[CAR T cells in solid tumors: resistance mechanisms].

Abstract

Background: Chimeric antigen receptor (CAR) T cell treatment is based on the concept of specifically targeting the patient's cytolytic T cells against tumors using a synthetic receptor signaling molecule (CAR).

Objective: While CAR T cells show unprecedented efficacy against hematological neoplasms, CAR T cell treatment of solid tumors has so far been largely disappointing, with causes still being only partially understood.

Method: Presentation of the dominant mechanisms that prevent CAR T cell activation in solid tumors and strategies to overcome these obstacles.

Results: Preclinical research on tumor models and clinical trials in recent years have shown that CAR T cell activation is effectively suppressed in many solid tumors by the prevention of T cell penetration into the tumor as well as active suppression of T cell functions and metabolic conditions that limit T cell survival within the tumor. To overcome these obstacles, various strategies are being tested experimentally and clinically, such as pretreatment of tumors, increasing T cell resistance to suppressive cytokines and metabolites as well as activation of resident immune cells by CAR-mediated release of therapeutically effective cytokines (T cells redirected for unrestricted cytokine-mediated killing, TRUCK).

Conclusion: There is considerable developmental potential to make CAR T cell treatment effective against solid tumors. Novel strategies that use CAR T cells as "biopharmaceutical factories" (TRUCK) to selectively activate natural killer (NK) cells and macrophages in tumor tissues recently entered the clinical trial stage.