Potential synergy between radiotherapy and CAR T-cells - a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has improved the limited overall survival (OS) of patients with intensively pretreated diffuse large B-cell lymphoma (DLBCL). However, the potentially life-threatening toxicities of CAR T-cells and early relapses remain a challenge. As suggested by smaller monocentric analyses, radiotherapy (RT) in combination with CAR T-cells may have an immunomodulatory effect. METHOD/ RESULTS: In this multicentric retrospective analysis, we investigated potentially synergistic effects of RT and CAR T-cells. Of 78 patients from four centers who received CAR T-cell therapy for DLBCL, 37 patients underwent bridging RT or received salvage RT. RTs (median 36 gray) were well tolerated. Therapy response and disease control of CAR T-cell therapy were comparable after bridging RT or bridging systemic therapy. High-grade neurotoxicity tended to occur less frequently after bridging RT. After further disease progression, patients with localized relapses showed better outcomes, compared to those in advanced stage. In the subgroup with localized relapse, patients receiving salvage RT had an increased OS, vs. those without salvage RT (1-year OS rate 89% vs. 38%, p = 0.03). CONCLUSION: Our analysis demonstrated that RT in combination with CAR T-cells led neither to high-grade toxicities, nor to a decreased response rate. We observed better outcomes of salvage therapies in patients with localized relapses vs. those with advanced stage relapses. Especially the patients who received salvage RTs for localized relapses seem to benefit more. Further analyses are necessary to clarify whether specific synergistic effects exist, such as an enhanced anti-tumor effect of CAR T-cells from RT sensitizing.

Outcome Prediction in Patients With Large B-cell Lymphoma Undergoing Chimeric Antigen Receptor T-cell Therapy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy has led to a fundamental shift in the management of relapsed and refractory large B-cell lymphoma. However, our understanding of risk factors associated with non-response is still insufficient and the search for predictive biomarkers continues. Some parameters measurable on 18F-fluorodeoxyglucose positron emission tomography (PET) may be of additional value in this context. A total of 47 individuals from three German university centers who underwent re-staging with PET prior to CAR T-cell therapy were enrolled into the present study. After multivariable analysis considering tumor characteristics and patient factors that might affect progression-free survival (PFS), we investigated whether metabolic tumor volume (MTV) or maximum standardized uptake value (SUVmax) further improve risk stratification. Their most suitable cut-offs were determined by Cox and logistic regression. Forward selection identified extra-nodal disease as the most predictive factor of those routinely available, and we found it to be associated with significantly inferior overall survival after CAR T-cell treatment (P = 0.012). Furthermore, patients with MTV and SUVmax higher than the optimal threshold of 11 mL and 16.7, respectively, experienced shorter PFS (P = 0.016 and 0.002, respectively). Hence, these risk factors might be useful for selection of individuals likely to benefit from CAR T-cell therapy and their management.