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

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-α lo 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.

Unstimulated apheresis for chimeric antigen receptor manufacturing in pediatric/adolescent acute lymphoblastic leukemia patients

“…Stopping rules for a number of potentially interfering medicines prior to CAR-apheresis are defined; evidence was provided by others that in addition to cell number also cell quality may benefit from allowing longest-possible wash-out time for any cytoreductive therapy. [1][2][3][4] Long-term outcomes after CAR-therapy, ultimately the true test of success also of the activities analyzed here, are beyond the scope of this article.…”

“…The quality of lymphocytes from patients who have received multiple rounds of chemotherapy may also not be optimal. [1][2][3][4] Leukapheresis is a standard procedure for collection of hematopoietic stem/progenitor cells from pharmacologically mobilized patients and donors. It is also routinely used for preparative leukocyte collection from unmobilized patients (for extracorporeal photopheresis in patients with chronic graft-vs-host disease or chronic solid organ transplant rejection) and donors (for adoptive T-cell transfer post-transplant).…”

Pediatric cancer mortality and survival in the United States, 2001‐2016

“…39,40 New immunotherapies such as chimeric antigen receptor T therapy have shown effectiveness for pediatric ALL and may further improve survival for patients with pediatric ALL and reduce chemotherapy-related toxicity. 41,42 Improvements in lymphoma outcomes were seen during the study period, and they may be due to the implementation of combined-modality and risk-adapted therapies. 43,44 Pediatric solid tumor death rates and survival have improved overall since the 1970s, but depending on the tumor type, age of the patient, and metastatic spread, improvements have been either modest or stable during the past 2 decades.…”

Impaired tumor death receptor signaling drives resistance to CAR T cell therapy

“…Until now, primary resistance to CART19 was presumed to be a result of intrinsic T cell defects 28,29 , leading to extensive efforts to use heathy donor (i.e. allogeneic donor or "universal" donor) T cells as a substrate for CAR T cell manufacturing.…”