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Review
. 2018 May 22:9:1104.
doi: 10.3389/fimmu.2018.01104. eCollection 2018.

Perspectives on Chimeric Antigen Receptor T-Cell Immunotherapy for Solid Tumors

Paris Kosti  1 , John Maher  1   2   3 , James N Arnold  1
Affiliations
Review

Perspectives on Chimeric Antigen Receptor T-Cell Immunotherapy for Solid Tumors

Paris Kosti et al. Front Immunol. .

Abstract

Chimeric antigen receptor (CAR) T-cell therapy entails the genetic engineering of a patient's T-cells to express membrane spanning fusion receptors with defined specificities for tumor-associated antigens. These CARs are capable of eliciting robust T-cell activation to initiate killing of the target tumor cells. This therapeutic approach has produced unprecedented clinical outcomes in the treatment of "liquid" hematologic cancers, but to date has not produced comparable responses in targeting solid malignancies. Advances in our understanding of the immunobiology of solid tumors have highlighted several hurdles which currently hinder the efficacy of this therapy. These barriers include the insufficient accumulation of CAR T-cells in the tumor due to poor trafficking or physical exclusion and the exposure of infiltrating CAR T-cells to a panoply of immune suppressive checkpoint molecules, cytokines, and metabolic stresses that are not conducive to efficient immune reactions and can thereby render these cells anergic, exhausted, or apoptotic. This mini-review summarizes these hurdles and describes some recent approaches and innovations to genetically re-engineer CAR T-cells to counter inhibitory influences found in the tumor microenvironment. Novel immunotherapy drug combinations to potentiate the activity of CAR T-cells are also discussed. As our understanding of the immune landscape of tumors improves and our repertoire of immunotherapeutic drugs expands, it is envisaged that the efficacy of CAR T-cells against solid tumors might be potentiated using combination therapies, which it is hoped may lead to meaningful improvements in clinical outcome for patients with refractory solid malignancies.

Keywords: T-cells; chimeric antigen receptor; immunotherapy; solid tumor; tumor microenvironment.

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Figures

Figure 1
Figure 1
Generations of chimeric antigen receptor (CAR) molecules. First generation CARs contain a CD3ζ signaling endodomain. Second and third generation CARs, in addition to the CD3ζ domain, incorporate CD28 (second generation) or two or more additional co-stimulatory domains which may include CD27, 4-1BB, ICOS, or OX40 (third generation). Fourth generation CARs include constitutive or inducible expression of co-receptors or soluble cytokines alongside that of the CAR molecule which further promote T-cell activation.
Figure 2
Figure 2
Overview of the barriers to CAR T-cells in solid tumors.
See this image and copyright information in PMC

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