The Pharmacology of T Cell Therapies

Abstract

Adoptive cellular therapy using T cells with tumor specificity derived from either natural T cell receptors (TCRs) or an artificial chimeric antigen receptor (CAR) has reached late phase clinical testing, with two CAR T cell therapies achieving regulatory approval within the United States in 2017. The effective use of these therapies depends upon an understanding of their pharmacology, which is quite divergent from traditional small molecule or biologic drugs. We review the different types of T cell therapy under clinical development, the factors affecting cellular kinetics following infusion, and the relationship between these cellular kinetics and anti-cancer activity. We also discuss the toxicity associated with T cell therapies, with an emphasis on cytokine release syndrome and neurotoxicity, and the gaps in knowledge regarding these frequent and unique adverse effects.

Keywords: T cell; cellular therapy; chimeric antigen receptor; gene therapy; immunotherapy.

Figure 1

Schematic Depiction of the Adoptive T Cell Immunotherapy Process for Tumor-Infiltrating Lymphocyte or Engineered T Cell Therapy

Figure 2

Variables Impacting Efficacy of T Cell Therapy Many recipient and product factors are thought to impact the efficacy of adoptive T cell therapy. Although effects have largely not been tested in human trials, in vitro, preclinical in vivo, and human trial evidence implicate parameters at all points of the T cell therapy “life cycle”: (1) disease type, (2) prior therapy, (3) expansion culture conditions (e.g., cytokine and length of culture), including T cell phenotype of the product, (4) synthetic antigen receptor design, (5) pre-conditioning regimen and tumor burden, (6) T cell dose, and (7) post-infusion therapy. (8) Recipient genetics, especially those related to immunity, likely also impact efficacy.