Adoptive Therapy With Chimeric Antigen Receptor–Modified T Cells of Defined Subset Composition

Abstract

The ability to engineer T cells to recognize tumor cells through genetic modification with a synthetic chimeric antigen receptor has ushered in a new era in cancer immunotherapy. The most advanced clinical applications are in in targeting CD19 on B cell malignancies. The clinical trials of CD19 CAR therapy have thus far not attempted to select defined subsets prior to transduction or imposed uniformity of the CD4 and CD8 cell composition of the cell products. This review will discuss the rationale for and challenges to utilizing adoptive therapy with genetically modified T cells of defined subset and phenotypic composition.

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

“…This experiment demonstrated a potential advantage to low-dose (0.05 mg/kg) switch treatment in its ability to maintain a larger CD62-L + central memory compartment compared with high-dose (2.5 mg/kg) treatment, which produced more TEMRA cells at day 21 (15 d after T-cell infusion). The formation of central memory CAR-T cells has been shown to provide prolonged persistence in clinical trials, and persistence has been correlated with sustained remissions for ALL and chronic lymphocytic leukemia patients (51,52). In the sCAR-T-cell system, clinical persistence will also be critical to enable redosing strategies in the case of relapse.…”

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

“…Fourteen patients, including one who had an unsuccessful CD8 + T CM selection, had profound lymphopenia (CD4 + , median 150 ation in CAR-T cell doses administered to patients, differences in the phenotypic composition of T cells isolated from patients for genetic modification and in the infused products, and differences in chemotherapy regimens administered to patients to provide lymphodepletion before CAR-T cells are infused (11).…”

CAR therapy: the CD19 paradigm

“…The quasi uniformity of successful outcomes has thus not revealed an optimal CD4 + /CD8 + T cell ratio or a superior T cell subset, yet we know from murine studies that, although CD8 + or CD4 + CAR T cells alone can exert significant therapeutic effects (61, 100), a mixture of both subsets displays superior efficacy (100,101). Much remains to be learned about the potential of virus-specific T cells (102) and defined T cell subsets, in particular the central memory (T CM ) and the stem cell-like memory (T SCM ) subsets (103,104). It is likely that the selection of optimal T cell subsets for CAR therapy will impact the efficacy, consistency, and safety of CAR therapy (104,105).…”

“…Much remains to be learned about the potential of virus-specific T cells (102) and defined T cell subsets, in particular the central memory (T CM ) and the stem cell-like memory (T SCM ) subsets (103,104). It is likely that the selection of optimal T cell subsets for CAR therapy will impact the efficacy, consistency, and safety of CAR therapy (104,105). The principles to be uncovered in clinical studies utilizing defined T cell products will also inform the choice of alternative (i.e., nonautologous) T cell sources that are likely to emerge in the future (106).…”