Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

Abstract

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient's existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

Keywords: adoptive cell therapy; immunotherapy; metastatic treatment; tumor-infiltrating T cells.

Figure 1

Schematic overview of the TIL-ACT protocol. Patients with metastatic tumors undergo metastastectomy of one lesion, which is then digested into multiple small tumor fragments or single-cell suspensions. Tumor fragments are cultured with IL-2 in vitro for the initial TIL isolation and expansion. Isolated TILs are screened for tumor reactivity via co-culture with autologous digested tumor cells for IFN-γ secretion as assessed by IFN-γ ELISA. Tumor specific TIL clones are then consolidated and rapidly expanded in the presence of anti-CD3 monoclonal antibody, IL-2, and irradiated autologous feeder cells. Once the number of TILs has reached treatment levels (typically > 1 × 10¹⁰ cells), they are harvested and transferred back into a lymphodepleted host in one infusion. TIL (tumor-infiltrating lymphocytes); ACT (adoptive cell therapy); IL-2 (interleukin-2); IFN-γ (interferon-gamma); ELISA (enzyme-linked immunosorbent assay).

Figure 2

Major resistance mechanisms to TIL-ACT. This figure demonstrates four major resistance mechanisms to TIL therapy as well as strategies (highlighted in green) to overcome these mechanisms. Tumor cells may downregulate MHC molecules or neoantigen expression to avoid immune detection by neoantigen-specific T cells. Radiation therapy, chemotherapy, and targeted therapy are common ways to increase neoantigen generation and upregulate neoantigen presentation. Tumor cells and other components of the TME may upregulate checkpoint molecules such as PD-L1 to induce T cell exhaustion, a dysfunction state by which T cells cannot proliferate or secrete effector molecules. Exhausted T cells can regain effector function with immune checkpoint inhibitor treatment. Another way to bypass T cell exhaustion is by selecting for TILs that are less prone to exhaustion. Immunosuppressive cell types within the TME, such as myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs), can secrete factors that inhibit TIL function. These host immunosuppressive cells can be depleted prior to or simultaneously with adoptive cell transfer by chemotherapy or radiation therapy regimens as well as cell type specific inhibition. Lastly, the TME itself may pose barriers that exclude T cells and inhibit their migration. Experimental therapies that modify chemotactic and migratory pathways may restore or increase tumor infiltration by TILs. TIL (tumor-infiltrating lymphocytes); ACT (adoptive cell therapy); MHC (major histocompatibility complex); TME (tumor microenvironment); PD-L1 (programmed death-ligand 1); PD-1 (programmed cell death protein 1); CTLA-4 (cytotoxic T-lymphocyte-associated protein 4); MDSC (myeloid-derived suppressor cells); Tregs (regulatory T cells).

Figure 3

Structural and functional differences between TILs and CAR-Ts in antitumor treatment. ACT can be accomplished using either TILs or CAR-Ts. TILs use endogenous T cell receptors (TCRs) that are MHC restricted. The inherent diversity of TCRs present on TILs allows recognition of a wide range of tumor neoantigens expressed by heterogeneous tumor cells. In contrast, CAR-Ts have synthetic receptors modeled after non-MHC restricted monoclonal antibodies. These receptors contain co-stimulatory and signaling molecules that can independently activate the T cell without recruitment of additional factors. However, as CARs are synthesized to have high affinity binding against one known neoantigen, they are more prone to have off-target effects if the neoantigen is present on normal tissues. TIL (tumor-infiltrating lymphocytes); CAR (chimeric antigen receptor); TCR (T cell receptor); MHC (major histocompatibility complex).

Figure 4

Schematic depiction of centralized TIL production chain. Commercialization of TIL production can increase TIL-ACT implantation by reducing the requirements for local medical centers. By outsourcing TIL production, treatment facilities only need to have the surgical and medical capacities to remove the tumor and treat potential infusion-associated adverse effects. TIL (tumor-infiltrating lymphocytes); ACT (adoptive cell therapy).