IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

CAR T Cell Immunotherapy Beyond Haematological Malignancy

  • Cedric Hupperetz (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Sangjoon Lah (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Hyojin Kim (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)) ;
  • Chan Hyuk Kim (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
  • Received : 2021.12.29
  • Accepted : 2022.01.28
  • Published : 2022.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Chimeric antigen receptor (CAR) T cells, which express a synthetic receptor engineered to target specific antigens, have demonstrated remarkable potential to treat haematological malignancies. However, their transition beyond haematological malignancy has so far been unsatisfactory. Here, we discuss recent challenges and improvements for CAR T cell therapy against solid tumors: Antigen heterogeneity which provides an effective escape mechanism against conventional mono-antigen-specific CAR T cells; and the immunosuppressive tumor microenvironment which provides physical and molecular barriers that respectively prevent T cell infiltration and drive T cell dysfunction and hypoproliferation. Further, we discuss the application of CAR T cells in infectious disease and autoimmunity.

Keywords

Acknowledgement

This work was supported by KAIST END-run program.

References

  1. June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Sci Transl Med 2015;7:280ps7.
  2. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013;3:388-398. https://doi.org/10.1158/2159-8290.CD-12-0548
  3. Tokarew N, Ogonek J, Endres S, von Bergwelt-Baildon M, Kobold S. Teaching an old dog new tricks: next-generation CAR T cells. Br J Cancer 2019;120:26-37. https://doi.org/10.1038/s41416-018-0325-1
  4. Finney HM, Lawson AD, Bebbington CR, Weir AN. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 1998;161:2791-2797. https://doi.org/10.4049/jimmunol.161.6.2791
  5. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002;20:70-75. https://doi.org/10.1038/nbt0102-70
  6. Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004;18:676-684. https://doi.org/10.1038/sj.leu.2403302
  7. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-1517. https://doi.org/10.1056/NEJMoa1407222
  8. Ali SA, Shi V, Maric I, Wang M, Stroncek DF, Rose JJ, Brudno JN, Stetler-Stevenson M, Feldman SA, Hansen BG, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688-1700. https://doi.org/10.1182/blood-2016-04-711903
  9. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol 2018;15:366-381. https://doi.org/10.1038/s41571-018-0007-1
  10. Wherry EJ. T cell exhaustion. Nat Immunol 2011;12:492-499. https://doi.org/10.1038/ni.2035
  11. Maldini CR, Ellis GI, Riley JL. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 2018;18:605-616. https://doi.org/10.1038/s41577-018-0042-2
  12. Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov 2018;8:1219-1226. https://doi.org/10.1158/2159-8290.CD-18-0442
  13. Rafiq S, Brentjens RJ. Tumors evading CARs-the chase is on. Nat Med 2018;24:1492-1493. https://doi.org/10.1038/s41591-018-0212-6
  14. O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJ, Martinez-Lage M, Brem S, Maloney E, Shen A, 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 2017;9:eaaa0984.
  15. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol 2020;17:147-167. https://doi.org/10.1038/s41571-019-0297-y
  16. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, Wolters P, Martin S, Delbrook C, Yates B, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018;24:20-28. https://doi.org/10.1038/nm.4441
  17. Pan J, Niu Q, Deng B, Liu S, Wu T, Gao Z, Liu Z, Zhang Y, Qu X, Zhang Y, et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia 2019;33:2854-2866. https://doi.org/10.1038/s41375-019-0488-7
  18. Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, Krueger W, Worden AA, Kadan MJ, Yim S, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med 2020;26:1569-1575. https://doi.org/10.1038/s41591-020-1081-3
  19. Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, Frank MJ, Shiraz P, Sahaf B, Craig J, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med 2021;27:1419-1431. https://doi.org/10.1038/s41591-021-01436-0
  20. Goebeler ME, Bargou RC. T cell-engaging therapies - BiTEs and beyond. Nat Rev Clin Oncol 2020;17:418-434. https://doi.org/10.1038/s41571-020-0347-5
  21. Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A, Larson RC, Bailey SR, Boroughs AC, Frigault MJ, Leick MB, et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol 2019;37:1049-1058. https://doi.org/10.1038/s41587-019-0192-1
  22. Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res 2014;74:93-103. https://doi.org/10.1158/0008-5472.CAN-13-1365
  23. Urbanska K, Lanitis E, Poussin M, Lynn RC, Gavin BP, Kelderman S, Yu J, Scholler N, Powell DJ Jr. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res 2012;72:1844-1852. https://doi.org/10.1158/0008-5472.CAN-11-3890
  24. Tamada K, Geng D, Sakoda Y, Bansal N, Srivastava R, Li Z, Davila E. Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin Cancer Res 2012;18:6436-6445. https://doi.org/10.1158/1078-0432.CCR-12-1449
  25. Ma JS, Kim JY, Kazane SA, Choi SH, Yun HY, Kim MS, Rodgers DT, Pugh HM, Singer O, Sun SB, et al. Versatile strategy for controlling the specificity and activity of engineered T cells. Proc Natl Acad Sci U S A 2016;113:E450-E458. https://doi.org/10.1073/pnas.1524193113
  26. Rodgers DT, Mazagova M, Hampton EN, Cao Y, Ramadoss NS, Hardy IR, Schulman A, Du J, Wang F, Singer O, et al. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc Natl Acad Sci U S A 2016;113:E459-E468. https://doi.org/10.1073/pnas.1524155113
  27. Cho JH, Collins JJ, Wong WW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 2018;173:1426-1438.e1411. https://doi.org/10.1016/j.cell.2018.03.038
  28. Cho JH, Okuma A, Sofjan K, Lee S, Collins JJ, Wong WW. Engineering advanced logic and distributed computing in human CAR immune cells. Nat Commun 2021;12:792.
  29. Kim MS, Ma JS, Yun H, Cao Y, Kim JY, Chi V, Wang D, Woods A, Sherwood L, Caballero D, et al. Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J Am Chem Soc 2015;137:2832-2835. https://doi.org/10.1021/jacs.5b00106
  30. Lee YG, Marks I, Srinivasarao M, Kanduluru AK, Mahalingam SM, Liu X, Chu H, Low PS. Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. Cancer Res 2019;79:387-396. https://doi.org/10.1158/0008-5472.CAN-18-1834
  31. Newick K, O'Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annu Rev Med 2017;68:139-152. https://doi.org/10.1146/annurev-med-062315-120245
  32. Jin MZ, Jin WL. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther 2020;5:166.
  33. Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM, Foster AE. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 2010;33:780-788. https://doi.org/10.1097/CJI.0b013e3181ee6675
  34. Moon EK, Carpenito C, Sun J, Wang LC, Kapoor V, Predina J, Powell DJ Jr, Riley JL, June CH, Albelda SM. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res 2011;17:4719-4730. https://doi.org/10.1158/1078-0432.CCR-11-0351
  35. Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, Heslop HE, Brenner MK, Dotti G, Savoldo B. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 2009;113:6392-6402. https://doi.org/10.1182/blood-2009-03-209650
  36. Cadilha BL, Benmebarek MR, Dorman K, Oner A, Lorenzini T, Obeck H, Vanttinen M, Di Pilato M, Pruessmann JN, Stoiber S, et al. Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors. Sci Adv 2021;7:eabi5781.
  37. Lesch S, Blumenberg V, Stoiber S, Gottschlich A, Ogonek J, Cadilha BL, Dantes Z, Rataj F, Dorman K, Lutz J, et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat Biomed Eng 2021;5:1246-1260. https://doi.org/10.1038/s41551-021-00737-6
  38. Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 2015;21:524-529. https://doi.org/10.1038/nm.3833
  39. Chang ZL, Lorenzini MH, Chen X, Tran U, Bangayan NJ, Chen YY. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat Chem Biol 2018;14:317-324. https://doi.org/10.1038/nchembio.2565
  40. Tormoen GW, Crittenden MR, Gough MJ. Role of the immunosuppressive microenvironment in immunotherapy. Adv Radiat Oncol 2018;3:520-526. https://doi.org/10.1016/j.adro.2018.08.018
  41. Leen AM, Sukumaran S, Watanabe N, Mohammed S, Keirnan J, Yanagisawa R, Anurathapan U, Rendon D, Heslop HE, Rooney CM, et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol Ther 2014;22:1211-1220. https://doi.org/10.1038/mt.2014.47
  42. Wilkie S, Burbridge SE, Chiapero-Stanke L, Pereira AC, Cleary S, van der Stegen SJ, Spicer JF, Davies DM, Maher J. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J Biol Chem 2010;285:25538-25544. https://doi.org/10.1074/jbc.M110.127951
  43. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, Huang X, Caldwell S, Liu K, Smith P, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 2006;103:13132-13137. https://doi.org/10.1073/pnas.0605251103
  44. Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, Drake CG, Powell JD. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 2008;111:251-259. https://doi.org/10.1182/blood-2007-03-081646
  45. Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS, Davenport AJ, John LB, Mardiana S, Slaney CY, et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J Clin Invest 2017;127:929-941. https://doi.org/10.1172/JCI89455
  46. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167:829-842.e13. https://doi.org/10.1016/j.cell.2016.09.031
  47. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5:641-654. https://doi.org/10.1038/nri1668
  48. Fultang L, Booth S, Yogev O, Martins da Costa B, Tubb V, Panetti S, Stavrou V, Scarpa U, Jankevics A, Lloyd G, et al. Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood 2020;136:1155-1160. https://doi.org/10.1182/blood.2019004500
  49. Marasco M, Berteotti A, Weyershaeuser J, Thorausch N, Sikorska J, Krausze J, Brandt HJ, Kirkpatrick J, Rios P, Schamel WW, et al. Molecular mechanism of SHP2 activation by PD-1 stimulation. Sci Adv 2020;6:eaay4458.
  50. Jeong S, Park SH. Co-Stimulatory Receptors in Cancers and Their Implications for Cancer Immunotherapy. Immune Netw 2020;20:e3.
  51. Liu X, Ranganathan R, Jiang S, Fang C, Sun J, Kim S, Newick K, Lo A, June CH, Zhao Y, et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res 2016;76:1578-1590. https://doi.org/10.1158/0008-5472.CAN-15-2524
  52. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, Marson A. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 2017;7:737.
  53. Guo X, Jiang H, Shi B, Zhou M, Zhang H, Shi Z, Du G, Luo H, Wu X, Wang Y, et al. Disruption of PD-1 enhanced the anti-tumor activity of chimeric antigen receptor T cells against hepatocellular carcinoma. Front Pharmacol 2018;9:1118.
  54. Hu B, Zou Y, Zhang L, Tang J, Niedermann G, Firat E, Huang X, Zhu X. Nucleofection with plasmid DNA for CRISPR/Cas9-mediated inactivation of programmed cell death protein 1 in CD133-specific CAR T cells. Hum Gene Ther 2019;30:446-458. https://doi.org/10.1089/hum.2017.234
  55. Hu W, Zi Z, Jin Y, Li G, Shao K, Cai Q, Ma X, Wei F. CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol Immunother 2019;68:365-377. https://doi.org/10.1007/s00262-018-2281-2
  56. Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med 2015;212:1125-1137. https://doi.org/10.1084/jem.20142237
  57. Wartewig T, Kurgyis Z, Keppler S, Pechloff K, Hameister E, Ollinger R, Maresch R, Buch T, Steiger K, Winter C, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 2017;552:121-125. https://doi.org/10.1038/nature24649
  58. Lee YH, Lee HJ, Kim HC, Lee Y, Nam SK, Hupperetz C, Ma JSY, Wang X, Singer O, Kim WS, et al. PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells. Mol Ther 2022;30:579-592. https://doi.org/10.1016/j.ymthe.2021.10.004
  59. Zou F, Lu L, Liu J, Xia B, Zhang W, Hu Q, Liu W, Zhang Y, Lin Y, Jing S, et al. Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56. Nat Commun 2019;10:4109.
  60. Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 2016;126:3130-3144. https://doi.org/10.1172/JCI83092
  61. Chen J, Lopez-Moyado IF, Seo H, Lio CJ, Hempleman LJ, Sekiya T, Yoshimura A, Scott-Browne JP, Rao A. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 2019;567:530-534.  https://doi.org/10.1038/s41586-019-0985-x
  62. Scott AC, Dundar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 2019;571:270-274. https://doi.org/10.1038/s41586-019-1324-y
  63. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 2019;571:211-218. https://doi.org/10.1038/s41586-019-1325-x
  64. Kim K, Park S, Park SY, Kim G, Park SM, Cho JW, Kim DH, Park YM, Koh YW, Kim HR, et al. Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Med 2020;12:22.
  65. Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang YH, Lopez-Moyado IF, Georges RO, Zhang W, Onodera A, et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion (vol 116, pg 12410, 2019). Proc Natl Acad Sci U S A 2019;116:19761-19761. https://doi.org/10.1073/pnas.1914896116
  66. Good CR, Kuramitsu S, Samareh P, Donahue G, Ishiyama K, Ma Y, Wellhausen N, Tian L, Agarwal S, Guedan S, et al. Induction of T cell dysfunction and NK-like T cell differentiation in vitro and in patients after CAR T cell treatment. Cancer Res 2021;81 Suppl:A60.
  67. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015;21:581-590. https://doi.org/10.1038/nm.3838
  68. Murphy TL, Tussiwand R, Murphy KM. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks. Nat Rev Immunol 2013;13:499-509. https://doi.org/10.1038/nri3470
  69. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, Carter R, Awad W, Neale G, Thomas PG, et al. De novo epigenetic programs inhibit PD-1 Blockade-mediated T cell rejuvenation. Cell 2017;170:142-157.e19. https://doi.org/10.1016/j.cell.2017.06.007
  70. Wang Y, Tong C, Dai H, Wu Z, Han X, Guo Y, Chen D, Wei J, Ti D, Liu Z, et al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat Commun 2021;12:409.
  71. Prinzing B, Zebley CC, Petersen CT, Fan Y, Anido AA, Yi Z, Nguyen P, Houke H, Bell M, Haydar D, et al. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci Transl Med 2021;13:eabh0272.
  72. Weber EW, Parker KR, Sotillo E, Lynn RC, Anbunathan H, Lattin J, Good Z, Belk JA, Daniel B, Klysz D, et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science 2021;372: eaba1786.
  73. Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016;354:1160-1165. https://doi.org/10.1126/science.aaf2807
  74. Deeks SG, Overbaugh J, Phillips A, Buchbinder S. HIV infection. Nat Rev Dis Primers 2015;1:15035.
  75. Maldini CR, Claiborne DT, Okawa K, Chen T, Dopkin DL, Shan X, Power KA, Trifonova RT, Krupp K, Phelps M, et al. Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. Nat Med 2020;26:1776-1787. https://doi.org/10.1038/s41591-020-1039-5
  76. Rust BJ, Kean LS, Colonna L, Brandenstein KE, Poole NH, Obenza W, Enstrom MR, Maldini CR, Ellis GI, Fennessey CM, et al. Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates. Blood 2020;136:1722-1734. https://doi.org/10.1182/blood.2020006372
  77. Zhen A, Peterson CW, Carrillo MA, Reddy SS, Youn CS, Lam BB, Chang NY, Martin HA, Rick JW, Kim J, 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 2017;13:e1006753.
  78. Young LS, Yap LF, Murray PG. Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer 2016;16:789-802.  https://doi.org/10.1038/nrc.2016.92
  79. Dragon AC, Zimmermann K, Nerreter T, Sandfort D, Lahrberg J, Kloss S, Kloth C, Mangare C, Bonifacius A, Tischer-Zimmermann S, et al. CAR-T cells and TRUCKs that recognize an EBNA-3C-derived epitope presented on HLA-B*35 control Epstein-Barr virus-associated lymphoproliferation. J Immunother Cancer 2020;8:e000736.
  80. Slabik C, Kalbarczyk M, Danisch S, Zeidler R, Klawonn F, Volk V, Kronke N, Feuerhake F, Ferreira de Figueiredo C, Blasczyk R, et al. CAR-T cells targeting Epstein-Barr virus gp350 validated in a humanized mouse model of EBV infection and lymphoproliferative disease. Mol Ther Oncolytics 2020;18:504-524. https://doi.org/10.1016/j.omto.2020.08.005
  81. Griffiths P, Reeves M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat Rev Microbiol 2021;19:759-773. https://doi.org/10.1038/s41579-021-00582-z
  82. Full F, Lehner M, Thonn V, Goetz G, Scholz B, Kaufmann KB, Mach M, Abken H, Holter W, Ensser A. T cells engineered with a cytomegalovirus-specific chimeric immunoreceptor. J Virol 2010;84:4083-4088. https://doi.org/10.1128/JVI.02117-09
  83. Ali A, Chiuppesi F, Nguyen M, Hausner MA, Nguyen J, Kha M, Iniguez A, Wussow F, Diamond DJ, Yang OO. Chimeric antigen receptors targeting human cytomegalovirus. J Infect Dis 2020;222:853-862. https://doi.org/10.1093/infdis/jiaa171
  84. Brey CU, Proff J, Teufert N, Salzer B, Brozy J, Munz M, Pendzialek J, Ensser A, Holter W, Lehner M. A gB/CD3 bispecific BiTE antibody construct for targeting Human Cytomegalovirus-infected cells. Sci Rep 2018;8:17453.
  85. Manns MP, Buti M, Gane E, Pawlotsky JM, Razavi H, Terrault N, Younossi Z. Hepatitis C virus infection. Nat Rev Dis Primers 2017;3:17006.
  86. Sautto GA, Wisskirchen K, Clementi N, Castelli M, Diotti RA, Graf J, Clementi M, Burioni R, Protzer U, Mancini N. Chimeric antigen receptor (CAR)-engineered T cells redirected against hepatitis C virus (HCV) E2 glycoprotein. Gut 2016;65:512-523. https://doi.org/10.1136/gutjnl-2014-308316
  87. Yuen MF, Chen DS, Dusheiko GM, Janssen HL, Lau DT, Locarnini SA, Peters MG, Lai CL. Hepatitis B virus infection. Nat Rev Dis Primers 2018;4:18035.
  88. Bohne F, Chmielewski M, Ebert G, Wiegmann K, Kurschner T, Schulze A, Urban S, Kronke M, Abken H, Protzer U. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology 2008;134:239-247. https://doi.org/10.1053/j.gastro.2007.11.002
  89. Krebs K, Bottinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, Jager C, Schmitt E, Bohne F, Aichler M, et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 2013;145:456-465. https://doi.org/10.1053/j.gastro.2013.04.047
  90. Festag MM, Festag J, Frassle SP, Asen T, Sacherl J, Schreiber S, Muck-Hausl MA, Busch DH, Wisskirchen K, Protzer U. Evaluation of a fully human, hepatitis B virus-specific chimeric antigen receptor in an immunocompetent mouse model. Mol Ther 2019;27:947-959. https://doi.org/10.1016/j.ymthe.2019.02.001
  91. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021;184:861-880. https://doi.org/10.1016/j.cell.2021.01.007
  92. Guo X, Kazanova A, Thurmond S, Saragovi HU, Rudd CE. Effective chimeric antigen receptor T cells against SARS-CoV-2. iScience 2021;24:103295.
  93. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. 'Off-the-shelf ' allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov 2020;19:185-199. https://doi.org/10.1038/s41573-019-0051-2
  94. van de Veerdonk FL, Gresnigt MS, Romani L, Netea MG, Latge JP. Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 2017;15:661-674. https://doi.org/10.1038/nrmicro.2017.90
  95. Kumaresan PR, Manuri PR, Albert ND, Maiti S, Singh H, Mi T, Roszik J, Rabinovich B, Olivares S, Krishnamurthy J, et al. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A 2014;111:10660-10665. https://doi.org/10.1073/pnas.1312789111
  96. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 2018;6:15.
  97. Zhang B, Wang Y, Yuan Y, Sun J, Liu L, Huang D, Hu J, Wang M, Li S, Song W, et al. In vitro elimination of autoreactive B cells from rheumatoid arthritis patients by universal chimeric antigen receptor T cells. Ann Rheum Dis 2021;80:176-184. https://doi.org/10.1136/annrheumdis-2020-217844
  98. Hammers CM, Stanley JR. Mechanisms of disease: pemphigus and bullous pemphigoid. Annu Rev Pathol 2016;11:175-197. https://doi.org/10.1146/annurev-pathol-012615-044313
  99. Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, Di Zenzo G, Lanzavecchia A, Seykora JT, Cotsarelis G, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 2016;353:179-184. https://doi.org/10.1126/science.aaf6756
  100. Lee J, Lundgren DK, Mao X, Manfredo-Vieira S, Nunez-Cruz S, Williams EF, Assenmacher CA, Radaelli E, Oh S, Wang B, et al. Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris. J Clin Invest 2020;130:6317-6324. https://doi.org/10.1172/JCI138416
  101. Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G. Systemic lupus erythematosus. Nat Rev Dis Primers 2016;2:16039.
  102. Kansal R, Richardson N, Neeli I, Khawaja S, Chamberlain D, Ghani M, Ghani QU, Balazs L, Beranova-Giorgianni S, Giorgianni F, et al. Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Sci Transl Med 2019;11:eaav1648.
  103. Jin X, Xu Q, Pu C, Zhu K, Lu C, Jiang Y, Xiao L, Han Y, Lu L. Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. Cell Mol Immunol 2021;18:1896-1903. https://doi.org/10.1038/s41423-020-0472-1
  104. Mougiakakos D, Kronke G, Volkl S, Kretschmann S, Aigner M, Kharboutli S, Boltz S, Manger B, Mackensen A, Schett G. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 2021;385:567-569. https://doi.org/10.1056/NEJMc2107725
  105. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers 2018;4:43.
  106. Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, Harris RA, Magnusson PU, Brittebo E, Loskog AS. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation 2012;9:112.
  107. De Paula Pohl A, Schmidt A, Zhang AH, Maldonado T, Konigs C, Scott DW. Engineered regulatory T cells expressing myelin-specific chimeric antigen receptors suppress EAE progression. Cell Immunol 2020;358:104222.
  108. Frisoli ML, Essien K, Harris JE. Vitiligo: mechanisms of pathogenesis and treatment. Annu Rev Immunol 2020;38:621-648. https://doi.org/10.1146/annurev-immunol-100919-023531
  109. Mukhatayev Z, Dellacecca ER, Cosgrove C, Shivde R, Jaishankar D, Pontarolo-Maag K, Eby JM, Henning SW, Ostapchuk YO, Cedercreutz K, et al. Antigen specificity enhances disease control by tregs in vitiligo. Front Immunol 2020;11:581433.
  110. Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, Scholler J, Monslow J, Lo A, Han W, et al. Targeting cardiac fibrosis with engineered T cells. Nature 2019;573:430-433. https://doi.org/10.1038/s41586-019-1546-z