Tara Vrooman - Graduate Student, Advisor: Scott Gerber, PhD
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is currently the fourth leading cause of cancer related deaths, with a 5-year survival rate of only 10%. Surgical resection is the only successful cure thus far, but even with resection there is an 80% chance of recurrence. Immunotherapy, which involves stimulating the immune system to recognize and destroy tumor cells, has emerged as a viable therapy for a variety of tumors, but has been largely unsuccessful in treating PDAC due to the inherent suppressive nature of this malignancy. However, recent data suggests that the efficacy of immunotherapy may be enhanced when combined with standard of care treatments such as radiotherapy. Our laboratory has developed a novel treatment that combines the potent antitumor immune cytokine, interleukin-12 (IL-12) with highly effectivestereotactic body radiation therapy (SBRT), which results in remarkable tumor control and cure in a preclinical orthotopic model of PDAC.
Due to the high likelihood of recurrence in this malignancy, we investigated whether this combinatorial treatment approach can promote long-lasting antitumor immunity. Our data demonstrated that mice cured of primary PDAC tumors following SBRT + IL-12 therapy are protected against tumor rechallenge for as long as 8 months post-cure. Importantly, transfer studies revealed that CD4+ memory T cells, but not CD8+ memory T cells are the predominant immune subset responsible for long-lasting immunity. We further characterized this CD4+ T cell memory subset and determined that the cells within the peripheral lymphoid tissues expressed phenotypic markers for central memory T cells (Tcm), which have been reported to be ideal for providing durable antitumor immunity. Additionally, while investigating the cured pancreas 6-8 months after treatment, we observed pronounced changes in tissue architecture by immunohistochemistry and flow cytometry, with adipose rich areas containing abundant CD4+ T cells, which exhibited a tissue-resident memory (Trm) phenotype of CD44+, CD62L-, & CD69+. These data suggest that local SBRT + IL-12 therapy results in the presence of long-lived Trm cells in the pancreas that may be poised to attack recurrent tumor cells.Future plans will translate these findings into a clinical trial where PDAC patients eligible for surgical resection will first receive treatment with SBRT + IL-12 in a neoadjuvant setting before surgery. We hypothesize this innovative combination therapy will act as an in-situ vaccine and induce memory cells toprotect against PDAC recurrence
Oct 27, 2022 @ 12:00 p.m.
Medical Center | K-307 (3-6804)