CAR-NK Therapy: Translating a Novel Immunotherapy Treatment to Solid Organ Transplantation.

C antigen receptor (CAR) therapy is an emerging therapy that has recently gained much recognition in the oncological world for its ability to harness the command of cytotoxic T cells against tumors. Toxicities, however, have limited the clinical utility of this approach. In a recent issue of the New England Journal of Medicine, Liu et al presented results of phase 1 and 2 trial that uses CAR-transduced natural killer (NK) cells to treat relapsed or refractory CD19positive cancers. HLA-mismatched NK cells were modified to express an anti-CD19 CAR using donor cells from umbilical cord blood. These engineered cells express caspase 9 an inducible safety switch enzyme in addition to interleukin (IL)15, enhancing expansion and persistence after transferal. The trial involved 11 patients with relapsed or refractory nonHodgkin’s lymphoma or chronic lymphocytic leukemia who underwent lymphodepleting chemotherapy before CAR-NK treatment. Remarkably, within 30 days of a single infusion of CAR-NK therapy, 8 of 11 patients had responded—7 of whom were in complete remission at a median follow-up time of 13.8 months. Moreover, CAR-NK cells were still present and expanding at low levels at least 1 year after infusion, facilitating immunosurveillance. Importantly, the authors highlighted the safety profile of CAR-NK therapy as compared to previous CAR-T cell therapy as no patients experienced cytokine release syndrome or neurotoxicity representing common adverse effects of CAR-T therapy. As suggested, one of the major upsides of this therapy is its flexibility and availability as multiple doses of CAR-NK cells can be produced from a single unit of cord-blood and used with minimal HLA-matching requirements needed between donor and recipient. Its apparent safety, availability, and efficacy demonstrates the potential for translating CAR-NK therapy into solid organ transplantation, where graft rejection and loss are still prevalent, especially in intestinal, kidney, liver, and lung transplants developing malignancies. Thus, CAR-NK therapy’s success in blood cancer patients could have significant implications in an alternative method of posttransplant management to improve allograft survival and minimize secondary complications. While advancements in surgical technique and immunosuppression have improved outcomes in solid organ transplantation, further understanding of the dynamics between innate and adaptive immunity will likely yield more targeted insight and possible treatment options. NK cells have been well studied as key players that regulate the immune system in a dual fashion, maintaining a balance between rejection and tolerance. Specifically, NK cells are known for their capacity to recognize and kill virally infected cells and tumor cells, yet they can also play a role in both transplant rejection and tolerance. Due to the persistent immunosuppression required, transplant recipients are at an increased risk for developing malignancies, including posttransplant lymphoproliferative disorders (PTLD). Epstein-Barr virus (EBV) is well known to be involved in the pathogenesis of PTLD, persisting in B cells and becoming reactivated in the absence of T cells in the presence of immunosuppression. Management of PTLD often includes immunosuppressive adjustments to augment T-cell responses against the virus and supporting the removal of EBV-infected cells. Early studies have attempted to use cytotoxic T lymphocytes targeting EBV in the treatment of PTLD with some success. However, most of these studies were merely experimental, only available in clinical trials, and hampered by a long production time of up to 10–12 weeks for a single therapy attempt. As NK cells have antiviral fighting capacity, they have recently been successfully engineered to target EBVrelated PTLD after stem cell transplant. Use of CAR-NK therapy could provide another strategy either alone or in combination with current protocols in the management of PTLD if engineered to target EBV-infected B cells, providing the added advantage of a shorter production time, potentially infusible by day 15 after retrieval. While the adaptable role of NK cells in both rejection and tolerance continues to be explored, there is growing evidence that NK cells play a role in tolerance via killing donor professional antigen-presenting cells (APCs) and secreting IL-10 to promote a potentially tolerogenic immune response. In support of a tolerant compared to a proinflammatory environment, the CAR-NK trial by Liu et al showed that levels of major inflammatory cytokines ISSN: 0041-1337/20/1048-1523