Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: The Past and the Future

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is the new standard treatment for various indications in patients with advanced hematologic malignancies. Despite the several preclinical and early phase clinical trials, the overall clinical experience has been disappointing when applying this innovative therapy in solid tumors. The failure of CAR T-cell therapy and its limited antitumor activity in solid tumors have been attributed to several mechanisms, including tumor antigen heterogeneity, the hostile tumor microenvironment and poor trafficking of CAR T cells into tumor sites, and the unacceptable toxicities in some settings, among others. However, remarkable improvements have been made in understanding many of these failure mechanisms for which several emerging novel approaches are being applied to overcome these challenges. In this review, after a brief historic background for immunotherapy in solid tumors, we highlight the recent developments achieved in CAR T-cell designs, summarize completed clinical trials, and discuss current challenges facing CAR T-cell therapy and the suggested strategies to overcome these barriers.

Keywords: CAR T-cell; chimeric antigen receptor; immunotherapy; solid tumors.

Figure 1

(Left panel) Basic characteristics of the original CAR T-cell design consisting of an extracellular antigen-recognition domain and intracellular signaling domains linked by a TM domain. (Right panel) Evolution of CAR T-cell generations. The first-generation CARs contained only CD3ζ as the signaling domain that activates T cells. CD3ζ usually maintains the cytotoxic effector function of CAR-T cells. The next generations of CARs consist of modifications added to the first and second CAR generations. Second-generation CARs included one CD (CD1) linked to CD3ζ. Third-generation CARs consisted of two CDs (CD1, CD2) linked to CD3ζ to improve CAR T-cell cytotoxicity and persistence; CD28, OX40, and 4-1BB are examples of the CDs. The fourth-generation CARs consisted of second-generation CARs paired with gene cassettes for cytokine (e.g., IL-12) production under the control of an NFAT transcription factor. The fifth-generation CARs are also derived from the second-generation CARs, with the addition of a JAK-STAT activation domain derived from intracellular domains of cytokine receptors (e.g., IL-2Rβ). CAR: chimeric antigen receptor; CD: costimulatory domain; IL: interleukin; JAK: Janus kinase; NFAT: nuclear factor of activated T-cells; STAT: signal transducer and activator of transcription protein; TM: transmembrane. Created with BioRender.com.

Figure 2

Challenges facing CAR T-cell therapy in solid tumors and the proposed strategies to overcome them. (A) Target antigen heterogeneity. (B) Trafficking into tumor tissue. (C) The suppressive tumor microenvironment. (D) Toxicity related to CAR T-cell therapy. CAR: chimeric antigen receptor; ECM: extracellular matrix; IL: interleukin; PD: programmed cell death. Created with BioRender.com.