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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
Morgan, R. A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
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).
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).
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).
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).
Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).
Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).
Zacharakis, N. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24, 724–730 (2018).
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).
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).
Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).
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).
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).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2019).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Hammill, J. A. et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J. Immunother. Cancer 3, 55 (2015).
Hermanson, D. L. et al. A novel Bcma-specific, centyrin-based CAR-T product for the treatment of multiple myeloma. Blood 128, 2127 (2016).
Kudo, K. et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–103 (2014).
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).
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).
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).
Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).
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).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).
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).
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).
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).
Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).
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).
Bielamowicz, K. et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-oncol. 20, 506–518 (2018).
Hegde, M. et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016).
Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 1039–1041 (2017).
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).
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).
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).
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).
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).
Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432 e416 (2016).
Leen, A. M. et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014).
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).
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).
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).
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).
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).
Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).
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).
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).
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).
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).
Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).
Cornetta, K. et al. Absence of replication-competent lentivirus in the clinic: analysis of infused T cell products. Mol. Ther. 26, 280–288 (2018).
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).
Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).
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).
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).
Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
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).
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).
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).
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).
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Roth, T. L. et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 559, 405–409 (2018).
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).
Ruella, M. & Kenderian, S. S. Next-generation chimeric antigen receptor T-cell therapy: going off the shelf. BioDrugs 31, 473–481 (2017).
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).
Osborn, M. J. et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Mol. Ther. 24, 570–581 (2016).
Provasi, E. et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat. Med. 18, 807–815 (2012).
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).
Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).
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).
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).
Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).
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).
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).
Mehta, R. S. & Rezvani, K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front. Immunol. 9, 283 (2018).
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).
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).
Micucci, F. et al. High-efficient lentiviral vector-mediated gene transfer into primary human NK cells. Exp. Hematol. 34, 1344–1352 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Chen, K. H. et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 31, 2151–2160 (2017).
Pinz, K. G. et al. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Oncotarget 8, 112783–112796 (2017).
Moyes, K. W. et al. Genetically engineered macrophages: a potential platform for cancer immunotherapy. Hum. Gene Ther. 28, 200–215 (2017).
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).
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).
Ray, M. et al. CRISPRed macrophages for cell-based cancer immunotherapy. Bioconjug. Chem. 29, 445–450 (2018).
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).
Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).
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).
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).
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).
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).
Gschweng, E., De Oliveira, S. & Kohn, D. B. Hematopoietic stem cells for cancer immunotherapy. Immunol. Rev. 257, 237–249 (2014).
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).
Li, S. et al. Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther. 12, 600–607 (2005).
Martinez-Quintanilla, J. et al. Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors. Stem Cells 31, 1706–1714 (2013).
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).
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).
Aboody, K. S. et al. Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci. Transl. Med. 5, 184ra59 (2013).
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).
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).
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).
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).
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).
Mooney, R. et al. Neural stem cell-mediated intratumoral delivery of gold nanorods improves photothermal therapy. ACS Nano 8, 12450–12460 (2014).
Roger, M. et al. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31, 8393–8401 (2010).
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).
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).
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).
Boroughs, A. C. et al. Chimeric antigen receptor costimulation domains modulate human regulatory T cell function. JCI Insight 5, 126194 (2019).
Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353, 179–184 (2016).
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).
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).
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).
Hale, M. et al. Engineering HIV-resistant, anti-HIV chimeric antigen receptor T cells. Mol. Ther. 25, 570–579 (2017).
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy
Stem Cell Research & Therapy (2021)
Journal of Clinical Oncology (2021)
HDAC inhibition prevents transgene expression downregulation and loss-of-function in T cell-receptor-transduced T cells
Molecular Therapy - Oncolytics (2021)
Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release
Advanced Science (2021)
Advanced Drug Delivery Reviews (2021)