Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies

Abstract

Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies.

Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies

“…15 Moreover, unselected populations, especially those skewed toward T EM and T TE , often fail to generate viable clinical products due to poor in vitro cell expansion. 16 Recently, several clinical trials in which tumor-redirected T cells were derived from T CM have been reported. 17,18 However, clinical exploitation of T SCM has so far been hampered by their relative paucity in the circulation and the lack of robust, clinical-grade protocols capable of isolating and maintaining this cell type in vitro.…”

CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients

“…Therefore, our study was not biased due to exclusion of patients with poor lymphocyte numbers and function. A clinical trial of CD19 CAR-T cell therapy for pediatric B-ALL excluded 24% of patients due to the failure of T cells to meet predefined criteria for in vitro proliferation (21).…”

Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion

“…Yet, the expansion efficiency is likely lower with patient-derived cell material, although such difference was not observed in this study. Efficient expansion in the absence of IL-2 can also be obtained using IL-7 and IL-15, which was needed especially for patients with lymphoma [28].…”