Coengineering specificity, safety, and function into T cells for cancer immunotherapy

Abstract

SummaryAdoptive T‐cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene‐modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer‐types. The field of ACT has been driven forward by the clinical success of CD19‐CAR therapy against various advanced B‐cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non‐hematological solid tumors. Indeed, in addition to pre‐infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post‐transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T‐cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down‐regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity‐optimized TCRs can improve T‐cell function and innovative CAR designs as well as gene‐modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T‐cell coengineering strategies, including of tools, receptors, and gene‐cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.