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

• Text
• PDF

Abstract

BACKGROUND. 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. METHODS. We analyzed 43 pediatric and young adult subjects participating in a phase I trial of defined composition CD19 CAR T cells (ClinicalTrials.gov, NCT02028455). CAR T cell phenotype, function, and expansion, as well as starting material T cell repertoire, were analyzed in relationship to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia-free survival and B cell aplasia. RESULTS. 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 with products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3+/TNF-αlo CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained minimal residual disease–negative remission, 15 are still in remission, 10 of whom underwent allogenic hematopoietic stem cell transplantation (alloHSCT) following CAR T treatment. Subsequent remission durability correlated with therapeutic products having increased frequencies of TNF-α–secreting CAR CD8+ T cells, but was dependent on a sufficiently high CD19+ antigen load at time of infusion to trigger CAR T cell proliferation. CONCLUSION. 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. TRIAL REGISTRATION. ClinicalTrials.gov, NCT02028455. FUNDING. Partial funding for this study was provided by a Stand Up to Cancer and St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113), R01 CA136551-05, an Alex Lemonade Stand Phase I/II Infrastructure Grant, a Conquer Cancer Foundation Career Development Award, the Washington State Life Sciences Discovery Fund, the Ben Towne Foundation, the William Lawrence & Blanche Hughes Foundation, and Juno Therapeutics Inc., a Celgene Company.

Authors

Olivia C. Finney, Hannah Brakke, Stephanie Rawlings-Rhea, Roxana Hicks, Danielle Doolittle, Marisa Lopez, Ben Futrell, Rimas J. Orentas, Daniel Li, Rebecca Gardner, Michael C. Jensen