Abstract 3766: Radiation enhances anti-tumor activity of immune checkpoint blockade in syngeneic tumor models
Authors: Urs Sumithra , Meade Mary Anne , Guley Kevin , Krueger Sarah , Wong Alden , Wise Scott , Franklin Maryland 
Published: August 2018

More than 50% of cancer patients receive some sort of radiation therapy during the course of their illness. While radiation treatment is a mainstay in clinical oncology, there is limited preclinical data in syngeneic models. The advent of image-guided small animal irradiators such as the Small Animal Radiation Research Platform (SARRP; Xstrahl) allow for use of targeted focal irradiation (RT) in a broad range of models. Here we evaluated the use of RT to broaden efficacy and response duration of immunomodulatory therapies.

As a first step, subcutaneous syngeneic tumor models were tested with single doses of RT. The A20 B cell lymphoma, the CT26 colon carcinoma, and the Pan02 pancreatic carcinoma all demonstrated dose response anti-tumor activity with increasing dose (5, 10 or 20Gy) of RT. In the A20 model, doses of 10 and 20Gy RT resulted in 2 tumor free survivors (TFS) each. CT26 had 1, 2 and 2 TFS each in RT groups of 5, 10 and 20Gy, respectively. In these 2 models, tumor free mice were rechallenged with appropriate tumor cell implants on the contralateral flank and, in all cases, tumors failed to develop suggesting a memory immune response was elicited. In Pan02 we found 1 and 5 TFS in the 10 and 20Gy groups, respectively.

In follow-on work, we used the CT26 model to compare 5Gy RT, bi-weekly dosing of anti-PD-1 (RMP1-14; Bio X Cell) or the combination. Treatments were initiated at approximately 100mm3 tumor volumes. Anti-PD-1 resulted in a slight tumor growth delay (TGD) of 5 days compared to isotype control, whereas RT resulted in a 19 day TGD and more than doubled the time to evaluation size (TES) from 16 days in the control to 35 days. In combination, the TGD was further improved to 40 days and TES to 56 days.

An additional colon model, MC38, was tested with 10Gy RT alone or in combination with anti-PD-1, or anti-PD-L1. Either antibody resulted in modest single agent activity with anti-PD-1 being slightly more efficacious than anti-PD-L1 with 15 days TGD compared to 7 days, respectively. Mice in the RT group demonstrated 20 days TGD. RT in combination with anti-PD-1 resulted in 37 days TGD, however, in combination with anti-PD-L1 TGD was not improved over RT alone. Effects of radiation and anti-PD-1 therapy on tumor infiltrating lymphocytes is being investigated in the MC38 model, and data will be shown.

GL261-luc, an orthotopic model of murine GBM, was also tested. We found that anti-PD-1 improved anti-tumor activity from control, a single dose of 7.5Gy RT further improved activity against control, and the combination was 100% curative. Evaluation of tumor infiltrating lymphocytes showed increased CD8+ T cells along with increased regulatory T cells (Tregs) as the model progressed. RT reduced the number of Tregs and a further reduction was observed following combination therapy. In summary, the

data presented here provides rationale for further evaluation of immunomodulatory agents in combination with RT.

Citation Format: Sumithra Urs, Mary Anne Meade, Kevin Guley, Sarah Krueger, Alden Wong, Scott Wise, Maryland Franklin. Radiation enhances anti-tumor activity of immune checkpoint blockade in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3766.