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Gene editing for immune cell therapies

Nature Biotechnology volume 37, pages 1425–1434 (2019)Cite this article

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Abstract

Autologous T cells that have been genetically modified to express a chimeric antigen receptor (CAR) targeting the B cell antigen CD19 have yielded remarkable clinical responses in patients with B cell malignancies, and are now on the market as anticancer ‘drugs’. Riding on this success, the field of immune cell engineering is rapidly growing, with creative solutions to major outstanding challenges, such as limitations in target antigen selection, the hostility of the tumor microenvironment and the logistical challenges of generating autologous therapies. Innovations in antigen receptor design, coupled with advances in gene transfer and gene-editing technologies, have enabled the engineering of T cells to have sophisticated sensing circuits, to have synthetic functionalities, and to be used as off-the-shelf, universal cellular products. As these technologies are applied to other immune cells, such as natural killer cells, hematopoietic cells or induced pluripotent stem cells, the potential to transform the treatment of many cancers, as well as other diseases, is palpably exciting. We discuss the pipeline of several influential innovations in the preclinical setting, the early translational results from clinical trials of these next-generation approaches, and the outlook for gene-modified or gene-edited cell therapies.

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Fig. 1: T-cell immune-editing strategies.
Fig. 2: Macrophages in immunotherapy: a two-pronged approach.
Fig. 3: Engineering stem cells for cancer therapy.

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References

  1. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Rapoport, A. P. et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. D’Angelo, S. P. et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 c259T cells in synovial sarcoma. Cancer Discov. 8, 944–957 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Johnson, L. A. et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Leisegang, M. et al. Eradication of large solid tumors by gene therapy with a T-cell receptor targeting a single cancer-specific point mutation. Clin. Cancer Res. 22, 2734–2743 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. Matsuda, T. et al. Induction of neoantigen-specific cytotoxic T cells and construction of T-cell receptor-engineered T cells for ovarian cancer. Clin. Cancer Res. 24, 5357–5367 (2018).

    Article  PubMed  CAS  Google Scholar 

  12. Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Eshhar, Z., Waks, T., Gross, G. & Schindler, D. G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl Acad. Sci. USA 90, 720–724 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Turtle, C. J. et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Locke, F. L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 20, 31–42 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Ali, S. A. et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim, M. Y. et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell 173, 1439–1453.e1419 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gomes-Silva, D. et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood 130, 285–296 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Maus, M. V. et al. An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity. Mol. Ther. Oncolytics 3, 1–9 (2017).

    PubMed  PubMed Central  Google Scholar 

  24. Brown, C. E. et al. Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol. Ther. 26, 31–44 (2018).

    Article  CAS  PubMed  Google Scholar 

  25. Caruso, H. G. et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 75, 3505–3518 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hammill, J. A. et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J. Immunother. Cancer 3, 55 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hermanson, D. L. et al. A novel Bcma-specific, centyrin-based CAR-T product for the treatment of multiple myeloma. Blood 128, 2127 (2016).

    Article  Google Scholar 

  28. Kudo, K. et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–103 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Urbanska, K. et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 72, 1844–1852 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438.e1411 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fedorov, V. D., Themeli, M. & Sadelain, M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5, 215ra172 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Srivastava, S. et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489–503.e488 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jacoby, E. et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Huang, L. et al. Sequential infusion of anti-CD22 and anti-CD19 chimeric antigen receptor T cells for adult patients with refractory/relapsed B-cell acute lymphoblastic leukemia. Blood 130, 846 (2017).

    Article  Google Scholar 

  41. 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 

  42. 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 

  43. Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 1039–1041 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Friedman, C. F., Proverbs-Singh, T. A. & Postow, M. A. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2, 1346–1353 (2016).

    Article  PubMed  Google Scholar 

  46. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Suarez, E. R. et al. Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model. Oncotarget 7, 34341–34355 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432 e416 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Leen, A. M. et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rupp, L. J. et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7, 737 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Pegram, H. J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Boice, M. et al. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell 167, 405–418.e413 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Siriwon, N. et al. CAR-T cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol. Res. 6, 812–824 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kochenderfer, J. N. et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bobisse, S. et al. Reprogramming T lymphocytes for melanoma adoptive immunotherapy by T-cell receptor gene transfer with lentiviral vectors. Cancer Res. 69, 9385–9394 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Cornetta, K. et al. Absence of replication-competent lentivirus in the clinic: analysis of infused T cell products. Mol. Ther. 26, 280–288 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Bear, A. S. et al. Replication-competent retroviruses in gene-modified T cells used in clinical trials: is it time to revise the testing requirements? Mol. Ther. 20, 246–249 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Peng, P. D. et al. Efficient nonviral Sleeping Beauty transposon-based TCR gene transfer to peripheral blood lymphocytes confers antigen-specific antitumor reactivity. Gene Ther. 16, 1042–1049 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118, 3132–3142 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).

    Article  PubMed  Google Scholar 

  70. MacLeod, D. T. et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol. Ther. 25, 949–961 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sather, B. D. et al. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template. Sci. Transl. Med. 7, 307ra156 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. Wang, J. et al. Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery. Nucleic Acids Res. 44, e30 (2016).

    Article  PubMed  CAS  Google Scholar 

  73. Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Abou-El-Enein, M., Bauer, G., Medcalf, N., Volk, H. D. & Reinke, P. Putting a price tag on novel autologous cellular therapies. Cytotherapy 18, 1056–1061 (2016).

    Article  PubMed  Google Scholar 

  76. Ruella, M. & Kenderian, S. S. Next-generation chimeric antigen receptor T-cell therapy: going off the shelf. BioDrugs 31, 473–481 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mirzaei, H. R., Mirzaei, H., Lee, S. Y., Hadjati, J. & Till, B. G. Prospects for chimeric antigen receptor (CAR) γδ T cells: a potential game changer for adoptive T cell cancer immunotherapy. Cancer Lett. 380, 413–423 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Osborn, M. J. et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol. Ther. 24, 570–581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Provasi, E. et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18, 807–815 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Torikai, H. et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119, 5697–5705 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Cooper, M. L. et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32, 1970–1983 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gautron, A. S. et al. Fine and predictable tuning of TALEN gene editing targeting for improved T cell adoptive immunotherapy. Mol. Ther. Nucleic Acids 9, 312–321 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gornalusse, G. G. et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol. 35, 765–772 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Benjamin, R. et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia. Blood 132, 896 (2018).

    Article  Google Scholar 

  87. Mehta, R. S. & Rezvani, K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front. Immunol. 9, 283 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Boissel, L., Betancur, M., Wels, W. S., Tuncer, H. & Klingemann, H. Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells. Leuk. Res. 33, 1255–1259 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Boissel, L. et al. Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. Leuk. Lymphoma 53, 958–965 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Micucci, F. et al. High-efficient lentiviral vector-mediated gene transfer into primary human NK cells. Exp. Hematol. 34, 1344–1352 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Jiang, H. et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol. Oncol. 8, 297–310 (2014).

    Article  CAS  PubMed  Google Scholar 

  92. Chu, J. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28, 917–927 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Genßler, S. et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Oncoimmunology 5, e1119354 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Zhang, Q. et al. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. J. Immunol. Res. 2017, 6915912 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Schönfeld, K. et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol. Ther. 23, 330–338 (2015).

    Article  PubMed  CAS  Google Scholar 

  96. Kruschinski, A. et al. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc. Natl Acad. Sci. USA 105, 17481–17486 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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 

  98. Chu, Y. et al. Targeting CD20+ aggressive B-cell non-Hodgkin lymphoma by anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG mice. Cancer Immunol. Res. 3, 333–344 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, E. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520–531 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, K. H. et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 31, 2151–2160 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pinz, K. G. et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget 8, 112783–112796 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Moyes, K. W. et al. Genetically engineered macrophages: a potential platform for cancer immunotherapy. Hum. Gene Ther. 28, 200–215 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Ho, C. C. et al. “Velcro” engineering of high affinity CD47 ectodomain as signal regulatory protein α (SIRPα) antagonists that enhance antibody-dependent cellular phagocytosis. J. Biol. Chem. 290, 12650–12663 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Ray, M. et al. CRISPRed macrophages for cell-based cancer immunotherapy. Bioconjug. Chem. 29, 445–450 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vizcardo, R. et al. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 12, 31–36 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Vizcardo, R. et al. Generation of tumor antigen-specific iPSC-derived thymic emigrants using a 3D thymic culture system. Cell Rep. 22, 3175–3190 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhao, Y. et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 67, 2425–2429 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Giannoni, F. et al. Allelic exclusion and peripheral reconstitution by TCR transgenic T cells arising from transduced human hematopoietic stem/progenitor cells. Mol. Ther. 21, 1044–1054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Gschweng, E., De Oliveira, S. & Kohn, D. B. Hematopoietic stem cells for cancer immunotherapy. Immunol. Rev. 257, 237–249 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Senju, S. et al. Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy. Gene Ther. 18, 874–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Li, S. et al. Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther. 12, 600–607 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Martinez-Quintanilla, J. et al. Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors. Stem Cells 31, 1706–1714 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Aboody, K. S. et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl Acad. Sci. USA 97, 12846–12851 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Altaner, C. et al. Complete regression of glioblastoma by mesenchymal stem cells mediated prodrug gene therapy simulating clinical therapeutic scenario. Int. J. Cancer 134, 1458–1465 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Aboody, K. S. et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci. Transl. Med. 5, 184ra59 (2013).

    Article  PubMed  CAS  Google Scholar 

  119. Kauer, T. M., Figueiredo, J. L., Hingtgen, S. & Shah, K. Encapsulated therapeutic stem cells implanted in the tumor resection cavity induce cell death in gliomas. Nat. Neurosci. 15, 197–204 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ling, X. et al. Mesenchymal stem cells overexpressing IFN-β inhibit breast cancer growth and metastases through Stat3 signaling in a syngeneic tumor model. Cancer Microenviron. 3, 83–95 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tobias, A. L. et al. The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma. Stem Cells Transl. Med. 2, 655–666 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Duebgen, M. et al. Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy. J. Natl Cancer Inst. 106, dju090 (2014).

    Article  PubMed  Google Scholar 

  123. Ong, H. T. et al. Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth. J. Hepatol. 59, 999–1006 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mooney, R. et al. Neural stem cell-mediated intratumoral delivery of gold nanorods improves photothermal therapy. ACS Nano 8, 12450–12460 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Roger, M. et al. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31, 8393–8401 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Auffinger, B. et al. Drug-loaded nanoparticle systems and adult stem cells: a potential marriage for the treatment of malignant glioma? Oncotarget 4, 378–396 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Kim, Y. C. et al. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood 125, 1107–1115 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yoon, J. et al. FVIII-specific human chimeric antigen receptor T-regulatory cells suppress T- and B-cell responses to FVIII. Blood 129, 238–245 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Boroughs, A. C. et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight 5, 126194 (2019).

    Article  PubMed  Google Scholar 

  130. Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Mitsuyasu, R. T. et al. Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4+ and CD8+ T cells in human immunodeficiency virus-infected subjects. Blood 96, 785–793 (2000).

    Article  CAS  PubMed  Google Scholar 

  132. Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhen, A. et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLoS Pathog. 13, e1006753 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Hale, M. et al. Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol. Ther. 25, 570–579 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    Stefanie R. Bailey & Marcela V. Maus

  2. Harvard Medical School, Boston, MA, USA

    Stefanie R. Bailey & Marcela V. Maus

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Correspondence to Marcela V. Maus.

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M.V.M. is an inventor on patents in the field of CAR-T cell therapies; these patents are held either by University of Pennsylvania or by Massachusetts General Hospital/Partners Healthcare.

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Bailey, S.R., Maus, M.V. Gene editing for immune cell therapies. Nat Biotechnol 37, 1425–1434 (2019). https://doi.org/10.1038/s41587-019-0137-8

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