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  • Review Article
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Forks in the road for CAR T and CAR NK cell cancer therapies

Nature Immunology volume 24, pages 1994–2007 (2023)Cite this article

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Abstract

The advent of chimeric antigen receptor (CAR) T cell therapy has resulted in unprecedented long-term clearance of relapse/refractory hematological malignancies in both pediatric and adult patients. However, severe toxicities, such as cytokine release syndrome and neurotoxicity, associated with CAR T cells affect therapeutic utility; and treatment efficacies for solid tumors are still not impressive. As a result, engineering strategies that modify other immune cell types, especially natural killer (NK) cells have arisen. Owing to both CAR-dependent and CAR-independent (innate immune-mediated) antitumor killing capacity, major histocompatibility complex-independent cytotoxicity, reduced risk of alloreactivity and lack of major CAR T cell toxicities, CAR NK cells constitute one of the promising next-generation CAR immune cells that are also amenable as ‘off-the-shelf’ therapeutics. In this Review, we compare CAR T and CAR NK cell therapies, with particular focus on immunological synapses, engineering strategies and challenges.

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Fig. 1: Canonical versus CAR immunological synapses in T cells and NK cells.
Fig. 2: CAR design and engineering strategies to overcome solid tumor evasion by CAR T and CAR NK cells.
Fig. 3: CAR T and CAR NK combination immunotherapies and methods of CAR cell engineering.

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References

  1. Irvine, D. J., Maus, M. V., Mooney, D. J. & Wong, W. W. The future of engineered immune cell therapies. Science 378, 853–858 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Lu, H., Zhao, X., Li, Z., Hu, Y. & Wang, H. From CAR-T cells to CAR-NK cells: a developing immunotherapy method for hematological malignancies. Front. Oncol. 11, 720501 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmidt, P., Raftery, M. J. & Pecher, G. Engineering NK Cells for CAR therapy-recent advances in gene transfer methodology. Front. Immunol. 11, 611163 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Berrien-Elliott, M. M., Jacobs, M. T. & Fehniger, T. A. Allogeneic natural killer cell therapy. Blood 141, 856–868 (2023).

    Article  CAS  PubMed  Google Scholar 

  6. Coyle, K. M., Hawke, L. G. & Ormiston, M. L. Addressing natural killer cell dysfunction and plasticity in cell-based cancer therapeutics. Cancers 15, 1743 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Laskowski, T. J., Biederstädt, A. & Rezvani, K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat. Rev. Cancer 22, 557–575 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ramírez-Labrada, A. et al. All About (NK cell-mediated) death in two acts and an unexpected encore: initiation, execution and activation of adaptive immunity. Front. Immunol. 13, 896228 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Huntington, N. D., Cursons, J. & Rautela, J. The cancer-natural killer cell immunity cycle. Nat. Rev. Cancer 20, 437–454 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Pai, J. A. et al. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell 41, 776–790 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).

    Article  PubMed  Google Scholar 

  13. Oh, D. Y. et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625(2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Steele, M. M. et al. T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control. Nat. Immunol. 24, 664–675 (2023). This study unveils the CXCR4–CXCL12 axis as an important target for enhancing intratumoral T cell retention in vivo.

    Article  CAS  PubMed  Google Scholar 

  17. Thacker, G. et al. Immature natural killer cells promote progression of triple-negative breast cancer. Sci. Transl. Med. 15, eabl4414 (2023). This study uncovers a ‘regulatory-like’ immature NK cell population that could be targeted to improve efficacy of immunotherapies against triple-negative breast cancer.

  18. Nuñez, S. Y. et al. Human M2 macrophages limit NK cell effector functions through secretion of TGF-β and engagement of CD85j. J. Immunol. 200, 1008–1015 (2018).

    Article  PubMed  Google Scholar 

  19. Kloosterman, D. J. & Akkari, L. Macrophages at the interface of the co-evolving cancer ecosystem. Cell 186, 1627–1651 (2023).

    Article  CAS  PubMed  Google Scholar 

  20. Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282–288 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zalfa, C. & Paust, S. Natural killer cell interactions with myeloid derived suppressor cells in the tumor microenvironment and implications for cancer immunotherapy. Front. Immunol. 12, 633205 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eschweiler, S. et al. Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy. Nat. Immunol. 22, 1052–1063 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Maalej, K. M. et al. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances. Mol. Cancer 22, 20 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tai, L. H., Zhang, J. & Auer, R. C. Preventing surgery-induced NK cell dysfunction and cancer metastases with influenza vaccination. Oncoimmunology 2, e26618 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xiao, X. et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J. Exp. Clin. Cancer Res. 40, 367 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang, X. et al. Cytokine release syndrome after modified CAR-NK therapy in an advanced non-small cell lung cancer patient: a case report. Cell Transplant. 31, 9636897221094244 (2022).

    Article  PubMed  Google Scholar 

  28. Klingemann, H. Are natural killer cells superior CAR drivers? Oncoimmunology 3, e28147 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Paul, S. & Lal, G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front. Immunol. 8, 1124 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Whang, M. et al. Large-scale expansion and engineering of human NK cells sourced from peripheral blood versus umbilical cord blood. J. Immunother. Cancer 10, A401 (2022).

    Google Scholar 

  31. Min, B. et al. Optimization of large-scale expansion and cryopreservation of human natural killer cells for anti-tumor therapy. Immune Netw. 18, e31 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Davenport, A. J. et al. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc. Natl Acad. Sci. USA 115, E2068–E2076 (2018). This study identifies an immature immunological synapse formed by CAR molecules in CAR-T cells as compared to canonical TCR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Watanabe, K., Kuramitsu, S., Posey, A. D. Jr. & June, C. H. Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front. Immunol. 9, 2486 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Al-Aghbar, M. A., Jainarayanan, A. K., Dustin, M. L. & Roffler, S. R. The interplay between membrane topology and mechanical forces in regulating T cell receptor activity. Commun. Biol. 5, 40 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Somersalo, K. et al. Cytotoxic T lymphocytes form an antigen-independent ring junction. J. Clin. Invest. 113, 49–57 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Potter, T. A., Grebe, K., Freiberg, B. & Kupfer, A. Formation of supramolecular activation clusters on fresh ex vivo CD8+ T cells after engagement of the T cell antigen receptor and CD8 by antigen-presenting cells. Proc. Natl Acad. Sci. USA 98, 12624–12629 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stinchcombe, J. C., Bossi, G., Booth, S. & Griffiths, G. M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 8, 713–725 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schmied, L. et al. SHP-1 localization to the activating immune synapse promotes NK cell tolerance in MHC class I deficiency. Sci. Signal. 16, eabq0752 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Davis, D. M. & Dustin, M. L. What is the importance of the immunological synapse? Trends Immunol. 25, 323–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Mukherjee, M., Mace, E. M., Carisey, A. F., Ahmed, N. & Orange, J. S. Quantitative imaging approaches to study the CAR immunological synapse. Mol. Ther. 25, 1757–1768 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jenkins, M. R. et al. Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time. J. Exp. Med. 212, 307–317 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Masilamani, M., Nguyen, C., Kabat, J., Borrego, F. & Coligan, J. E. CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J. Immunol. 177, 3590–3596 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Williams, G. S. et al. Membranous structures transfer cell surface proteins across NK cell immune synapses. Traffic 8, 1190–1204 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. McCann, F. E. et al. The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J. Immunol. 170, 2862–2870 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Zheng, X. et al. Tumors evade immune cytotoxicity by altering the surface topology of NK cells. Nat. Immunol. 24, 802–813 (2023). This study introduces a mechanism of tumor evasion in which tumor cells alter sphingomyelin content on intratumoral NK cells, leading to perturbed membrane protrusions and decreased cytotoxicity.

    Article  CAS  PubMed  Google Scholar 

  48. Chockley, P. J., Ibanez-Vega, J., Krenciute, G., Talbot, L. J. & Gottschalk, S. Synapse-tuned CARs enhance immune cell anti-tumor activity. Nat. Biotechnol. https://doi.org/10.1038/s41587-41022-01650-41582 (2023). This study introduces an approach by which tuning the synapse of CAR T or CAR NK cells could enhance their efficacy and intratumoral survival against solid tumors.

  49. Lin, J. & Weiss, A. The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling. J. Cell Biol. 162, 673–682 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Anikeeva, N. et al. Efficient killing of tumor cells by CAR-T cells requires greater number of engaged CARs than TCRs. J. Biol. Chem. 297, 101033 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Labanieh, L. & Mackall, C. L. CAR immune cells: design principles, resistance and the next generation. Nature 614, 635–648 (2023).

    Article  CAS  PubMed  Google Scholar 

  52. Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tian, Y., Li, Y., Shao, Y. & Zhang, Y. Gene modification strategies for next-generation CAR T cells against solid cancers. J. Hematol. Oncol. 13, 54 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat. Med. 24, 352–359 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dagher, O. K., Schwab, R. D., Brookens, S. K. & Posey, A. D. Jr. Advances in cancer immunotherapies. Cell 186, 1814–1814 (2023).

    Article  CAS  PubMed  Google Scholar 

  56. Curio, S., Jonsson, G. & Marinović, S. A summary of current NKG2D-based CAR clinical trials. Immunother. Adv. 1, ltab018 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Maali, A. et al. Nanobodies in cell-mediated immunotherapy: on the road to fight cancer. Front. Immunol. 14, 1012841 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lin, H., Cheng, J., Mu, W., Zhou, J. & Zhu, L. Advances in universal CAR-T cell therapy. Front. Immunol. 12, 744823 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wang, B. et al. Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells. Nat. Biomed. Eng. 5, 429–440 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Doan, A. & Pulsipher, M.A. Hypogammaglobulinemia due to CAR T cell therapy. Pediatr. Blood Cancer 65, e26914 (2018).

  61. Tousley, A. M. et al. Co-opting signalling molecules enables logic-gated control of CAR T cells. Nature 615, 507–516 (2023). This study introduces a gated-CAR platform in whichreplacing CD3ζ with downstream intracellular molecules such as SLP-76 and LAT enhanced the antitumor activity and mitigated on-target off-tumor toxicities.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Garrison, B. S. et al. FLT3 OR CD33 NOT EMCN logic gated CAR-NK cell therapy (SENTI-202) for precise targeting of AML. Blood 138, 2799 (2021).

    Article  Google Scholar 

  63. Zhang, X., Zhu, L., Zhang, H., Chen, S. & Xiao, Y. CAR-T cell therapy in hematological malignancies: current opportunities and challenges. Front. Immunol. 13, 927153 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sayitoglu, E. C. et al. Boosting natural killer cell-mediated targeting of sarcoma through DNAM-1 and NKG2D. Front. Immunol. 11, 40 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ruppel, K. E., Fricke, S., Köhl, U. & Schmiedel, D. Taking Lessons from CAR-T cells and going beyond: tailoring design and signaling for CAR-NK cells in cancer therapy. Front. Immunol. 13, 822298 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wrona, E., Borowiec, M. & Potemski, P. CAR-NK cells in the treatment of solid tumors. Int. J. Mol. Sci. 22, 5899 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kloss, C. C. et al. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chaudhry, K. et al. Co-transducing B7H3 CAR-NK cells with the DNR preserves their cytolytic function against GBM in the presence of exogenous TGF-β. Mol. Ther. Methods Clin. Dev. 27, 415–430 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu, X. et al. A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma. Transl. Oncol. 14, 101085 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu, B. et al. Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors. Mol. Ther. 29, 2949–2962 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jung, I. Y. et al. CRISPR/Cas9-mediated knockout of DGK improves antitumor activities of human T cells. Cancer Res. 78, 4692–4703 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Aspuria, P. J. et al. An orthogonal IL-2 and IL-2Rβ system drives persistence and activation of CAR T cells and clearance of bulky lymphoma. Sci. Transl. Med. 13, eabg7565 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, Q. et al. A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia. Sci. Transl. Med. 13, eabg6986 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Thomas, S. & Abken, H. CAR T cell therapy becomes CHIC: ‘cytokine help intensified CAR’ T cells. Front. Immunol. 13, 1090959 (2022).

    Article  CAS  PubMed  Google Scholar 

  75. Ma, R. et al. An oncolytic virus expressing IL15/IL15Rα combined with off-the-shelf EGFR-CAR NK cells targets glioblastoma. Cancer Res. 81, 3635–3648 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Imai, C., Iwamoto, S. & Campana, D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106, 376–383 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Denman, C. J. et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7, e30264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Shum, T. et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 7, 1238–1247 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Adachi, K. et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat. Biotechnol. 36, 346–351 (2018).

    Article  CAS  PubMed  Google Scholar 

  80. Chen, Y. et al. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin. Cancer Res. 25, 2915–2924 (2019).

    Article  CAS  PubMed  Google Scholar 

  81. Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl. Med. 8, 357ra123 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wang, J. et al. Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells. Proc. Natl Acad. Sci. USA 118, e2107507118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hegde, M. et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Bielamowicz, K. et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro. Oncol. 20, 506–518 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Schmidts, A. et al. Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma. Neurooncol. Adv. 5, vdac185 (2023).

    PubMed  Google Scholar 

  86. Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jin, L. et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 10, 4016 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Bughda, R., Dimou, P., D’Souza, R. R. & Klampatsa, A. Fibroblast activation protein (FAP)-targeted CAR-T cells: launching an attack on tumor stroma. Immunotargets Ther. 10, 313–323 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Weiner, L. M. inventor. Fibroblast activation protein modulation to alter immune cell migration and tumor infiltration. US patent application no. 22/165,019 (2022).

  90. Storti, P. et al. Novel approaches to improve myeloma cell killing by monoclonal antibodies. J. Clin. Med. 9, 2864 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rataj, F. et al. High-affinity CD16-polymorphism and Fc-engineered antibodies enable activity of CD16-chimeric antigen receptor-modified T cells for cancer therapy. Br. J. Cancer 120, 79–87 (2019).

    Article  CAS  PubMed  Google Scholar 

  92. Capuano, C. et al. Harnessing CD16-mediated NK cell functions to enhance therapeutic efficacy of tumor-targeting mAbs. Cancers 13, 2500 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hsu, J. et al. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J. Clin. Invest. 128, 4654–4668 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Sharma, P. et al. Immune checkpoint therapy-current perspectives and future directions. Cell 186, 1652–1669 (2023).

    Article  CAS  PubMed  Google Scholar 

  95. Le, R. Q. et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 23, 943–947 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Xing, J. et al. BiHC, a T-cell-engaging bispecific recombinant antibody, has potent cytotoxic activity against Her2 tumor cells. Transl. Oncol. 10, 780–785 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Goebeler, M. E. & Bargou, R. Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leuk. Lymphoma 57, 1021–1032 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. van Faassen, H. et al. Incorporation of a novel CD16-specific single-domain antibody into multispecific natural killer cell engagers with potent ADCC. Mol. Pharm. 18, 2375–2384 (2021).

    Article  PubMed  Google Scholar 

  99. Arvindam, U. S. et al. A trispecific killer engager molecule against CLEC12A effectively induces NK-cell mediated killing of AML cells. Leukemia 35, 1586–1596 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br. J. Haematol. 164, 811–821 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, Z. et al. Lenalidomide enhances CAR-T cell activity against solid tumor cells. Cell Transplant. 29, 963689720920825 (2020).

    Article  PubMed  Google Scholar 

  102. Benson, D. M. Jr. et al. A phase I trial of the anti-KIR antibody IPH2101 and lenalidomide in patients with relapsed/refractory multiple myeloma. Clin. Cancer Res. 21, 4055–4061 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Park, A. K. et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci. Transl. Med. 12, eaaz1863 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Liu, D. D. et al. Umbilical cord blood: a promising source for allogeneic CAR-T cells. Front. Oncol. 12, 944248 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Motwani, K. et al. Human regulatory T cells from umbilical cord blood display increased repertoire diversity and lineage stability relative to adult peripheral blood. Front. Immunol. 11, 611 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhu, X., Li, Q. & Zhu, X. Mechanisms of CAR T cell exhaustion and current counteraction strategies. Front. Cell Dev. Biol. 10, 1034257 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Arpinati, L. & Scherz-Shouval, R. From gatekeepers to providers: regulation of immune functions by cancer-associated fibroblasts. Trends Cancer 9, 421–443 (2023).

    Article  CAS  PubMed  Google Scholar 

  108. Finck, A. V., Blanchard, T., Roselle, C. P., Golinelli, G. & June, C. H. Engineered cellular immunotherapies in cancer and beyond. Nat. Med. 28, 678–689 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Brookens, S. K. & Posey, A. D. Jr. Chimeric antigen receptor T-cell therapy: current perspective on T cell-intrinsic, T cell-extrinsic, and therapeutic limitations. Cancer J. 29, 28–33 (2023).

    Article  CAS  PubMed  Google Scholar 

  110. Nayar, S., Dasgupta, P. & Galustian, C. Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies—a review. Oncoimmunology 4, e1002720 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Mark, C. et al. Cryopreservation impairs 3-D migration and cytotoxicity of natural killer cells. Nat. Commun. 11, 5224 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yao, X. & Matosevic, S. Cryopreservation of NK and T cells without DMSO for adoptive cell-based immunotherapy. BioDrugs 35, 529–545 (2021).

    Article  CAS  PubMed  Google Scholar 

  113. Judge, S. J., Murphy, W. J. & Canter, R. J. Characterizing the dysfunctional NK cell: assessing the clinical relevance of exhaustion, anergy, and senescence. Front. Cell. Infect. Microbiol. 10, 49 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Heinrich, B. et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut 71, 1161–1175 (2022).

    Article  CAS  PubMed  Google Scholar 

  115. Zhang, W., Zhao, Z. & Li, F. Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy. Mol. Immunol. 144, 58–70 (2022).

    Article  CAS  PubMed  Google Scholar 

  116. El-Mayta, R., Zhang, Z., Hamilton, A. G. & Mitchell, M. J. Delivery technologies to engineer natural killer cells for cancer immunotherapy. Cancer Gene Ther. 28, 947–959 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Colamartino, A. B. L. et al. Efficient and robust NK-cell transduction with baboon envelope pseudotyped lentivector. Front. Immunol. 10, 2873 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ojeda, P. Biological engineering of natural killer cells for cellular therapy against cancer. Master’s thesis, Harvard Medical School (2020).

  119. Balke-Want, H. et al. Non-viral chimeric antigen receptor (CAR) T cells going viral. Immunooncol. Technol. 18, 100375 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Moretti, A. et al. The past, present, and future of non-viral CAR T cells. Front. Immunol. 13, 867013 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bozza, M. et al. A nonviral, nonintegrating DNA nanovector platform for the safe, rapid, and persistent manufacture of recombinant T cells. Sci. Adv. 7, eabf1333 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Georgiadis, C. et al. Base-edited CAR T cells for combinational therapy against T cell malignancies. Leukemia 35, 3466–3481 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tang, X. et al. Magnetic-acoustic sequentially actuated CAR T cell microrobots for precision navigation and in situ antitumor immunoactivation. Adv. Mater. 35, e2211509 (2023). This study uses biomedical engineering strategies that enable the use of CAR T cells as live microrobots that could be targeted and activated in situ.

    Article  PubMed  Google Scholar 

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Acknowledgements

A.D.P. is supported by funding from the V Foundation, Lustgarten Foundation and Veterans Affairs (I01 BX006247).

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Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

    Oula K. Dagher & Avery D. Posey Jr.

  2. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA

    Avery D. Posey Jr.

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  1. Oula K. Dagher
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  2. Avery D. Posey Jr.
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O.K.D. and A.D.P. contributed to the writing and editing of the manuscript. O.K.D. designed the figures.

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Correspondence to Oula K. Dagher or Avery D. Posey Jr..

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A.D.P. is an inventor on patents related to CAR T cell therapies. The other authors declare no competing interests.

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Dagher, O.K., Posey, A.D. Forks in the road for CAR T and CAR NK cell cancer therapies. Nat Immunol 24, 1994–2007 (2023). https://doi.org/10.1038/s41590-023-01659-y

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