Current Progress in CAR-T Cell Therapy for Solid Tumors

Abstract

Cancer immunotherapy by chimeric antigen receptor-modified T (CAR-T) cells has shown exhilarative clinical efficacy for hematological malignancies. Recently two CAR-T cell based therapeutics, Kymriah (Tisagenlecleucel) and Yescarta (Axicabtagene ciloleucel) approved by US FDA (US Food and Drug Administration) are now used for treatment of B cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) respectively in the US. Despite the progresses made in treating hematological malignancies, challenges still remain for use of CAR-T cell therapy to treat solid tumors. In this landscape, most studies have primarily focused on improving CAR-T cells and overcoming the unfavorable effects of tumor microenvironment on solid tumors. To further understand the current status and trend for developing CAR-T cell based therapies for various solid tumors, this review emphasizes on CAR-T techniques, current obstacles, and strategies for application, as well as necessary companion diagnostics for treatment of solid tumors with CAR-T cells.

Keywords: CAR-T cells; CTC; chimeric antigen receptor; companion diagnostics; solid tumors.

Figure 1

A. Improving CAR-T cell trafficking and infiltration. 1) Targeting the tumor stroma or vasculature: tumor fibroblasts are depleted by FAP-targeting CAR-T cells to inhibit tumor growth. 2) ECM consumption by a secreted enzyme: the ECM (heparan sulfate proteoglycans) can be disintegrated by HPSE. 3) Homing to tumors expressing chemokine receptors (CCR4, CCR2b): genetically modified CAR-T cells express chemokine receptor(s) matching the tumor chemokine to facilitate migration to the tumor cells. B. Overcoming the immunosuppressive tumor microenvironment. 1) Anti-PD-L1-secreting CAR-T cells: human NK cells are recruited to the tumor site through secretion of anti-PD-L1 antibodies from CAR-T cells. 2) CAR-T cell therapy is potently enhanced by PD-1 blockade. 3) Blockade with the IL-10/TGFβ receptor. 4) Proinflammatory cytokines secreted by armored-CARs and TRUCKS (IL-12 showed an increased antitumor efficacy). C. Multiplex CAR-T cells to target the tumor profile. 1) Pooled CAR-T cells: multiple single-targeting CAR-T cells are mixed together. 2) Multi-specific CAR-T cells: one bispecific CAR-T cell consists of two specific CARs. 3) Tandem CAR-T cells: two different CARs connected in tandem possessing a common intracellular domain. 4) Conditional CAR-T cells: one CAR has a CD3ζ signaling domain, and the other has a costimulatory domain. D. Minimizing CAR-T cell toxicity. 1) EGFRvIII CAR: EGFRvIII is the only truly tumor-specific antigen that is completely restricted to human cancer, such as glioblastoma. 2) Dual CAR: the first CAR activates T cell function through the CD3 signaling domain, and the second CAR contains CD28/CD137 to co-stimulate the signaling function. 3) Affinity-tuned CAR. 4) Inhibitory CAR (iCAR): normal cells are maintained safely because of negative signaling by iCARs that only have antigens that are expressed on normal cells. 5) 'ON' switch CAR-T cells: a CAR molecule is attached with a costimulatory CD3ζ signaling domain that can only be activated in the presence of a small molecule acting as an 'ON' switch. FAP: fibroblast activation protein; ECM: extracellular matrix; HPSE: heparanase; TRUCKs: T cells redirected for universal cytokine killing; CAR: chimeric antigen receptor. Note: The lines represent what A, B, C and D include respectively.

Figure 2

Microscope images showing CTC analysis results in a bladder cancer patient. CTCsare characterized as two mesothelin (MSLN)⁺ CTCs (expressing yellow), three EGFR⁺ CTCs (expressing green), MSLN^-/EGFR^- CTCs and circulating tumor microemboli (CTM). In addition, each CTC is identified as triploid, tetraploid or polyploid by a FISH probe for CEP8. WBC: white blood cell; CTC: circulating tumor cell; MSLN: mesothelin; CTM: circulating tumor microemboli; EGFR: epidermal growth factor receptor