Emerging Cellular Therapies for Cancer

Abstract

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell-based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.

Keywords: CAR-T cell; adoptive cell transfer; chimeric antigen receptor; immune-oncology; leukemia; synthetic biology.

Figure 1

Adoptive T cell transfer therapies. Tumor-specific T cells can be isolated from tumors or generated by genetic engineering of peripheral T cells. To eliminate the tumor, infused therapeutic T cells need to reach cancer cells, proliferate, and survive in a hostile tumor microenvironment. Research approaches to overcome these challenges while preventing toxicity and ensuring access to every patient are exemplified. Abbreviations: CAR, chimeric antigen receptor; TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte; TRUCK, T cell redirected for universal cytokine-mediated killing; UCAR-T, universal CAR-T cell; UTCR-T, universal TCR-T cell.

Figure 2

Future strategies with adoptive transfer of neoantigen-reactive T cells. Tumor-reactive T cells are isolated from tumors or peripheral blood after sorting for specific markers (PD-1⁺ and 4–1BB⁺ cells), expanded ex vivo, and reinfused into the tumors. Alternatively, neoantigen-specific TCRs can be identified and cloned in viral vectors and used to genetically modify peripheral T cells. These strategies can be combined with immunological-checkpoint inhibitors or neoepitope vaccination. Abbreviations: TCR, T cell receptor; TIL, tumor-infiltrating lymphocyte.

Figure 3

Reconstitution of the patient’s immune system with genome-edited hematopoietic stem cells to prevent on-target, off-tumor toxicity after CAR-T cell treatment. CD33 is expressed in both AML cells and normal myeloid progenitors, and therefore CAR-T cells targeting CD33 could induce myelotoxicity. In this strategy, CD33 is genetically disrupted in hematopoietic stem and progenitor cells to regenerate an antigen-negative myeloid system that is resistant to CAR-T cell therapy. Anti-CD33 CAR-T cells can eradicate AML while sparing CD33-deficient hematopoietic stem and progenitor cells. Abbreviations: AML, acute myeloid leukemia; CAR, chimeric antigen receptor; HSPC, hematopoietic stem and progenitor cell; KO, knockout.

Figure 4

Next-generation CAR-T cells. Novel CAR designs can mitigate toxicities and/or address tumor escape. (a) Second-generation CARs consist of an extracellular domain that recognizes the tumor antigen, a hinge region, a transmembrane domain, and two intracellular signaling domains that transmit the signal. Optimization of each module is required for optimal T cell function and persistence. (b) Combinatorial CARs consist of two separate receptors targeting two different tumor antigens. One receptor bears the CD3ζ intracellular domain, and the other bears the costimulatory domain. Full activation is only achieved after recognition of both antigens. (c) Inhibitory CARs contain the intracellular domain from inhibitory molecules. Antigen recognition in normal cells by inhibitory CARs turns T cells off. (d) Synthetic Notch receptors involve a combination of two receptors. Activation of one receptor induces the expression of a second receptor (a CAR or TCR) that mediates cell killing. Efficient T cell activation occurs only when both antigens are recognized. (e) Tandem CARs contain two different scFvs in a single CAR construct. These receptors can be activated by two different cognate antigens. (f) Dual CARs consist of two separate second-generation CARs targeting two different tumor antigens. (g) Universal CAR constructs include T cells engineered to express the universal CAR, an antibody that will recognize the tumor antigen, and a switch that acts as a bridge between the target cell and the CAR, allowing targets to be switched without reengineering the T cells. Abbreviations: CAR, chimeric antigen receptor; scFv, single-chain variable fragment; synNotch, synthetic Notch; TCR, T cell receptor; TM, transmembrane.