Pancreatic Cancer Immunotherapy: T-Cell Receptor Sequencing and Personalized Gene Fusion Vaccines

Immunotherapy has struggled to reduce the high mortality rate of pancreatic cancer,in part due to the low mutation burden and immunosuppressive microenvironment associated with the disease. Early successes have been limited to a small number of patients, highlighting the difficulty of attempts to modulate immune systems that have evolved to be unique in each patient. To better understand the mechanisms of anti-tumor immune responses and elucidate the differences between clinical responders and non-responders, an analysis of T-cell receptor repertoires of 106 pancreatic cancer immunotherapy patients was performed using a newly developed analysis package, immunoSeqR. The data provides new insights into the effects of several immunotherapies used in current clinical trials, including immune checkpoint blockade. Additionally, diverse baseline repertoires and treatment induced clonal expansion were found to be significantly associated with clinical response. Cancer vaccines must provide a source of antigens to direct an immune response, and while neoantigens arising from point mutations are often utilized for this purpose, fusion antigens, derived from genomic rearrangements are frequently overlooked. Seventeen putative fusion neoantigens were identified in two pre-clinical models and tested for their ability to induce immune responses and protect against tumor challenge when administered as a peptide vaccine. Antigen identification from next generation sequencing data was identified as a critical bottleneck for the development of personalized fusion vaccines. Analysis of the T-cell receptor repertoire in clinical trial patients provides new insights into the effects that vaccines, radiation, chemotherapy and checkpoint blockade have on the complex lymphocyte compartment. Current vaccine approaches typically proceed without knowledge of whether antigens included in the vaccine are shared by the patient. Personalized vaccine approaches solve this problem, and advances in technology are reducing the cost and time required for their development. Together, these two approaches represent significant steps in closing the response gap in pancreatic cancer immunotherapy