CD19 CAR T cell product and disease attributes predict leukemia remission durability

• Published in: The Journal of clinical investigation Vol. 129; no. 5; pp. 2123 - 2132
• Main Authors: Finney, Olivia C., Brakke, Hannah, Rawlings-Rhea, Stephanie, Hicks, Roxana, Doolittle, Danielle, Lopez, Marisa, Futrell, Ben, Orentas, Rimas J., Li, Daniel, Gardner, Rebecca, Jensen, Michael C.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.05.2019
• Subjects: Adolescent; Adoptive transfer; Adult; Antigens; Antigens, CD - metabolism; Antigens, CD19 - metabolism; Aplasia; Biomedical research; Bone marrow; Cancer therapies; Care and treatment; CD19 antigen; CD223 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; Cell activation; Cell Proliferation; Cell survival; Chemotherapy; Child; Child, Preschool; Chimeric antigen receptors; Clinical Medicine; Clinical trials; Disease-Free Survival; Effector cells; Failure; Female; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hepatitis A Virus Cellular Receptor 2 - metabolism; Humans; Immunophenotyping; Immunotherapy; Immunotherapy, Adoptive; Infant; Influenza; K562 Cells; Kaplan-Meier Estimate; Leukemia; Leukemia - immunology; Leukemia - therapy; Lymphocyte Activation; Lymphocyte Activation Gene 3 Protein; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Male; Medical research; Medicine, Experimental; Minimal residual disease; Patients; Pediatrics; Peripheral blood; Phenotype; Phenotypes; Programmed Cell Death 1 Receptor - metabolism; Receptors, Chimeric Antigen - metabolism; Recurrence; Remission; Remission (Medicine); Remission Induction; Stem cell transplantation; Stem cells; Survival analysis; T cells; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Young Adult; Young adults; Oncology; Immunology; Cancer immunotherapy; Leukemias
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI125423

Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. We analyzed 43 pediatric and young adult subjects participating in a Phase I trial of defined composition CD19CAR T cells (NCT02028455). CAR T cell phenotype, function and expansion, as well as starting material T cell repertoire, were analyzed in relation to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia free survival and B cell aplasia. These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared to products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3+/TNF-αlow CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained MRD-neg remission, remission durability correlated with therapeutic products having increased frequencies of TNF-α-secreting CAR CD8+ T cells, and was dependent on a sufficiently high CD19+ antigen load at time of infusion to trigger CAR T cell proliferation. These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen. ClinicalTrials.gov NCT02028455. Partial funding for this study was provided by Stand Up to Cancer & St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113), RO1 CA136551-05, Alex Lemonade Stand Phase I/II Infrastructure Grant, Conquer Cancer Foundation Career Development Award, Washington State Life Sciences Discovery Fund, Ben Towne Foundation, William Lawrence & Blanche Hughes Foundation, and Juno Therapeutics, Inc., a Celgene Company.