Abstract 3272: Tumor treating fields combined with the PULSAR paradigm for radiotherapy and an immune checkpoint inhibitor enhances antitumor efficacy in vivo
Authors: Karanam Narasimha K. , Shang Zengfu , Timmerman Robert , Story Michael D. , Saha Debabrata 
Published: April 2023

Abstract
Tumor Treating Fields (TTFields) is a new mode of physical cancer treatment that delivers low-intensity, intermediate frequency, alternating electric fields to tumors in a non-invasive manner. A number of in vitro studies have demonstrated that TTFields play an important role in suppressing the DNA damage pathways and increasing replication stress, in addition to interfering with mitosis. During interphase TTFields creates a conditional vulnerability environment that would make cells more susceptible to radiation and chemotherapy. The PULSAR concept relies on ablative doses of radiation spaced at least one week apart to allow a tumor to adapt to the first radiation dose before a second dose of radiation is applied. As a result, the therapy should be less toxic and be adaptable according to changes in tumor morphology, location, and response to radiation. TTFields seems well suited to the PULSAR paradigm given the time between radiation doses where TTFields application would have the potential to enhance tumor response to a subsequent radiation exposure and this is described here. First, in in vitro studies, a greater increase in radiation susceptibility was observed when cells were exposed to TTFields before radiation (IR) treatment compared to IR treatment followed by TTFields. In the present study, TTFields were combined with IR or IR+immune checkpoint inhibitor (ICI) to evaluate the combinatorial effectiveness in mouse tumor models. Three syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer), were used in the initial tumor growth delay (TGD) studies. TTFields exposure increased TGD in all three mouse models, but the difference in tumor volume over time was not statistically significant due to small sample sizes. Combination studies were then initiated using the MC38 mouse model since TTFields resulted in a greater TGD effect in this model. The first in vivo experiment combined one round of TTFields with radiation therapy, which significantly delayed tumor growth. The combined efficacy of two rounds of TTFields and IR treatment was further delayed compared to radiation or TTFields alone. The combination of TTFields prior to each IR dose, two rounds of IR spaced one week apart, and an ICI (PD-L1 Ab) given sequentially inhibited tumor growth far more than either TTFields plus the ICI or TTFields plus IR or IR plus the ICI alone. To explain this increased efficacy immune-related changes in the tumor microenvironment is being evaluated. In addition, gene expression analysis is also ongoing to confirm the changes in gene expression underlying the in vitro TTFields effect on DNA repair and replication stress. In conclusion, the PULSAR paradigm for radiotherapy seems well suited for the application of TTFields prior to each radiation dose and that effect is enhanced when an ICI is also introduced.
Citation Format: Narasimha K. Karanam, Zengfu Shang, Robert Timmerman, Michael D. Story, Debabrata Saha. Tumor treating fields combined with the PULSAR paradigm for radiotherapy and an immune checkpoint inhibitor enhances antitumor efficacy in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3272.