J. Fan1, N. Kutsch2, J. M. Heger2, N. Sieg2, P. Gödel2, H. Gruell3, E. Heger4, J. Rosenbrock1, E. Celik1,5, P. Linde1, E. Fokas1, P. Borchmann2, B. von Tresckow6, and C. Baues1,5; 1Department of Radiation Oncology, Cyberknife and Radiotherapy, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, 2Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Cologne Lymphoma Working Group (CLWG), Cologne, Germany, 3Laboratory of Experimental Immunology, Institute of Virology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, 4Institute of Virology, University of Cologne, Cologne, Germany, 5Department of Radiotherapy, University Hospitals of the Ruhr-University of Bochum, Bochum, Germany, 6Department of Hematology and Stem Cell Transplantation, West German Cancer Center and German Cancer Consortium (DKTK partner site Essen), University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Purpose/Objective(s): Previous research suggested that expansion and persistence of chimeric antigen receptor (CAR) T-cells may affect the therapy response and patient outcomes. This study examined whether the persistence of CAR T-cells, at the time of post-CART progression or residual disease (PD), influences the efficiency of salvage radiotherapy (S-RT) and patient outcomes. Materials/
Methods: Patients with diffuse large B-cell lymphoma (DLBCL) were included if they received CAR T-cell therapy and subsequent S-RT for post-CART PD. CAR T-cell levels in peripheral blood were analyzed using qPCR detecting lentiviral nucleic acids of the CAR transgene. Other data were collected retrospectively. Results: After the diagnosis of PD, data on CAR T-cell levels were available for 14 patients. Of these, 9 patients exhibited stable or even increased CAR T cells levels (1.3 – 16.8 fold) compared to the last recorded value before diagnosis. The remaining 5 patients experienced a rapid decline in CAR T-cell levels (0.002 – 0.25 fold), leading to undetectable CAR T-cells in 2 of them. For the further analysis, patients were divided into two groups based on CAR T-cell levels during post-CART PD: persistence (n=9) vs. decline (n=5). A total of 21 lesions were irradiated (median dose: 40Gy). A local therapy response was observed in 18 lesions (86%). Within the persistence group, 4 patients underwent combined salvage therapy, while 5 received S-RT alone. Seven of these patients achieved long-term remission (> 17 months). In the decline group, 3 patients underwent combined salvage therapy, and two received S-RT alone, with one achieving long-term remission. Patient and disease characteristics at the diagnosis of PD did not significantly differ between the 2 groups, except for median age (58 vs. 72 in the decline group). Patients with decreased CAR T-cell levels tended to have PD with advanced tumor stage and bulky disease. Patients in the persistence group exhibited a better local therapy response (100% vs. 57%), a trend toward better 1-year local control (78% vs. 50%, p=0,24), significantly longer 1-year PFS (78% vs. 20%, p=0,02) and improved 1-year OS (100% vs. 20%, p<0,005), compared to patients in the decline group. Conclusion: Our analysis is the first to demonstrate that different dynamics in CAR T-cell levels occur at the diagnosis of post-CART progression or residual disease. Patients with stable or even increased CAR T-cell levels had better responses to S-RT and better outcomes compared to those with decreased levels, suggesting that dynamics of CAR T-cell levels could indicate the functionality of CAR T-cells. Further studies with more patients and other quantitative measurement like flow cytometry are needed.
