Surmounting the obstacles that impede effective CAR T cell trafficking to solid tumors

Abstract

Innovative immunotherapies based on immune checkpoint targeting antibodies and engineered T cells are transforming the way we approach cancer treatment. However, although these T cell centered strategies result in marked and durable responses in patients across many different tumor types, they provide therapeutic efficacy only in a proportion of patients. A major challenge of immuno-oncology is thereby to identify mechanisms responsible for resistance to cancer immunotherapy in order to overcome them via adapted strategies that will ultimately improve intrinsic efficacy and response rates. Here, we focus on the barriers that restrain the trafficking of chimeric antigen receptor (CAR)-expressing T cells to solid tumors. Upon infusion, CAR T cells need to home into malignant sites, navigate within complex tumor environments, form productive interactions with cancer cells, deliver their cytotoxic activities, and finally persist. We review the accumulating evidence that the microenvironment of solid tumors contains multiple obstacles that hinder CAR T cells in the dynamic steps underlying their trafficking. We focus on how these hurdles may in part account for the failure of CAR T cell clinical trials in human carcinomas. Given the engineered nature of CAR T cells and possibilities to modify the tumor environment, there are ample opportunities to augment CAR T cell ability to efficiently find and combat tumors. We present some of these strategies, which represent a dynamic field of research with high potential for clinical applicability.

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

“…Thus, combinational use of immune checkpoint receptor inhibitors, such as PD-1/CTLA-4 inhibitors, might be beneficial [ 97 , 98 ]. Targeting extracellular components, such as VEGF or TGF-β, might also improve T-cell migration and expansion [ 99 ]. As for antigen escape, targeting multiple antigens simultaneously is currently under scrutiny for its efficacy and persistence [ 100 ].…”

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

“…Several resistance mechanisms to CAR-T-cell therapy in solid tumors may play a role in the observed lower effectiveness compared to CAR-T cells in hematologic malignancies [171][172][173][174]. For example, the tumor microenvironment can be hostile for CAR-T cells (e.g., unfavorable pH or oxygen levels) or unfavorable electrolyte or cytokine concentrations, inhibiting an effective immune response [175][176][177].…”

“…For example, the tumor microenvironment can be hostile for CAR-T cells (e.g., unfavorable pH or oxygen levels) or unfavorable electrolyte or cytokine concentrations, inhibiting an effective immune response [175][176][177]. Additionally, the homing of CAR-T cells can be hampered in solid tumors [172]. Furthermore, solid tumors can induce inhibitory receptors on CAR-T cells like PD1 and CTLA-4, making the CAR-T cells exhausted.…”

Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

“…Solid tumors have a more complex immunosuppressive microenvironment and there are many immunosuppressive cells and cytokines which inhibit the activation and survival of CAR-T cells within the tumor [11,12]. The dense extracellular matrix (ECM) also prevents CAR-T cells from in ltrating into solid tumors and can affect CAR-T cell activity [13,14].…”

“…However, adding extra IL-7 during cultivation has no effect in vivo. It is di cult for T cells, including CAR-T cells, to penetrate the extracellular matrix and thus in ltrate the tumor [13,14]. Reports suggest that recombinant hyaluronidase rHPH20 has a greater clinical effect on ECM degradation, promoting lymphocyte in ltration into tumor cells [17,18].…”