The success of messenger RNA (mRNA) technology in developing vaccines for infectious diseases has provided a foundation for its application in oncology. Moderna, a pioneer in this field, is strategically shifting its focus from preventing viral infection to treating existing cancer. This new approach involves therapeutic cancer vaccines, which are designed to harness the body’s immune system to recognize and attack tumor cells. These vaccines offer a form of personalized immunotherapy by instructing the immune system to specifically identify and eliminate malignant cells. This represents a significant evolution in the use of the mRNA platform.
Adapting mRNA Technology for Oncology
The fundamental challenge in developing cancer vaccines is teaching the immune system to distinguish cancer cells from healthy ones. The solution involves identifying tumor-specific protein fragments called neoantigens. These are mutated proteins unique to the tumor, arising from random somatic mutations, making them recognizable as “foreign.” The mRNA platform allows for the rapid encoding of blueprints for multiple neoantigens.
The process for a personalized cancer vaccine (PCV) begins with a biopsy and genetic sequencing of the patient’s tumor and normal cells. Bioinformatic algorithms analyze the tumor’s genetic signature to predict which specific neoantigens will provoke the strongest immune response. Up to 34 unique neoantigen blueprints can be encoded into a single synthetic mRNA molecule. This material is encapsulated within lipid nanoparticles (LNPs) to protect the fragile mRNA and facilitate efficient delivery.
This manufacturing process is time-sensitive, requiring the custom-made vaccine to be delivered within weeks of the biopsy. Moderna’s pipeline includes this personalized approach, such as mRNA-4157, which targets an individual’s unique mutational signature. The company is also exploring “off-the-shelf” approaches, like mRNA-4359, which encode for common tumor antigens shared across many patients.
Current Status of Key Clinical Programs
Moderna’s oncology pipeline centers on its lead personalized candidate, mRNA-4157, co-developed with Merck. This is the most clinically advanced program, currently in Phase III trials for the adjuvant treatment of high-risk stage III/IV melanoma following surgical resection. The Phase IIb KEYNOTE-942 trial showed promising results: combining the vaccine with the checkpoint inhibitor pembrolizumab reduced the risk of recurrence or death by 44% compared to pembrolizumab alone.
Building on the melanoma success, the personalized vaccine is expanding into other tumor types within the Phase III INTerpath trial program. This includes adjuvant treatment for non-small cell lung cancer (NSCLC), with Phase III trials underway for patients following surgical resection or those who did not achieve a complete pathological response after neoadjuvant therapy. The collaboration is also advancing mRNA-4157 through Phase II trials in other indications.
These Phase II studies include renal cell carcinoma, high-risk muscle-invasive urothelial carcinoma (bladder cancer), and first-line metastatic squamous NSCLC. Separately, Moderna is investigating the “off-the-shelf” vaccine mRNA-4359 in a Phase I/II trial for advanced solid tumors, including lung cancer and melanoma. Early data for mRNA-4359 showed an immune response against two proteins of interest, PD-L1 and IDO1, validating the company’s multi-pronged strategy.
Training the Immune System: The Therapeutic Mechanism
Once administered, the lipid nanoparticles deliver the genetic instructions into the patient’s cells, primarily specialized immune cells known as antigen-presenting cells (APCs), such as dendritic cells. These dendritic cells translate the mRNA blueprint to produce the targeted neoantigen proteins. They then process these tumor proteins into smaller peptide fragments and display them on their surface using major histocompatibility complex (MHC) molecules.
This display trains the immune system, signaling the presence of tumor cells. The antigen-loaded dendritic cells travel to the lymph nodes, where they encounter and activate T cells. Specifically, they activate cytotoxic T lymphocytes (CTLs), a type of CD8+ T cell programmed to directly kill foreign cells.
The vaccine prompts a robust T-cell response, creating cells tailored to recognize the tumor antigens. This process also generates long-lived memory T cells, which monitor the body for cancer recurrence, offering durable protection against relapse. The resulting immune activity helps transform a typically “cold,” non-responsive tumor microenvironment into an “inflamed,” immune-responsive one.
Strategic Use in Combination Therapies
Moderna’s therapeutic vaccines are primarily developed as a component of combination therapy, most notably with immune checkpoint inhibitors. Checkpoint inhibitors, such as pembrolizumab, block proteins like PD-1 or PD-L1, which tumors use to suppress the immune attack. By removing this natural brake on the immune system, these drugs allow pre-existing T cells to attack the tumor.
Checkpoint inhibitors are most effective when the patient already has T cells that recognize the cancer, which is often not the case in “cold” tumors. The cancer vaccine addresses this limitation by actively generating a high number of new, tumor-specific T cells. The checkpoint inhibitor then ensures these newly generated T-cells can aggressively engage and kill the cancer cells without suppression.
Clinical trial designs reflect this synergistic strategy, combining mRNA-4157 with pembrolizumab in an adjuvant setting to prevent cancer recurrence after surgery. This dual-action approach maximizes the anti-tumor effect: the vaccine creates a targeted immune cell population, and the checkpoint inhibitor ensures those cells function unimpeded. Early clinical data from the melanoma trial supports this combination, demonstrating superior patient outcomes compared to the checkpoint inhibitor alone.