Challenging Current Paradigms: Increasing the Efficacy of Radiation Therapy with Novel Radiation Schemes

Abstract

Cancer is the second leading cause of death in the United States. Currently over 50% of all patients are treated with radiation therapy (RT). Although RT is frequently used for local control of solid tumors, recent reports have shown both immune activating and immunosuppressing roles of RT. We have studied the immunomodulatory effects of RT and have designed different regimens of RT with varying roles in immunomodulation and tumor control. We propose to use radiation as an immunomodulatory drug and classify three regimens of RT: low-dose tumor microenvironment modulatory RT (TMEM-RT), sub-lethal immunomodulatory RT (IM-RT), and high-dose immunoablative RT (IA-RT).

Historically, RT fractionation has been divided into daily fractions of equal doses of radiation to reduce toxicity on the basis of time required for DNA repair in normal tissues. Although single high-dose IA-RT would release tumor associated antigens (TAA) and danger-associated molecular pattern (DAMP) signals for immune activation, it is also associated with reduced perfusion and an induction of regulatory T cells (Tregs) in the irradiated tumor microenvironment (TME). Low doses of RT have been shown to reprogram immunosuppressive macrophages and increase infiltration of immune effector cells. We, therefore, hypothesized that after a single high-dose IA-RT, post-ablation modulation (PAM) with low-dose TMEM-RT fractions would reprogram the THE by increasing inflammatory Ml macrophages, reducing the levels of Tregs and enabling the infiltration of immune effector cells, thereby increasing efficacy of tumor control. In this work, we challenge the current paradigm of equal fraction size in RT and propose a regimen of unequal radiation fractionation sizes by combining a single high-dose IA-RT fraction, followed by four 0.5 Gy fractions of TMEM-RT as PAM, applied either to increase local control or to suppress systemic metastases.

Using image guided radiation, we found that we could significantly delay local tumor growth and increase survival in 3LL tumor bearing mice with a single 22Gy dose, followed by four 0.5Gy PAM doses to the primary tumor, as compared to a single 24Gy IA-RT dose alone. PAM-mediated increase in local control of the primary tumor was associated with an increase in infiltration of leukocytes and a decrease in immunosuppressive immune cell phenotypes in treated areas and secondary lymphoid organs. In a separate tumor model, we administered whole lung TMEM-RT of four fractions of 0.5 Gy, twelve days after a course of three IA-RT fractions of 20 Gy to the primary tumor and observed an increased survival with suppression of pulmonary metastases in mice with highly metastatic 4T1 breast cancer. Systemic PAM remodels the metastatic niche by reducing Treg and increasing the infiltration of immune effector cells, thereby, converting the "soil" of the metastases-prone organ, resistant to tumor growth.

Thus, low dose TMEM-RT can be used as PAM for two applications: i) Local control with PAM administered directly after immune-ablative radiation to the primary tumor, and ii) Systemic control with PAM administered to potential metastatic prone organs, such as, whole lungs for targeted systemic control of tumors that can be locally controlled by IA-RT. By optimizing the immunomodulatory properties of radiation fractionation regimens, we laid the foundation for combining immunotherapeutics, such as tumor vaccines, checkpoint blockade and immune activating agents, for increasing local and systemic control of solid tumors.