Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward

Abstract

Recently, the US Food and Drug Administration (FDA) approved the first chimeric antigen receptor T cell (CAR-T) therapy for the treatment CD19-positive B cell acute lymphoblastic leukemia. While CAR-T has achieved remarkable success in the treatment of hematopoietic malignancies, whether it can benefit solid tumor patients to the same extent is still uncertain. Even though hundreds of clinical trials are undergoing exploring a variety of tumor-associated antigens (TAA), no such antigen with comparable properties like CD19 has yet been identified regarding solid tumors CAR-T immunotherapy. Inefficient T cell trafficking, immunosuppressive tumor microenvironment, suboptimal antigen recognition specificity, and lack of safety control are currently considered as the main obstacles in solid tumor CAR-T therapy. Here, we reviewed the solid tumor CAR-T clinical trials, emphasizing the studies with published results. We further discussed the challenges that CAR-T is facing for solid tumor treatment and proposed potential strategies to improve the efficacy of CAR-T as promising immunotherapy.

Keywords: Antigen recognition specificity; CAR-T; Safety control; Solid tumor; Tumor microenvironment.

Fig. 1

Molecular mechanism of chimeric antigen receptor T cell-mediated antitumor activity. a The chimeric T cell receptor coding sequence is delivered by viral vector. After entering into T cells (beige), virus was uncoated and transgene was preferably integrated at genome transcriptional start sites using specific vector designs, such as MLV retrovirus and piggyBac transposon. b CAR transgenes were endogenously transcript by host machinery, translated, and later inserted onto the T cell surface. c Association of CARs to TAA (orange) on tumor cell surface activates T cell for immunological response, for example, signaling network of CAR-T composed of CD8-CD28-CD137-CD3ζ domains was shown in (d). CAR-T-mediated immune response was reported to be amplified by ZAP70, TRAF1, PI3K, and GRB2 as well as other uncharacterized factors, giving rise to upregulation of signaling intermediates and subsequent pro-death gene transcriptions. e Upon CAR activation, T cells secreted cytokines (brown), perforins (bright yellow), and granzymes (blue) as well as activated death receptors, which triggered downstream targets. These subcellular events directly or subsequently contribute to specific death of tumor cells, including perforin and granzyme release, cytokine production, direct lysis, apoptosis, necrosis, reprogrammed phenotype, and immuno-memory formation in T cells, tumor cells (gray), macrophages (pink) (via IL-6, IL-10, IL-12, MCP-1, IP-10, TNF-α, MIP-1α, MIP-1β, IFN-γ), NK cells (cyan) (via IL-12, TNF-α, IFN-γ), Treg cells (navy) (via IL-2, IL-4, IL-7, IL-12, IL-15, IFN-β, IFN-γ, TSLP), and dendritic cells (yellow) (via IL-6, IL-10, IL-12, TNF-α, MIP-1α, MIP-1β, IFN-γ). Abbreviation: NK cells natural killer cells, TAA tumor-associated antigen, Treg cells regulatory T cells

Fig. 2

Tumor-associated antigens targeted in CAR-T therapy. Schematic illustration of a human body whose tissues or organs have been investigated in preclinical and clinical studies for solid tumor immunotherapy using CAR-T, including brain (green), lungs (beige), mammary gland (orange), liver (purple), stomach (red), pancreas (blue), kidneys (pink), colon (cyan), male reproductive system (brown), ovary (yellow), and bones (gray) as well as skin (black). Abbreviation: CCA cholangiocarcinoma, MPM malignant pleural mesothelioma, NSCLC non-small-cell lung carcinoma, RCC renal cell carcinoma

Fig. 3

Strategies being exploited to overcome challenges in CAR-T therapy in solid tumor. Various strategies are currently being tested in preclinical and clinical studies to overcome the challenges facing CAR-T therapy for solid tumor (gray), including a, b enhancing T cell (beige) trafficking, c reforming tumor microenvironment (pink represented physiological barriers), d, e anti-immunosuppression, elevating antigen recognition towards tumor (f, g), and healthy cells (darker beige) (h), as well as i–l improving safety control using suicide switch or on-switch. Detailed mechanisms were further illustrated in the section “Overcoming Challenges with Smarter CAR Designs”