KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape

Li, Ye; Basar, Rafet; Wang, Guohui; Liu, Enli; Moyes, Judy S.; Li, Li; Kerbauy, Lucila Nassif; Uprety, Nadima; Fathi, Mohsen; Rezvan, Ali; Banerjee, Pinaki P.; Muniz-Feliciano, Luis; Laskowski, Tamara; Ensley, Emily L.; Daher, May; Shanley, Mayra; Mendt, Mayela Carolina; Acharya, Sunil; Liu, Bin; Biederstädt, Alexander; Rafei, Hind; Guo, Xingliang; Garcia, Luciana Melo; Lin, Paul; Ang, Sonny; Marín, David; Chen, Ken; Bover, Laura; Champlin, Richard E.; Varadarajan, Navin; Shpall, Elizabeth J.; Rezvani, Katayoun

doi:10.1038/s41591-022-02003-x

Cited by 91 publications

(79 citation statements)

References 68 publications

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“…NK cells are a signifcant component of the nonspecifc immune response that exert antitumor efects by both direct cytolytic activity and the secretion of immunostimulatory cytokines [13][14][15][16]. Studies have confrmed that the occurrence of many tumors is related to the loss of the recognition function of NK cells, which is also one of the main mechanisms of tumor immune evasion [17][18][19][20]. Te release of lytic granules containing granzymes and perforin mediates the cytolytic activity of NK cells via binding death receptors on tumor cells, and this can be demonstrated by the expression of CD107a on the surface of NK cells.…”

Section: Discussionmentioning

confidence: 99%

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

Wang

Jia³

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and, in its advanced stages, has a 5-year survival rate of only 3% to 5%. Despite novel mechanisms and treatments being uncovered over the past few years, effective strategies for HCC are currently limited. Previous studies have proven that aconite can suppress tumor growth and progression and prevent the recurrence and metastasis of multiple cancers, but the underlying molecular mechanisms are largely unknown. In this study, different doses of aconite were applied to mice bearing subcutaneous HCC tumors. It was found that aconite had a therapeutic effect on H22 tumor-bearing mice in a dose-dependent manner by reducing tumor volumes and prolonging survival times, which could be attributed to the immunoregulatory effect of aconite. Furthermore, results showed that high-dose administration of aconite could enhance adaptive immunity and natural killer (NK) cell-mediated immunity by regulating the secretion of interferon-γ, upregulating T cells and NK cells, and modulating the expression of the NK cytotoxicity biomarker CD107a and the inhibitory receptor TIGIT. This study revealed a novel mechanism through which aconite exerts antitumor effects, not merely through apoptosis induction pathways, providing more sound evidence that aconite has the potential to be developed into an effective anti-HCC agent.

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Section: Discussionmentioning

confidence: 99%

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

Wang

Jia³

et al. 2023

Evidence-Based Complementary and Alternative Medicine

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“…Besides widening the therapeutic window when targeting shared antigens, dual CAR strategies can also be harnessed to mitigate fratricidal killing of neighboring CAR-engineered IECs, which can occur following transfer of the targeted antigen from the tumor cells to the IECs through means of trogocytosis. As was recently illustrated for CD19-directed CAR-NK cells, integration of KIR-based inhibitory CAR receptors can shield NK cells from such effects and yield more potent tumor killing ( 86 ).…”

Section: Multiplexed Engineering As a Tool To Enhance Cellular Therapiesmentioning

confidence: 95%

Multiplexed engineering and precision gene editing in cellular immunotherapy

2022

Self Cite

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The advent of cellular immunotherapy in the clinic has entirely redrawn the treatment landscape for a growing number of human cancers. Genetically reprogrammed immune cells, including chimeric antigen receptor (CAR)-modified immune effector cells as well as T cell receptor (TCR) therapy, have demonstrated remarkable responses across different hard-to-treat patient populations. While these novel treatment options have had tremendous success in providing long-term remissions for a considerable fraction of treated patients, a number of challenges remain. Limited in vivo persistence and functional exhaustion of infused immune cells as well as tumor immune escape and on-target off-tumor toxicities are just some examples of the challenges which restrain the potency of today’s genetically engineered cell products. Multiple engineering strategies are being explored to tackle these challenges.The advent of multiplexed precision genome editing has in recent years provided a flexible and highly modular toolkit to specifically address some of these challenges by targeted genetic interventions. This class of next-generation cellular therapeutics aims to endow engineered immune cells with enhanced functionality and shield them from immunosuppressive cues arising from intrinsic immune checkpoints as well as the hostile tumor microenvironment (TME). Previous efforts to introduce additional genetic modifications into immune cells have in large parts focused on nuclease-based tools like the CRISPR/Cas9 system or TALEN. However, nuclease-inactive platforms including base and prime editors have recently emerged and promise a potentially safer route to rewriting genetic sequences and introducing large segments of transgenic DNA without inducing double-strand breaks (DSBs). In this review, we discuss how these two exciting and emerging fields—cellular immunotherapy and precision genome editing—have co-evolved to enable a dramatic expansion in the possibilities to engineer personalized anti-cancer treatments. We will lay out how various engineering strategies in addition to nuclease-dependent and nuclease-inactive precision genome editing toolkits are increasingly being applied to overcome today’s limitations to build more potent cellular therapeutics. We will reflect on how novel information-rich unbiased discovery approaches are continuously deepening our understanding of fundamental mechanisms governing tumor biology. We will conclude with a perspective of how multiplexed-engineered and gene edited cell products may upend today’s treatment paradigms as they evolve into the next generation of more potent cellular immunotherapies.

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“…Interestingly, Clinical trials CAR-NK cells can recognize and kill the residual tumor cells after long-term treatment. because CAR-NK cells contain CAR-dependent and CAR-independent target recognition and killing capabilities, the incidence of tumor escape in CAR-NK therapy is less ( 59 , 78 , 79 ). In addition, mature NK cells have a short lifespan in blood, which reduces the risk of cellular memory responses and cellular defects resulting from targeted/non-tumor effects ( 80 ).…”

Section: Combined Applications Of Car-nk Cells and Immune Checkpoint ...mentioning

confidence: 99%

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

Yang

Zhao²,

Sun³

et al. 2023

Front. Immunol.

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Chimeric antigen receptor (CAR) engineering of natural killer (NK) cells is an attractive research field in tumor immunotherapy. While CAR is genetically engineered to express certain molecules, it retains the intrinsic ability to recognize tumor cells through its own receptors. Additionally, NK cells do not depend on T cell receptors for cytotoxic killing. CAR-NK cells exhibit some differences to CAR-T cells in terms of more precise killing, numerous cell sources, and increased effectiveness in solid tumors. However, some problems still exist with CAR-NK cell therapy, such as cytotoxicity, low transfection efficiency, and storage issues. Immune checkpoints inhibit immune cells from performing their normal killing function, and the clinical application of immune checkpoint inhibitors for cancer treatment has become a key therapeutic strategy. The application of CAR-T cells and immune checkpoint inhibitors is being evaluated in numerous ongoing basic research and clinical studies. Immune checkpoints may affect the function of CAR-NK cell therapy. In this review, we describe the combination of existing CAR-NK cell technology with immune checkpoint therapy and discuss the research of CAR-NK cell technology and future clinical treatments. We also summarize the progress of clinical trials of CAR-NK cells and immune checkpoint therapy.

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KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape

Cited by 91 publications

References 68 publications

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

The Immunoregulatory Effect of Aconite Treatment on H22 Tumor‐Bearing Mice via Modulating Adaptive Immunity and Natural Killer‐Related Immunity

Multiplexed engineering and precision gene editing in cellular immunotherapy

Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy

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