Main Session
Sep
27
PQA 01 - Gastrointestinal Cancer and Central Nervous System
2118 - Exploring the Potential of Immune Priming Through Proton FLASH Radiation in Pancreatic Cancer
Presenter(s)
Varintra Lander, MD, PhD - Washington University in St. Louis, St. Louis, MO
V. E. Lander1, C. S. Bathula1, H. Zhang1, W. Smith1, M. Lowe1, T. Zhao1, B. E. Sells2, M. Rance2, B. Knolhoff2, L. I. Kang3, B. Rogers1, H. Kim1,4, C. J. DeSelm1,4, S. M. Perkins1,4, D. Denardo2,4, and J. K. Schwarz1,4; 1WashU Medicine, Department of Radiation Oncology, Saint Louis, MO, 2WashU Medicine, Department of Medicine (Oncology), Saint Louis, MO, 3WashU Medicine, Department of Pathology & Immunology, Saint Louis, MO, 4Siteman Cancer Center, Barnes Jewish Hospital, Saint Louis, MO
Purpose/Objective(s):
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options. Radiation therapy (RT) has been utilized in many PDAC patients to improve resectability. However, the highly ablative doses necessary for effective tumor control have been limited by toxicity to adjacent radiation-sensitive tissues. Recent studies suggest that FLASH-RT, which delivers ultra-high dose rates, may limit radiation-induced toxicity while maintaining anti-cancer effects. More specifically, FLASH-RT targeted to the whole abdomen has shown improved intestinal crypt survival, faster body weight recovery, and higher survival probability. Nevertheless, the impact of FLASH-RT on PDAC remains underexplored. Our study aims to compare FLASH-RT and conventional/CONV-RT’s effects on PDAC tumor control and immune response to enhance treatment approaches for this highly recalcitrant tumor.Materials/Methods:
To elucidate how the different RT modalities reduce tumor burden and prime antigen-specific T cell responses, we compared vehicle-treated PDAC-bearing mice with those treated with 14Gy of FLASH-RT (60-80Gy/sec; at the center of a pulsed 2.2cm spread-out Bragg peak delivered with a synchrocyclotron) and those with CONV-RT (0.5-1.2Gy/sec).Results:
Both FLASH-RT-treated and CONV-RT-treated mice showed reduced tumor burden compared to vehicle-treated mice. Analysis of one-week post-treatment revealed increased CD8+ T cell infiltration and a reduction in pro-tumorigenic cells (B cells and eosinophils) in both RT groups. FLASH-RT maintained stable cDC1 and NK cell numbers, unlike CONV-RT, which reduced them. FLASH-RT also increased anti-tumorigenic cells (CCR7+-migratory DCs and Ki67+-proliferating CD8+ T cells) and decreased pro-tumorigenic cells including granulocytes, monocytes, and PD1+-exhausted CD8+ T cells; benefits not observed with CONV-RT. Importantly, FLASH-RT did not cause lymphopenia, highlighting its potential as an immune-priming therapy for PDAC.Conclusion:
Despite comparable reductions in tumor burden, the immune response profile differed, with FLASH-RT-treated tumors displaying more favorable anti-tumor immune responses compared to CONV-RT-treated tumors. Notably, mice treated with CONV-RT exhibited a trend towards greater weight loss compared to those treated with FLASH-RT or Vehicle mice, although this difference was not statistically significant. We are currently conducting further validation studies, including histopathological analyses and survival rate assessments. Overall, these results suggest that FLASH-RT leads to a unique tumor immune response compared to CONV-RT, warranting further investigation.