Bright future or blind alley? CAR-T cell therapy for solid tumors

Abstract

Chimeric antigen receptor (CAR) T cells therapy has emerged as a significant breakthrough in adoptive immunotherapy for hematological malignancies with FDA approval. However, the application of CAR-T cell therapy in solid tumors remains challenging, mostly due to lack of suitable CAR-T target antigens, insufficient trafficking and extravasation to tumor sites, and limited CAR-T survival in the hostile tumor microenvironment (TME). Herein, we reviewed the development of CARs and the clinical trials in solid tumors. Meanwhile, a "key-and-lock" relationship was used to describe the recognition of tumor antigen via CAR T cells. Some strategies, including dual-targets and receptor system switches or filter, have been explored to help CAR T cells matching targets specifically and to minimize on-target/off-tumor toxicities in normal tissues. Furthermore, the complex TME restricts CAT T cells activity through dense extracellular matrix, suppressive immune cells and cytokines. Recent innovations in engineered CARs to shield the inhibitory signaling molecules were also discussed, which efficiently promote CAR T functions in terms of expansion and survival to overcome the hurdles in the TME of solid tumors.

Keywords: CAR-T cells; adoptive immunotherapy; cytokine release syndrome; immune evasion; solid tumor; tumor infiltration; tumor microenvironment.

Figure 1

Structure diagram and simple pathway map of CAR-T cells. The pathway map is referenced from KEGG (https://www.genome.jp/kegg/).

Figure 2

Search results of CAR-T cell therapies for solid tumors in NIH Clinical Trials Database (as of November 21, 2022). (A) Research frequencies of every target. (B) Status of clinical trials; over 60% of trials are ongoing. A total of 53 targets appeared in these clinical trials. The figure does not list the targets that appear only once (0.4%), which are: CD20, EphA2, CLDN6, CD40, TM4SF1, EpCAM, Nectin4/FAP, AFP, B4T2-001, ROR2, U87, ALPP, CD52, CD22, IL17Rα, CAIX, IM83, E2, IM92, CD171, IM96, ROR1, KKLC1, TAG72, CD56, CD33, MMP2, ICAM1 and gp100. (C) Countries or regions where the trials are located. The most clinical trials of CAR-T cell therapies for solid tumors are conducted in China, followed by the U.S. (D) Species of solid tumors studied in the clinical trials. Liver cancer, pancreatic cancer, breast cancer, sarcoma, and lung cancer are the five most studied solid tumors in clinical trials.

Figure 3

Methods of improving CAR-T cell therapy for solid tumors. (A) Find new targets with better specificity. (B) Construct dual-target CARs. (C) Change the affinity of the extracellular ScFv segment of CAR. (D) Construct SynNotch-receptor switch. (E) Block receptors of the inhibitory signaling from the tumor microenvironment (TME). (F) Armored CARs with cytokines. (G) Prevent CAR-T cell exhaustion through immune checkpoints.

Figure 4

CAR-T cell-related tumor microenvironment (TME). A variety of cells participate in the formation of the tumor suppressive immune microenvironment, which limits the effect of CAR-T cells in solid tumors. TGF-β plays a central role in the TME, is produced by a variety of immunosuppressive cells, and can further negatively regulate the proliferation, differentiation, and activation of immune cells through downstream proteins and other factors. CAR, Chimeric Antigen Receptor; TGF-β, Transforming Growth Factor-β; TAMs, Tumor Associated Macrophages; Treg, Regulor T-cell; CAF, Cancer Associated Fibroblasts; ECM, Extracellular Matrix; MMPs, Matrixmetalloproteinases; DAMPs, Damage Associated Molecular Patterns.

Figure 5

CAR-T cell therapy-related adverse events. *Grading is quoted from ASTCT (2018) (92). **Scale is referred from a study by Harvard Medical School (93). WBC, White Blood Cells; CRS, Cytokine Release Syndrome; CRP, C-reactive Protein; FiO₂, Fraction of Inspiration O₂.