Over the past decade, the rapid advancement of immunotherapies has been revolutionary in several cancers. However, pancreatic ductal adenocarcinoma, or PDAC, has been described as a “cold tumor” where immunosuppression results in low T-cell infiltration and poor treatment responses to immunotherapy. PDAC is an aggressive form of cancer with an average 5-year survival rate of less than 10% and a nearly 90% rate of recurrence.
In a 2017 publication1, Dr. Vinod Balachandran, surgical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), worked with Adaptive to leverage our T-cell receptor beta (TCRB) sequencing assay on research that found long-term survivors of PDAC could mount spontaneous T-cell responses against tumor-specific neoantigens not shared among patients. From there, he hypothesized that personalized mRNA vaccines could provide clinical benefit.
Results from Balachandran’s Phase 1 study2 of a personalized mRNA vaccine were recently published in Nature, and demonstrated a potential breakthrough for PDAC treatment. Again, Adaptive Immunosequencing provided critical insight into the T-cell response elicited by the vaccine, and its correlation with delayed disease recurrence.
T-Cell Clonal Expansion as a Potential Prognostic Biomarker
To investigate the diversity and specificity of T-cell clonal expansion generated by the mRNA vaccine, the study authors developed a mathematical method using Adaptive Immunosequencing that analyzed peripheral blood pre- and post-vaccination. They identified vaccine-induced expanded clones in 8 of 8 responders and 1 of 8 non-responders, serving as a potential prognostic biomarker of disease recurrence. Adaptive Immunosequencing provided a quantitative and molecular characterization of T-cell clones, allowing for identification of vaccine vs immune checkpoint inhibitor (ICI) expanded T cells and uncovering a T-cell response in a non-responder that was missed by ELISpot (a traditional functional assay).
About the Study
Balachandran and his team of MSKCC researchers shipped samples of PDAC patient tumors to scientists at BioNTech and Genentech. The tumors were sequenced to identify individual patient neoantigens to create a patient-specific vaccine, autogene cevumeran.
The vaccine was given in combination with an ICI and chemotherapy after surgery. At 18-months median follow-up, half of those treated (eight patients) who had T-cell responses to autogene cevumeran were recurrence-free, with a significantly longer recurrence-free survival compared to 13.4 months median in eight non-responders.
A Critical Tool in Drug Development
This study highlights how Adaptive Immunosequencing can assess response and provide quantitative data to inform the development of new vaccines that can have significant impact on patient lives. This is the power of Immune Medicine in action.
References:
- Balachandran VP, Leach SD, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature (2017)
- Rojas LA, Balachandran VP, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature (2023)