The Current and Future Role of Radiation Therapy in the Era of CAR T-cell Salvage

Abstract

Radiation therapy has the potential to modulate the immune system in a variety of ways, and given the critical role of the immune system in cancer elimination, it is becoming increasingly important to understand how radiation can be strategically implemented in conjunction with approved immunotherapies to improve the cancer patient's chance of cure and/or quality of life. Current successful, approved cancer immunotherapies fall into two broad classes: antibodies and cellular therapies. Approved cellular therapies thus far consist of Chimeric Antigen Receptor (CAR) T-cells targeting CD19 for refractory non-Hodgkin lymphoma and relapsed or refractory acute lymphoblastic leukemia. Part of the ardor surrounding CAR T-cells stems from the fact that the survival curve of treated patients has a clear plateau, meaning that a number of patients with aggressive, disseminated disease who would have otherwise died rather rapidly appear to now be cured, commonly after just one dose. Despite an encouraging number of these durable remissions, the majority do still relapse. In this review, we discuss the potential for strategically utilizing radiation to further improve CAR T-cell patient outcomes. Given that there are currently over 750 cellular therapies in development, half of which are now in clinical trial, CAR T-cell usage will inevitably expand; as the field grows in importance and effectiveness, radiation oncology has the opportunity to coevolve symbiotically and steer these novel, exciting live therapies to new depths.

Figure 1.

CAR T-cell design. Endogenous T-cells require stimulation through the TCR as well as costimulatory signaling to become fully functional. CARs combine signaling domains from both to create one simplified receptor. This receptor consists of an extracellular tumor-binding domain (blue), most commonly derived from an antibody fragment, an extracellular linker, a transmembrane domain, an intracellular costimulatory domain (yellow), and an intracellular stimulatory domain, most commonly derived from the ζ domain of the TCR (purple). CAR, Chimeric Antigen Receptor; TCR, T-cell receptor.

Figure 2.

Potential outcomes after CAR T-cells. Cancer may progress or relapse after CAR T-cells due to tumor-related factors (red background), such as antigen escape, tumor-induced immunosuppression such as PD-L1 or suppressive cytokine production, or high tumor burden relative to functional CAR T-cells; T-cell factors may dominate (orange background), such as intrinsic CAR T-cell dysfunction, inadequate persistence or expansion of the CAR T-cells in vivo, or inadequate memory phenotype achieved by the CAR T-cells; host factors (blue background) may impel resistance to CAR T-cells, such as microenvironment-induced immunosuppression driven by CAF, TAM, MDSC, TAN, or Treg. CAFs, cancer-associated fibroblasts; MDSCs, marrow-derived suppressor cells; TAMs, tumor-associated macrophages; TAN, tumor-associated neutrophils; Tregs, regulatory T cells.

Figure 3.

Potential future roles of RT in modulating CAR T-cell outcomes. Beyond simple tumor debulking, RT may be utilized in the future at appropriate doses to address tumor-related factors (red background), T-cell factors (orange background), or host factors (blue background) that are operative in driving resistance to CAR T-cells. CAF, cancer associated fibroblasts; MDSC, myeloid derived suppressive cells; RT, radiation therapy; TAM, tumor associated macrophages; TAN, tumor associated neutrophils; Treg, regulatory T-cells.