a new cancer vaccine may help prevent recurrence in patients with KRAS-mutated pancreatic and colorectal (large bowel) cancers.

Study Rationale and Importance

Colorectal cancer and pancreatic ductal adenocarcinoma are the second and third most common causes of cancer-related death. Standard postoperative treatments for these cancers are reported to keep only 20% of patients alive at 5 years, and effective options are limited if cancer recurs. In microsatellite-stable (MSS) colorectal cancer, the ineffectiveness of immunotherapies is associated with low numbers of the specialized immune cells (TILs) needed to attack cancer cells and low numbers of the expected mutations in cancer cells. However, cancer-driving KRAS mutations occur in 93% of pancreatic cancers and 50% of colorectal cancers. They persist throughout cancer progression and play an important role in cancer-cell survival. Immunotherapies targeting KRAS mutations are therefore considered a promising target in cancer treatment.

T-cell therapy focused on the KRAS gene can directly target cancer cells without the risk of harming the body's healthy cells. It is not affected by the processes that normally cause the immune system to avoid attacking healthy cells. This treatment has shown promising results in people with the specific HLA C*08:02 genetic type who have KRAS G12D-mutated pancreatic cancer or certain colorectal cancers. However, it works only in patients with particular genetic characteristics, requires complex preparation, is expensive, and may sometimes cause serious side effects. Vaccines, by contrast, have broader potential to increase KRAS-directed T cells in people with different genetic characteristics, involve simpler manufacturing, and can be available off the shelf.

KRAS-mutated cancers account for approximately 25% of all solid tumors (those arising in organs or tissues).

The innovative lymph-node-targeted ELI-002 vaccine was designed to reduce recurrence by enabling T cells to recognize KRAS G12D- or G12R-mutated cancer and eliminate tumor cells. Because ELI-002 is a premade biotechnology product, it does not need to be formulated individually for each person.

Study Details

Patients who undergo surgery for pancreatic cancer remain at risk of recurrence even after completing chemotherapy... This is particularly true of patients positive for circulating tumor DNA [ctDNA], which places them at greater risk. Once they relapse, the disease becomes much harder to treat, making this a clear area of unmet need.

Study Methods and Results

In the phase I AMPLIFY-201 trial, 25 previously operated patients with pancreatic or colorectal cancer at high risk of recurrence were selected to try a new vaccine called ELI-002. They received up to 10 doses.

Researchers observed that the vaccine activated the immune system, generating a T-cell response, in most participants (84%) and all patients receiving the highest dose (100%). This immune response was associated with lower cancer markers and clearance of cancer DNA (ctDNA), and was found to reduce the risk of cancer recurrence or death by 86%.

Among patients with a strong immune response, the times to cancer recurrence and death had not yet been determined; most were still well. Among those with a weak immune response, however, median cancer-free survival was only 4 months. These are important findings indicating the vaccine's effectiveness.

According to researchers, no patient experienced dose-related toxicity, cytokine release syndrome, or any treatment-related side effect above grade 3. The most common side effects were fatigue (24%), injection-site reactions (16%), and myalgia (12%).

Conclusion

It is still early, but promising results suggest that this vaccine may help many patients avoid recurrence and thereby improve survival. It also showed a favorable safety profile, which is exciting.

The researchers stated that the positive findings led to a new phase II trial scheduled to begin in 2024, using a new formulation of ELI-002 that would target additional KRAS mutations.