The Emerging Landscape of Immune Cell Therapies

Abstract

Cell therapies present an entirely new paradigm in drug development. Within this class, immune cell therapies are among the most advanced, having already demonstrated definitive evidence of clinical benefits in cancer and infectious disease. Numerous features distinguish these "living therapies" from traditional medicines, including their ability to expand and contract in proportion to need and to mediate therapeutic benefits for months or years following a single application. Continued advances in fundamental immunology, genetic engineering, gene editing, and synthetic biology exponentially expand opportunities to enhance the sophistication of immune cell therapies, increasing potency and safety and broadening their potential for treatment of disease. This perspective will summarize the current status of immune cell therapies for cancer, infectious disease, and autoimmunity, and discuss advances in cellular engineering to overcome barriers to progress.

Figure 1.. Immune cell therapies for the treatment of human disease.

Recent advances in synthetic biology and bioengineering have broadened the applicability of immune cell therapies to include cancer, infection, allogeneic transplantation, and autoimmunity. CAR-T or NK cells, engineered TCRs, and TIL therapy have been and continue to be tested in hematologic and solid cancers. Tregs, CAR-Tregs, and CAAR-T cells are being developed to treat various autoimmune diseases and prevent rejection of transplanted tissues.

Figure 2.. The continuum of immune cell therapies.

Non-engineered immune cell therapies (left) have also exhibited clinical efficacy in various disease contexts, including peripheral Tregs isolated from patient apheresis that are expanded and reinfused into the patient to treat autoimmune disease, GVHD, or organ rejection. Tumor-infiltrating lymphocytes (TILs) are isolated from resected tumors (usually from melanoma patients), expanded ex vivo, and reinfused into the patient. Banked donor virus-specific CTLs are thawed, expanded, and reinfused into HLA-matched recipients for treatment of chronic infections. Engineered immune cell therapies (right) are generated by first apheresing or drawing blood from the patient, isolating T cells, and using viral or non-viral approaches to insert a transgene encoding a synthetic receptor. Examples of engineered T cells include (1) T cells expressing an engineered TCR consisting of TCR alpha and beta subunits; (2) CAR-expressing T cells (CAR-Ts) or NK cells (CAR-NKs), which consist of an extracellular antigen-binding domain fused to intracellular domains involved in TCR signaling; (3) CAAR T cells (CAAR-Ts), where the chimeric receptor is comprised of an antigen-binding domain that targets autoreactive B cells; and (4) CAR-Tregs, where Tregs are isolated from peripheral blood and engineered to express a CAR that redirects them to tissue affected by autoimmune disease. All engineered T cell types are further expanded ex vivo prior to re-infusion into the patient. Of note, T cells modified to express a CAR or TCR mainly comprise cytotoxic effectors since Tregs are not substantially enriched by current culture methods.

Figure 3.. Engineering strategies to enhance adoptive Immune cell therapy.

Sophisticated bioengineering approaches are under development to enhance the potency, specificity, and safety of T cell therapies. Suicide switches, AND gating, and adaptor CAR platforms are being developed to mitigate CAR-mediated toxicity. Ectopic expression of c-Jun or genetic deletion of NR4a factors endows CAR T cells with exhaustion resistance, potentially improving efficacy in solid tumors and enhancing persistence. CAR T cells can also be engineered to secrete specific factors to augment expansion or persistence (e.g., IL-7, IL-12, IL-15, or IL-21), diminish the need for a lymphodepleting regimen, resist the suppressive tumor microenvironment (e.g., secretion of IL-18, expression of a truncated transforming growth factor β [TGF-β] receptor), or act as tumor-specific drug delivery vehicles (e.g., local secretion of anti-PD-1).