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

Adoptive 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.