Recent Advances in Solid Tumor CAR-T Cell Therapy: Driving Tumor Cells From Hero to Zero?

Abstract

Chimeric antigen receptor T-cells (CAR-Ts) are known as revolutionary living drugs that have turned the tables of conventional cancer treatments in certain hematologic malignancies such as B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) by achieving US Food and Drug Administration (FDA) approval based on their successful clinical outcomes. However, this type of therapy has not seen the light of victory in the fight against solid tumors because of various restricting caveats including heterogeneous tumor antigen expression and the immunosuppressive tumor microenvironments (TME) that negatively affect the tumor-site accessibility, infiltration, stimulation, activation, and persistence of CAR-Ts. In this review, we explore strategic twists including boosting vaccines and designing implementations that can support CAR-T expansion, proliferation, and tumoricidal capacity. We also step further by underscoring novel strategies for triggering endogenous antitumor responses and overcoming the limitation of poor CAR-T tumor-tissue infiltration and the lack of definitive tumor-specific antigens. Ultimately, we highlight how these approaches can address the mentioned arduous hurdles.

Keywords: chimeric antigen receptor; immunotherapy; infiltration; solid tumors; tumor microenvironment; vaccines.

Figure 1

Action mechanism of CAR-Ts for the elimination of target tumor cells expressing the CAR target antigen. Transduction of T cells with viral particles harboring the CAR-encoding transgene leads to the stable expression of CARs on the surface of the transduced T cells. Upon target antigen encountering, CAR-Ts are activated and they release perforin and granzymes leading to tumor cell death. CAR, chimeric antigen receptor; scFv, single-chain variable fragment; TM, transmembrane domain.

Figure 2

The hurdles of CAR-T therapy in solid tumors. (A) Tumor antigen heterogeneity. In such conditions, the tumor bulk consists of tumor cells only a fraction of which express the CAR-redirected TAA on their surface. Other tumor cells may express different TAAs. (B) Poor tumor site CAR-T infiltration. In the case of hematologic malignancies, the adoptively transferred CAR-Ts encounter their target cells in the bloodstream or the lymphatic system. On the contrary, in solid tumor CAR-T therapy, CAR-Ts have limited accessibility to the tumor site rendering CAR-T-mediated tumoricidal reactions ineffective and insufficient. (C) The immunosuppressive tumor microenvironment. The immunosuppressive characteristics of the tumor microenvironment have negative effects on both CAR-Ts and various immune cells responsible for endogenous antitumor responses. CAR-T, chimeric antigen receptor T cell; DC, dendritic cell; ECM, extracellular matrix; IL-10, interleukin-10; NK, natural killer cell; PD-1, programmed cell death receptor protein 1; TAA, tumor-associated antigen; TGF-β, transforming growth factor-beta.

Figure 3

Oncolytic vaccinia virus-mediated induction of CAR target antigen expression. This type of induced CAR target antigen expression in tumor cells results in efficient recognition and elimination of target antigen-expressing tumor cells by CAR-Ts. CAR; chimeric antigen receptor.

Figure 4

Bystander antitumor effect induction by TRBA-secreting CAR-Ts, cyclophosphamide administration, and CD40L-expressing CAR-Ts. (A) TRBA-secreting CAR-Ts. TRBAs are made of two scFvs fused via a linker peptide. One of these scFvs targets CD3 (present on the surface of endogenous T cells) and the other one targets a TAA or TSA of interest against which endogenous T-cell responses are intended to be redirected. TRBA-secreting CAR-Ts secrete these bispecific T-cell-redirecting antibodies which results in endogenous T-cell-mediated antitumor reactions against malignant cells alongside CAR-T-mediated tumoricidal responses enabling a more effective tumor cell elimination. (B) Cyclophosphamide administration. Cyclophosphamide administration mediates Treg depletion and enables a more efficient CAR-T engagement with its target antigen and the subsequent CAR-T-mediated tumoricidal reactions. Additionally, upon epitope spreading, APCs uptake the released peptide antigens and present them to CD4⁺ T cells and CD8⁺ T cells. This mechanism leads to the priming of endogenous T cells and the subsequent elimination of tumor cells through bystander antitumor effects mediated by these endogenous cells. (C) The mechanism of action of CD40L⁺ CAR-Ts. CD40L⁺ CAR-Ts can mediate tumor cell cytolysis through both their CAR and their CD40L interacting with the CAR target antigen and CD40 on the surface of tumor cells, respectively. Additionally, CD40L⁺ CAR-Ts mediate DC licensing as indicated by the upregulated level of CD40, CD86, and MHC-II. These APCs in turn recruit other immune effector cells such as endogenous T cells. INF-γ and TNF-α secretion by the recruited endogenous CD4⁺ T cells and CD8⁺ T cells also result in tumor cell cytolysis. APC, antigen-presenting cells; CAR, chimeric antigen receptor; CD40L, CD40 ligand; INF-γ, interferon γ; MHC-II, major histocompatibility complex class II; TNF-α, tumor necrosis factor α; TRBAs, T-cell-redirecting bispecific antibodies; Treg, regulatory T cell.

Figure 5

Bystander antitumor effect induction using IL-36γ-secreting CAR-Ts, IL-18-secreting CAR-Ts, and 4-1BBL-expressing CAR-Ts. (A) The effects of IL-36γ secreted by IL-36γ-secreting CAR-Ts. IL-36γ secreted by these engineered CAR-Ts results in the recruitment and activation of endogenous immune effector cells, which include type 1 lymphocytes such as CD8⁺ T cells, NK cells, and γδ T cells. These endogenous immune effector cells can mediate bystander antitumor immune reactions resulting in the suppression of tumor cell proliferation. (B) The effects of IL-18 secreted by IL-18-secreting CAR-Ts. CAR-T-secreted IL-18 has autocrine effects on the CAR-Ts themselves enhancing the antitumor activity of these cells. In case of endogenous tumoricidal effects, CAR-T-secreted IL-18 recruits endogenous T cells to the tumor sites and triggers their bystander antitumor reactions. Moreover, CAR-T-secreted IL-18 also modulates the TME and recruits M1 macrophages to the tumor site which results in M1 macrophage-mediated tumor cell cytolysis. (C) The beneficial effects of 4-1BBL expression by CAR-Ts. 4-1BBL-expressing CAR-Ts demonstrate enhanced functionality in comparison with their conventional counterparts in three ways. The 4-1BBL expressed on CAR-Ts self-interacts with the 4-1BB on these cells resulting in their enhanced in vivo persistence. 4-1BBL expressed on CAR-Ts also interacts with 4-1BB on the surface of DCs, inducing DC-secretion of IL-6 and IL-12. Additionally, CAR-T-expressed 4-1BBL interacts with 4-1BB on the surface of endogenous T cells leading to MHC-mediated bystander tumoricidal reactions. 4-1BBL, 4-1BB ligand; CAR, chimeric antigen receptor; DC, dendritic cell; IL-18R, IL-18 receptor; MHC-I, major histocompatibility complex class I; NK, natural killer cells; TCR, T-cell receptor; TME, tumor microenvironment.