Producer T cells: Using genetically engineered T cells as vehicles to generate and deliver therapeutics to tumors

Abstract

Adoptive cell transfer (ACT) is an emerging anticancer therapy that has shown promise in various malignancies. Redirecting antigen specificity by genetically engineering T cells to stably express receptors has become an effective variant of ACT. A novel extension of this approach is to utilize engineered T cells to produce and deliver anticancer therapeutics that enhance cytotoxic T cell function and simultaneously inhibit immunosuppressive processes. Here, we review the potential of using T cells as therapeutic-secreting vehicles for immunotherapies and present theoretical and established arguments in support of further development of this unique cell-based immunotherapy.

Keywords: Adoptive transfer; T cell; cancer therapy; cell vehicle; drug delivery; genetic engineering.

Figure 1.

Schematic of possible T cell vehicle biologics and their therapeutic targets. (A) TIL are isolated from tumors, expanded, and can be genetically engineered using a wide variety of transgenes. (B) Immunosuppressive cells generate a tumor microenvironment conducive to tumor cell growth which limits T cell function. (C) Immunosuppressive cytokines and bioactive molecules suppress T cell function. (D) Immune checkpoints are activated by interactions between T cells, tumor cells, and other cells of the tumor microenvironment and suppress effector cell function. (E) Transgenes can be designed with promotors allowing antigen-dependent expression. (F) A wide variety of transgene products can be selected for various purposes. Abbreviations: APC, antigen presenting cell; BiTE, bi-specific T-cell engager; CAR, chimeric antigen receptor; CTL, cytotoxic T lymphocyte; MDSC, myeloid-derived suppressive cell; NFAT, nuclear factor of activated T-cells; NK, natural killer; PD-1, programmed death-1; PD-L1, programmed death ligand 1; pNFAT, NFAT-responsive promoter; PTD, protein transduction domain; TAM, tumor-associated macrophage; TCR, T cell receptor; TGF-β, transforming growth factor β; TIL, tumor infiltrating lymphocyte; Treg, regulatory T cell; VEGF, vascular endothelial growth factor;.