In the modern treatment landscape of metastatic melanoma, patients are often refractory to first line checkpoint blockades. Forget et al. found that patients who recurred following checkpoint blockade were less likely to respond to adoptive transfer of TILs, had shorter durations of response and shorter overall survival. Previously known biomarkers of response to TILs (BTLA expression, infusion of high number of TILs, and infusion of a high portion of CD8+ TILs) were no longer valid in checkpoint blockade-refractory patients. Baseline serum level of IL-9 was identified as a biomarker of response irrespective of prior exposure to checkpoint blockade.
PURPOSE: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. EXPERIMENTAL DESIGN: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival. Immunologic factors associated with response were also evaluated. RESULTS: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naive patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naive patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA-4 naive patients, but not in anti-CTLA-4 refractory patients. Baseline serum levels of IL-9 predicted response to TIL ACT, while TIL persistence, tumor recognition and mutation burden did not correlate with outcome. CONCLUSIONS: This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL-9 levels can potentially serve as a predictive tool to appropriately select sequence for immunotherapies.
Author Info: (1) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (2) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Biostatistics, Unive
Author Info: (1) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (2) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Biostatistics, University of Texas MD Anderson Cancer Center. (4) Cancer Biology, Dana-Farber Cancer Institute. (5) Department of Systems Biology, University of Texas MD Anderson Cancer Center. (6) Genomic Medicine, University of Texas MD Anderson Cancer Center. (7) Melanoma Medica Oncology, UT MD Anderson Cancer Center. (8) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (9) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (10) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (11) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (12) University of Texas MD Anderson Cancer Center. (13) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (14) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (15) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (16) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (17) Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center. (18) University of Texas MD Anderson Cancer Center. (19) Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center. (20) Manufacturing Sciences and Technology, Iovance Biotherapeutics. (21) University of Texas MD Anderson Cancer Center. (22) IND Office, University of Texas MD Anderson Cancer Center. (23) ACB PACU, University of Texas MD Anderson Cancer Center. (24) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (25) University of Texas MD Anderson Cancer Center. (26) University of Texas MD Anderson Cancer Center. (27) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (28) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (29) Dept. of Surgical Oncology and Genomic Medicine, University of Texas MD Anderson Cancer Center. (30) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (31) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (32) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (33) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (34) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (35) Surgical Oncology, M.D. Anderson Cancer Center. (36) Surgical Oncology, University of Texas MD Anderson Cancer Center. (37) Surgical Oncology, The University of Texas MD Anderson Cancer Center. (38) Surgical Oncology, UT M. D. Anderson Cancer Center. (39) Department of Surgery, NIH. (40) M.D. Anderson Cancer Center, University of Texas at Austin. (41) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. (42) Global Immuno-Oncology Research, EMD Serono Research Institute. (43) Department of Pathology, University of Texas MD Anderson Cancer Center. (44) Cancer Biology, Dana-Faber Cancer Institute / Harvard Medical School. (45) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (46) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center. (47) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center cbernatchez@mdanderson.org.
