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.

Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis

“…Investigating the spatial distribution of E3K CAR-T cells would provide information as to whether the observed effects are solely due to targeting of perivascular cells or whether the CAR-T cells also target CAFs positioned more distally from vascular structures. Further, characterization of the E3K CAR-T cells that have homed to the tumor will be important to determining whether they would benefit from next generation engineering, 50 such as ablating TGFBR2 to prevent T cell exhaustion in the transforming growth factor-β (TGF-β)-rich TME 51 or co-expressing IL-7 and CCL19 to enhance infiltration and survival. 52 In this study, E3K CAR-T cell target specific toxicity was observed in 4T1 tumor-bearing BALB/c mice whereas no toxicity was observed in tumor-bearing C57BL/6 or FVB/N mice treated with equivalent or greater doses of CAR-T cells.…”

Metabolic predictors of response to immune checkpoint blockade therapy

“…Furthermore, the highlighted genes might be used for modifying T cell function through co-engineering strategies, thus improving T cells’ metabolic fitness and augmenting tumor control of T cell therapies. 74 Finally, more data have to be collected in order to address potential links between blood-based metabolic biomarkers and the metabolic landscape of the TME. This could also include a possible connection between the predictive value of serum LDH levels, 75 , 76 , 77 , 78 , 79 and the secretion of lactate into the TME, which was discussed here as a plausible factor related to an acquired ICI-resistance.…”

Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells

“…Adoptive T-cell transfer (ACT) therapy involves the infusion of tumor-specific T cells into patients and ranges from tumor-infiltrating lymphocytes (TIL) to lymphocytes engineered with antigen receptors (chimeric antigen receptor or T-cell receptor (TCR)). 1–6 Optimizing ACT to treat patients with aggressive malignancies is an important undertaking, given that this treatment shows promise in the clinic. 7–10 In particular, lymphodepleting preconditioning regimens prior to ACT are standard modalities to enhance the potency of ACT and do so via multiple mechanisms.…”