Radiation Biology

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SU_38_2382 - Radiation Therapy in Combination with Hyperthermia and Immunotherapy Inhibit Pancreatic Tumor Growth and Modulate Tumor Microenvironment in Mice

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Radiation Therapy in Combination with Hyperthermia and Immunotherapy Inhibit Pancreatic Tumor Growth and Modulate Tumor Microenvironment in Mice
J. Mahmood1, A. Alexander2, S. Samanta3, S. Soman2, H. Shukla2, E. Davila2, F. Carrier2, I. Jackson4, and Z. Vujaskovic5; 1University of Maryland Department of Radiation Oncology, Baltimore, MD, 2University of Maryland, Baltimore, Baltimore, MD, 3University of Maryland, Dept. of Radiation Oncology, Baltimore, MD, 4Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 5University of Maryland Medical Center, Baltimore, MD

Purpose/Objective(s): Pancreatic cancer (PCa) has 5-year survival rate of only 8% with standard multimodality treatment that includes surgery, radiation therapy (RT), and chemotherapy. Surgery is offered only to 10–20% of PCa patients. Current treatments are clearly inadequate for unresectable cases and new strategies are crucially required. PCa induces an immunosuppressive tumor microenvironment (ME). This attracts immunosuppressive cells (macrophages and regulatory T-cells) to the stroma that relates to treatment resistance by decreasing antitumor immunity. Single agent therapy including check point inhibitors (immunotherapy) are largely ineffective in PCa, suggesting the need for combined therapeutic modality approach. Cytotoxic CD8+ T cell responses require T cell receptor activation plus co-stimulation, which can be provided through ligation of OX40 (CD134), a tumor necrosis factor receptor family member. Further, tumor-targeted hyperthermia, a sensitizer to RT that can also modulate tumor-ME by recruiting T cells, thereby mitigating treatment resistance. Therefore, we hypothesize that RT combined with tumor targeted-HT in combination with an immune activating (agonist) anti-OX40 monoclonal antibody (tripartite treatment) will augment anti-tumor effect in PCa by modulating tumor immune-ME.

Materials/Methods: We used a syngeneic PCa mouse model by injecting mouse PCa (Panc02) cell line to induce subcutaneous tumor in the flank of male C57/6J mice. The SC tumor was heated to tumor targeted 42.50C using water bath 30-minutes prior to 4Gy fractionated RT in two days. Mice were intraperitoneally injected 3 shots of anti-OX40 antibody with 5 days interval. A cohort of mice were euthanized at 10 days to check tumor, and blood for immune response using flow cytometry and western blotting. Tumor growth was daily monitored until 45 days post-treatment.

Results: Tripartite treatment demonstrated a significant tumor growth inhibition (p<0.0001) up to 45 days post-treatment. Compared to the control, 39.1 ± 3.5 times fold reduction in the final tumor volume was observed in the tripartite treated animals with increased survival. Flow cytometric analysis of tumor and blood samples revealed a substantial immunomodulatory effect in animals receiving tripartite treatment. A significantly increased (p<0.01) population of CD4+, and CD8a+ cells were observed in the tumor-ME in tripartite treatment groups. A significantly higher population of helper T cells and cytotoxic T cells was observed in the PCa tumor-ME. Tripartite treatment showed a significantly (p<0.05) higher LAG3 (CD223) + cells in the tumor-ME suggesting increased infiltration and antigen presentation of the immune cells in the tumor. In addition, there was no toxicity observed in mice with tripartite treatment regimen.

Conclusion: Our results provide the first preclinical evidence about the effects of tripartite treatment as a novel therapeutic option to improve the PCa tumor response by altering the tumor immune-ME and survival.

Author Disclosure: J. Mahmood: None. A. Alexander: None. S. Soman: None. H. Shukla: None. Z. Vujaskovic: None.

Javed Mahmood, PhD

Biography:
Dr. Javed Mahmood joined as a faculty (Assistant Professor) in the Division of Translational Radiation Sciences (DTRS), Dept. of Radiation Oncology, School of Medicine, University of Maryland, Baltimore in August 2014. He did my post-doctoral research fellowship in Applied Molecular Oncology and Radiation Biology, Ontario Cancer Institute, Princess Margaret Hospital of Toronto University, Canada. Princess Margaret Hospital, which is one the 5 largest cancer research/treatment centers in the world. During his post-doctoral fellowship, he was trained by Prof. Richard Hill, a world-famous radiation biologist. He actively worked on radiation oncology research using different animal models and tumor xenografts. Dr. Mahmood also worked as a Research Associate and Project Lead at STTARR innovation center which is a center of excellence of Princess Margaret Cancer Centre of Toronto University, Canada where he was extensively involved in pre-clinical multi-modal tumor imaging, targeted radiation therapy and tumor microenvironment research in pancreas, lung, stomach, and prostate cancer animal xenograft model and targeted radiation therapy using small animal radiation research platform (SARRP). His current lab at the University of Maryland, Baltimore is highly focused on developing new drugs to increase radiotherapy response of Photon and Proton beam radiation in different animal tumor xenograft models (Prostate, Lung, Chordoma, and Pancreas cancer) and developing new drugs that have potential translational values (Bench side to Bedside).

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