Chimeric 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 al1 presented results of phase 1 and 2 trial that uses CAR-transduced natural killer (NK) cells to treat relapsed or refractory CD19-positive cancers. HLA-mismatched NK cells were modified to express an anti-CD19 CAR using donor cells from umbilical cord blood.1 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 non-Hodgkin’s lymphoma or chronic lymphocytic leukemia who underwent lymphodepleting chemotherapy before CAR-NK treatment.1 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.1 Moreover, CAR-NK cells were still present and expanding at low levels at least 1 year after infusion, facilitating immunosurveillance.1 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.2 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.1
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 patients1 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.3 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.4
Due to the persistent immunosuppression required, transplant recipients are at an increased risk for developing malignancies, including posttransplant lymphoproliferative disorders (PTLD).5 Epstein-Barr virus (EBV) is well known to be involved in the pathogenesis of PTLD,5 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.6 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 EBV-related PTLD after stem cell transplant.7 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.1
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)3,4,8 and secreting IL-10 to promote a potentially tolerogenic immune response.9 In support of a tolerant compared to a proinflammatory environment, the CAR-NK trial by Liu et al1 showed that levels of major inflammatory cytokines such as IL-1, tumor necrosis factor-α, and interferon-γ remained at low levels.1 In organ transplantation, where the risk of rejection continues to be one of the greatest management challenges, tailored CAR-NK therapy against highly immunogenic donor APC subsets, such as myeloid dendritic cells, may thus support shifting the alloimmune priming process, potentially creating tolerogenic effects (see Figure 1). Specifically, CAR-NK cells could be engineered to precisely and selectively target immunogenic while sparing tolerogenic graft-derived APC subsets in transplant recipients. Thus, translating the success of CAR-NK therapy into the management of solid organ transplantation could provide a novel strategy supporting graft survival while preventing side effects that have previously challenged CAR-NK applications.
Moreover, NK cells are once again rising to prominence with leading scientists pointing towards their relevance to combatting the coronavirus infections linked to severe acute respiratory syndrome coronavirus. Zheng et al10 have recently reported that NK cells and CD8+ T cells are functionally exhausted in patients with coronavirus disease 2019 suggesting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may deplete antiviral immunity. Specifically, they noted not only that cytotoxic NK cells and CD8+ T cells are significantly diminished in patients with SARS-CoV-2, but that the remaining populations were functionally exhausted as indicated by lower percentages of intracellular cytokines, including tumor necrosis factor-α, interferon-γ, IL-2, and granzyme B with increased expression of the inhibitory receptor NKG2A. Since this observation suggests that SARS-CoV-2 infected patients experience a breakdown in early NK-mediated antiviral immunity (see Figure 1), CAR-NK therapy could have the potential to target SARS-CoV-2 infected cells and mitigate damage caused by secondary depletion of NK and CD8+ T cells, leading to preservation of antiviral immunity.
1. Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020; 382:545–553
2. Gill S, Maus MV, Porter DL. Chimeric antigen receptor T cell therapy: 25years in the making. Blood Rev. 2016; 30:157–167
3. Benichou G, Yamada Y, Aoyama A, et al. Natural killer cells in rejection and tolerance of solid organ allografts. Curr Opin Organ Transplant. 2011; 26:47–53
4. Kroemer A, Xiao X, Degauque N, et al. The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol. 2008; 180:7818–7826
5. Gottschalk S, Rooney CM, Heslop HE. Post-transplant lymphoproliferative disorders. Annu Rev Med. 2005; 56:29–44
6. Bollard CM, Rooney CM, Heslop HE. T-cell therapy in the treatment of post-transplant lymphoproliferative disease. Nat Rev Clin Oncol. 2012; 9:510–519
7. Pfeffermann LM, Pfirrmann V, Huenecke S, et al. Epstein-Barr virus-specific cytokine-induced killer cells for treatment of Epstein-Barr virus-related malignant lymphoma. Cytotherapy. 2018; 20:839–850
8. Yu G, Xu X, Minh DV, et al. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med. 2006; 203:1851–1858
9. Maroof A, Beattie L, Zubairi S, et al. Post-transcriptional regulation of IL-10 gene expression allows NK cells to express immunoregulatory function. Immunity. 2008; 29:295–305
10. Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol. 2020; 17:533–535doi:10.1038/s41423-020-0402-2