Predicting response and improving efficacy of CAR T cell therapy

Professor Carl June (Center for Cellular Immunotherapies, University of Pennsylvania, USA) and co-workers discovered that patients with chronic lymphatic leukemia (CLL) with a subset of vital, healthier T cells prior to CAR T cell therapy had a partial or complete clinical responses, while those lacking enough of those T cells did not respond. These healthier T cells were marked by the expression of CD8 and CD27 and the absence of CD45RO. “Transcriptomic profiling revealed that CAR T cells from complete responding CLL patients were enriched in memory-related genes, including IL-6/STAT3 signature, while CAR T cells from non-responders up-regulated programs involved in effector differentiation, glycolysis, exhaustion, and apoptosis. CD27+PD-1-CD8+ CAR T cells expressing high levels of IL-6R strongly predict therapeutic response and are responsible for tumor control.”1

BiTEs are bispecific monoclonal antibodies that form a link between T cells and tumor cells.  June and colleagues found that an oncolytic adenovirus armed with an EGFR-targeting BiTE (OAd-BiTE) can act synergistically with CAR T cells.2

A recent discovery was made in a CAR19-treated myeloma patient with delayed tumor lysis syndrome. Integration of the CAR cassette at a TET2 locus in (only) one of the T cells led to massive clonal expansion, and June hypothesized that inhibition or intentional disruption of TET2 might increase CAR T cell proliferation and/or function.

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