Pulsed Radiation Therapy to Improve Systemic Control of Metastatic Cancer

Abstract

Radiation therapy (RT) is emerging as an interventional modality in the cancer-immunity cycle, augmenting the activation of an adaptive immune response against tumors. RT, particularly in combination with immunotherapy, can enhance immune memory effects and shape the tumor-directed T-cell populations. However, a single cycle of RT delivered to a limited number of polymetastatic lesions is rarely sufficient to achieve systemic control. We hypothesize that several rounds of RT, akin to several rounds of immunotherapeutic drugs, is likely to provide greater clinical benefit to patients with metastatic disease. We propose that the repeated exposure to tumor antigens released by "pulsed-RT" (i.e., treating 2-4 tumor lesions with 3 irradiation cycles given one month apart) may amplify the adaptive immune response by expanding the tumor-specific T-cell receptor repertoire, the production of high-affinity tumor antibodies, and the generation of memory lymphocytes and thereby improve immune control of systemic disease.

Keywords: adaptive immunity; immunotherapy; memory effect; metastatic cancer; radiation therapy.

Figure 1

Effector cytokines produced by pulsed-RT, bridging innate and adaptive immunity. (A, B) The right hind legs of 129Sv/Ev mice were subcutaneously implanted with 2.5×10⁵ 344SQ-P cells to establish primary tumors, while the left legs were concurrently implanted with 1×10⁵ cells on day 0 to establish secondary tumors. Primary tumors were irradiated with 12Gy×2 on days 9 and 10, while secondary tumors were irradiated on days 15 and 16 post-tumor inoculation for the pulsed-RT group. Where applicable anti-CTLA4 was given i.p. on days 6 and 12. Sera were collected on day 19 (n=5 mice/group) and subjected to multiplex cytokine/chemokine analysis. Plates were read with Luminex platform and values were compared using Student’s t-tests.

Figure 2

(A) Systemic effects of traditional vs. pulsed radiation therapy with anti-CTLA4. 1). Used with traditionally fractionated radiation therapy (RT), CTLA4 inhibitors boost the activation of T-cell clones with high-affinity T-cell receptors (TCRs) and expand the peripheral TCR repertoire, resulting in more robust activation of tumor-reactive T-cells and formation of memory T-cells (T_m). However, this combination usually fails to reach the assumed abscopal threshold, which may explain why abscopal effects are so rarely observed in the clinic. 2). With pulsed-RT, the host immune system has a greater chance of being repeatedly exposed to the same tumor antigen, leading to immediate differentiation of memory cells into effector cells (T_eff). Similarly, memory B-cells that differentiate into plasma cells would produce 10 to 100 times the number of antibodies than were produced during the primary response. As a result, the adaptive immune response triggered by pulsed-RT would presumably reach the abscopal threshold and have a greater chance of producing systemic response, which would be further improved by the concurrent use of anti-CTLA4. (B) Schematic overview of known and hypothesized functional interactions between lymphocytes in antitumor adaptive immune responses triggered by traditional vs. pulsed radiation therapy. 1). Traditional radiation therapy (RT) induces immunogenic cell death in cancer cells, releasing tumor neoantigens and activating antigen-presenting dendritic cells (DCs), which in turn migrate to local lymph nodes. In the lymph node, activated DCs present antigens to CD8⁺ T-cells through MHC-I molecules and CD4⁺ T-cells through MHC-II molecules. Clones of activated helper T-cells produce cytokines that initiate B-cells and CD8⁺ T-cells, which become cytotoxic T-cells. The latter ultimately leave the lymph node and travel to sites where cells bearing the target antigen reside, initiating a cytotoxic antitumor response. Conversely, at the time of the initial response to antigen, CTLA4 expressed on regulatory T-cells (Tregs) binds to CD80/CD86 on antigen-presenting cells (APCs) and inhibits T-cell activation. 2). In pulsed-RT, the initiated B-cells mature into effector B-cells and can further differentiate into plasma cells, which can produce antibodies against tumor-specific antigens. These antibodies in turn directly against their target proteins, triggering NK-cells−directed antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) reactions. Effector B-cells can also enhance T-cell responses by producing stimulatory cytokines. As T and B-cells mature into effector cells, a subset of each differentiates into memory cells and can immediately become effector cells upon re-exposure to the same tumor-specific antigen. As a result, a secondary exposure to a given antigen would trigger an immune response that is much more rapid and more vigorous than that seen with the first pulsed-RT exposure. Conversely, regulatory B-cell (Bregs) can act in concert with Tregs to suppress antitumor immune responses. IFN, interferon; IL, interleukin; TGF, tumor growth factor; TNF, tumor necrosis factor.