CAR-T NKR-2: leveraging the breadth of innate immunity

Cell-based immunotherapy employs specially modified T-cells to recognize and destroy tumor cells. Chimeric antigen receptor (CAR) T-cells recognize tumor antigens with high specificity, and the technique has achieved considerable success in the treatment of B-cell malignancies. However, this method requires careful selection and engineering for each tumor antigen, involves significant high-dose toxicity (including the potentially damaging cytokine release syndrome or CRS), and requires pre-conditioning chemotherapy to prevent rejection of the injected cells by the immune system.

As these challenges continue to be addressed, and amidst a growing interest in the field, CAR T NKR-2 is emerging as a novel treatment option that involves the NKG2D activating receptor, engineered to be expressed in T-cells harvested from the patient. This unique CAR T construct combines the multi-target specificity of the NKG2D receptor found naturally on NK cells with the effectiveness of a T-cell adaptive immune response, to identify and kill tumor cells.

The NKG2D receptor binds to multiple target ligands, namely MIC-A, MIC-B, and the ULBPs 1 to 6, that are expressed on tumor cells from 80% of cancer types, but not on normal, healthy cells. This makes CAR T NKR-2 applicable to both hematological and solid cancers. The recognition of multiple targets on tumor cells putatively reduces the development of target-negative tumor cell variants that could occur if a single target is employed. In addition, the use of a minimally engineered fully human construct, along with the reduced expansion and short persistence of the injected cells in the body, possibly minimizes toxicity and enables multiple administrations of the treatment. Collectively, this aims to deliver maximum efficacy without long term CAR T cell persistence. This controlled kinetics of CAR T NKR-2 is more comparable to that of a drug rather than that of current CAR Ts which follow a transplant paradigm.

Like the CAR Ts, CAR T NKR-2 functions through the direct killing of the tumor cells. However, beyond this direct killing activity, the breadth of target expression also enables CAR T NKR-2 to deliver a multi-pronged mechanism of action. Pre-clinical models have demonstrated that CAR T NKR-2 modulates local immune suppression within the tumor by decreasing the number of suppressive regulatory T-cells and myeloid-derived suppressor cells while also increasing macrophage recruitment to the tumor site. Additionally, CAR T NKR-2 can target tumor-localized endothelial cells lining newly developing blood vessels. The formation of new blood vessels (called angiogenesis) is essential for the tumor to grow, thus, CAR T NKR-2 appears to also deliver an anti-angiogenic effect through this specific targeting of tumor blood vessels. The combination of these mechanisms of action appears to release the body’s immune system to generate long-term immunological memory against specific tumor cells, thus decreasing the risk of disease relapse. This release of natural immunity is similar to the one sought to be achieved by the current range of checkpoint inhibitors. Importantly, the pre-clinical models also emphasize that pre-conditioning chemotherapy does not appear to be a pre-requisite for CAR T NKR-2 activity and thus avoids prolonged high dependency hospital stay for patients that results from pre-conditioning regimens. Together, these features suggest that CAR T NKR-2 has the potential to dramatically improve patient experience by reducing toxicity and hospitalization time.

CAR T NKR-2 has shown potential in pre-clinical safety and efficacy studies, and is currently being tested in early clinical development, to potentially improve the treatment of solid and hematological cancers that overexpress one or more of the range of specific target ligands. A recently concluded Phase I (CM-CS1) study using a low single dose of CAR T NKR-2 had an encouraging safety profile with no dose limiting toxicities or treatment related adverse events. This is currently being followed by the Phase I THINK study which involves three administrations of CAR T NKR-2 that correspond to the range of pharmacologically effective dose observed in in vivo experiments.

A complete White Paper describes the technology and early clinical development of the CAR T NKR-2 platform and elucidates its fundamental differences with classical CAR-T technologies, that could reshape the frontiers of cell-based cancer immunotherapy. It can be accessed by clicking here.

This article was created in collaboration with the sponsoring company and our sales and marketing team. The editorial team does not contribute.