The Role of Radiotherapy in Lymphoma Patients Undergoing CAR T Therapy: Past, Present, and Future

Chimeric antigen receptor (CAR) T-cell receptor therapy has transformed outcomes for patients with relapsed and refractory diffuse large B-cell lymphoma (R/R DLBCL). It is currently approved in the third line for all patients and in the second line for early relapsed or primary refractory disease. Although CAR T cell therapy offers the potential for improved outcomes, its use may also include logistical delays related to referral, medical, social, and financial clearance as well as manufacturing time; more than half of patients experience disease recurrence or progression while awaiting CAR T infusion. Bridging radiotherapy, defined as radiation delivered between the decision to pursue CAR T and infusion of CAR T cells, has become an attractive option for patients who would benefit from local disease control or palliation of symptoms. Additionally, patterns of failure analyses have revealed a dominant role of local disease progression, which has fueled investigations on bridging and early salvage radiation to improve long-term outcomes in patients, particularly those with localized or high-risk disease. Several potential mechanisms by which radiation therapy may improve CAR T efficacy have been proposed that include cytoreduction, tumor debulking, neutralization of immunosuppressive hypoxic and acidic tumor microenvironments, and immunologic and pro-apoptotic synergy between radiation and CAR T. Prospective clinical trials and translational work are ongoing and are needed to inform our conceptual understanding of potential mechanisms by which radiation therapy may improve CAR T efficacy and toxicity, identify which patients may be most likely to benefit, and confirm proposed clinical benefits.