Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns

Abstract

Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms. In early clinical trials, CAR-T cell-based therapies achieved complete and durable responses in a significant proportion of patients. Despite clinical successes and given the side effect profiles of immunotherapies based on engineered cells, potential concerns with the safety and toxicity of various therapeutic modalities remain. We discuss the concerns associated with the safety and stability of the gene delivery vehicles for cell engineering and with toxicities due to off-target and on-target, off-tumor effector functions of the engineered cells. We then overview the various strategies aimed at improving the safety of and resolving toxicities associated with cell-based immunotherapies. Integrating failsafe switches based on different suicide gene therapy systems into engineered cells engenders promising strategies toward ensuring the safety of cancer immunotherapies in the clinic.

Recent developments in immunotherapy of acute myeloid leukemia

“…Integration of so-called suicide gene systems into CAR constructs could act as safety switches enabling rapid on-demand elimination of CAR T cells that would otherwise turn uncontrollable. These suicide gene systems can be based on enzymatic activation of cytotoxic prodrugs, antibody-based targeting of overexpressed surface antigens, or pharmacological induction of apoptosis via inducible caspase 9 which is already tested in clinical phase I CAR T cell trials (NCT03016377 [95]).…”

CD8+ T cells and NK cells: parallel and complementary soldiers of immunotherapy

“…However, these therapeutic strategies may precipitate autoreactive T cell responses: checkpoint inhibitors override peripheral tolerance mechanisms, and CARs cross-react with healthy tissues. Many clinical studies have unfortunately fallen short of expectations; the nature of cancer causes it to generate large heterogeneities among patients and to mutate away from its immune attackers, resulting in non-response or relapse [4–6]. This has lead researchers to investigate the use of natural killer (NK) cells, another cytotoxic immune cell, for cancer therapy.…”

Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

“…The suicide genes, molecular safety switches, and inhibitory corticosteroids represent the earliest and still most popular rational approaches to managing unpredictable CAR T cell expansion and toxicities in patients. Essentially, a safety switch is an ectopically expressed safeguard gene, which can be activated on demand to remove the infused therapeutic cells from the body rapidly and permanently, in case of an adverse immune reaction [23,24,[44][45][46]. An ideal safety switch should be capable of depleting the transferred T cells with minimal injury to normal tissues.…”