Chimeric antigen receptor-modified T cells for the treatment of solid tumors: Defining the challenges and next steps

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown promise in CD19 expressing hematologic malignancies, but how to translate this success to solid malignancies remains elusive. Effective translation of CAR T cells to solid tumors will require an understanding of potential therapeutic barriers, including factors that regulate CAR T cells expansion, persistence, trafficking, and fate within tumors. Herein, we describe the current state of CAR T cells in solid tumors; define key barriers to CAR T cell efficacy and mechanisms underlying these barriers, outline potential avenues for overcoming these therapeutic obstacles, and discuss the future of translating CAR T cells for the treatment of patients with solid malignancies.

Keywords: CAR T cells; Cellular immunity; Chimeric antigen receptor; Solid malignancies; Tumor microenvironment.

Fig. 1. Schematic comparing the structure of T cell receptors (TCRs) and chimeric antigen receptors (CARs)

The TCR complex is composed of TCR-α and -β chains that are assembled together with invariant CD3 molecules. In contrast, a CAR is a modular protein that comprises an extracellular domain (ligand binding region), a hinge region, and an intracellular domain (signaling components). TCR: T cell receptor; CD3: cluster of differentiation 3; scFv: single-chain variable fragment.

Fig. 2. Clinical trials using TCR and CAR therapy in cancer

Both CAR- and TCR-based T cell immunotherapies are being investigated in solid and hematologic malignancies. Shown are active clinical trials using CAR and TCR adoptive cell therapy in solid and hematologic malignancies. Active studies were identified on clinicaltrials.gov as of March 31, 2016, using keywords “CAR,” “chimeric antigen,” and “TCR”.

Fig. 3. CAR T cell efficacy in solid malignancies is dependent on multiple steps

CAR T cell therapy is a multi-step process involving (i) pheresis to collect peripheral blood leukocytes (i.e. leukapheresis) and elutriation to isolate lymphocytes from the peripheral blood of patients (Lymphocyte Collection); (ii) manufacturing of CAR T cells including gene modification of T cells to express the CAR, stimulation/expansion of gene-modified T cells in vitro, and quality control measures to evaluate CAR expression levels, T cell quality, and infectious contamination (CAR T cell Manufacturing); and (iii) the adoptive transfer of T cells to patients which then must expand, persist, traffick to tumors, and mediate effector anti-tumor activity within the tumor microenvironment (Adoptive Cell Transfer). Each of these steps is critical to the efficacy of CAR T cell therapy in solid malignancies.