{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T21:01:48Z","timestamp":1785013308310,"version":"3.55.0"},"reference-count":76,"publisher":"Begell House","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Crit Rev Oncog"],"published-print":{"date-parts":[[2026]]},"abstract":"<p>Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for hematologic malignancies, achieving deep and durable responses across multiple FDA approved products. This progress stems from foundational discoveries initiated by Zelig Eshhar, whose early demonstrations that T cells could be redirected using synthetic receptors laid the conceptual groundwork for modern CAR-T design. Despite these successes, translating CAR-T therapy into solid cancers remains challenging. Solid tumors present unique obstacles including antigen heterogeneity, immunosuppressive microenvironments, limited T cell trafficking, and multiple mechanisms of antigen escape. Case studies across key solid tumor targets such as mesothelin, interleukin 13 receptor alpha 2 (IL13R&amp;alpha;2), claudin 18.2 (CLDN18.2), glypican 3 (GPC3), epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), and ganglioside D2 (GD2) highlight both the promise of CAR-T therapy and the biological complexities that limit durable clinical benefit. To address these barriers, next generation engineering strategies incorporating multispecific targeting, adaptor platforms, and logic gated receptor circuits (OR, AND, NOT, and multi-layered designs) are being developed to enhance tumor specificity, mitigate on-target\/off-tumor toxicity, and prevent antigen escape. Armored CAR-T cells capable of overcoming suppressive tumor microenvironments further expand therapeutic potential. Collectively, these advances signal a shift from single antigen targeting to programmable, modular T cell therapies capable of responding to the multifaceted challenges of solid tumors. As the field integrates synthetic biology innovations with lessons learned from decades of clinical practice, CAR-T therapy is poised for broader applicability across both hematologic and solid cancers, extending the legacy of Eshhar's pioneering work.<\/p>","DOI":"10.1615\/critrevoncog.2026064031","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T15:50:33Z","timestamp":1774367433000},"page":"51-66","source":"Crossref","is-referenced-by-count":0,"title":["Review Article: Overcoming Antigen Expression Barriers in CAR-T Therapy for Solid Tumors"],"prefix":"10.1615","volume":"31","author":[{"given":"Owen R.","family":"Moon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Bridgeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyuan","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"613","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, Nagase F, Kurosawa Y. Expression of chimeric receptor composed of immunoglobulin-derived V resions and T cell receptor-derived C regions. Biochem Biophys Res Commun. 1987;149(3):960-\u0080\u00938.","DOI":"10.1016\/0006-291X(87)90502-X"},{"key":"2","unstructured":"Gross G, Gorochov G, Waks T, Eshhar Z. Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity. Transpl Proc. 1989;21(1 Pt 1):127-\u0080\u009330."},{"key":"3","doi-asserted-by":"crossref","unstructured":"Eshhar Z, Waks T, Gross G, Schindler DG. 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 U S A. 1993;90(2):720-\u0080\u00934.","DOI":"10.1073\/pnas.90.2.720"},{"key":"4","doi-asserted-by":"crossref","unstructured":"Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, Rosenberg SA, Eshhar Z. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor \u00ce\u00b3 chain. J Exp Med. 1993;178(1): 361-\u0080\u00936.","DOI":"10.1084\/jem.178.1.361"},{"key":"5","doi-asserted-by":"crossref","unstructured":"Alvarez-Vallina L, Hawkins RE. Antigen-specific targeting of CD28-mediated T cell co-stimulation using chimeric single-chain antibody variable fragment-CD28 receptors. Eur J Immunol. 1996;26(10):2304-\u0080\u00939.","DOI":"10.1002\/eji.1830261006"},{"key":"6","doi-asserted-by":"crossref","unstructured":"Finney HM, Lawson ADG, Bebbington CR, Weir ANC. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol. 1998;161(6):2791-\u0080\u00937.","DOI":"10.4049\/jimmunol.161.6.2791"},{"key":"7","doi-asserted-by":"crossref","unstructured":"Maher J, Brentjens RJ, Gunset G, Rivi\u00e8re I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR\u00ce\u00b6\/CD28 receptor. Nat Biotechnol. 2002;20(1):70-\u0080\u00935.","DOI":"10.1038\/nbt0102-70"},{"key":"8","doi-asserted-by":"crossref","unstructured":"Finney HM, Akbar AN, Lawson ADG. Activation of resting human primary T cells with chimeric receptors: Costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR\u00ce\u00b6 chain. J Immunol. 2004;172(1):104-\u0080\u009313.","DOI":"10.4049\/jimmunol.172.1.104"},{"key":"9","doi-asserted-by":"crossref","unstructured":"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(4):676-\u0080\u009384.","DOI":"10.1038\/sj.leu.2403302"},{"key":"10","doi-asserted-by":"crossref","unstructured":"Hombach A, Abken H. Costimulation tunes tumor-specific activation of redirected T cells in adoptive immunotherapy. Cancer Immunol Immunother. 2007;56(5):731-\u0080\u00937.","DOI":"10.1007\/s00262-006-0249-0"},{"key":"11","unstructured":"Walker RE, Bechtel CM, Natarajan V, Baseler M, Hege KM, Metcalf JA, Stevens R, Hazen A, Blaese RM, Chen CC, Leitman SF, Palensky J, Wittes J, Davey RT, Falloon J, Polis MA, Kovacs JA, Broad DF, Levine BL, Roberts MR, Masur H, Lane HC. Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection. Blood. 2000;96(2):467-\u0080\u009374."},{"key":"12","doi-asserted-by":"crossref","unstructured":"Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006;12(20 Pt 1):6106-\u0080\u009315.","DOI":"10.1158\/1078-0432.CCR-06-1183"},{"key":"13","doi-asserted-by":"crossref","unstructured":"Park JR, DiGiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007;15(4):825-\u0080\u009333.","DOI":"10.1038\/sj.mt.6300104"},{"key":"14","doi-asserted-by":"crossref","unstructured":"Lamers CHJ, Langeveld SCL, Groot-Van Ruijven CM, Debets R, Sleijfer S, Gratama JW. Gene-modified T cells for adoptive immunotherapy of renal cell cancer maintain transgene-specific immune functions in vivo. Cancer Immunol Immunother. 2007;56(12):1875-\u0080\u009383.","DOI":"10.1007\/s00262-007-0330-3"},{"key":"15","doi-asserted-by":"crossref","unstructured":"Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld M, Nathan DAN, Lanier BJ, Morgan RA, Rosenberg SA. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099-\u0080\u0093102.","DOI":"10.1182\/blood-2010-04-281931"},{"key":"16","doi-asserted-by":"crossref","unstructured":"MacKay M, Afshinnekoo E, Rub J, Hassan C, Khunte M, Baskaran N, Owens B, Liu L, Roboz GJ, Guzman ML, Melnick AM, Wu S, Mason CE. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol. 2020;38(2):233-\u0080\u009344.","DOI":"10.1038\/s41587-019-0329-2"},{"key":"17","doi-asserted-by":"crossref","unstructured":"Li D, Guo X, Yang K, Yang Y, Zhou W, Huang Y, Liang X, Su J, Jiang L, Li J, Fu M, He H, Yang J, Shi H, Yang H, Tong A, Chen N, Hu J, Xu Q, Wei YQ, Wang W. EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors. Sci Adv. 2023;9(48): eadg9721.","DOI":"10.1126\/sciadv.adg9721"},{"key":"18","doi-asserted-by":"crossref","unstructured":"Hassan R, Butler M, O'\u0080\u0099Cearbhaill RE, Oh DY, Johnson M, Zikaras K, Smalley M, Ross M, Tanyi JL, Ghafoor A, Shah NN, Saboury B, Cao L, Quint\u00e1s-Cardama A, Hong D. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: Phase 1\/2 trial interim results. Nat Med. 2023;29(8):2099-\u0080\u0093109.","DOI":"10.1038\/s41591-023-02452-y"},{"key":"19","doi-asserted-by":"crossref","unstructured":"Li CH, Sharma S, Heczey AA, Woods ML, Steffin DHM, Louis CU, Grilley BJ, Thakkar SG, Wu M, Wang T, Rooney CM, Brenner MK, Heslop HE. Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma. Nat Med. 2025;31(4):1125-\u0080\u00939.","DOI":"10.1038\/s41591-025-03513-0"},{"key":"20","doi-asserted-by":"crossref","unstructured":"Steffin D, Ghatwai N, Montalbano A, Rathi P, Courtney AN, Arnett AB, Fleurence J, Sweidan R, Wang T, Zhang H, Masand P, Maris JM, Martinez D, Pogoriler J, Varadarajan N, Thakkar SG, Lyon D, Lapteva N, Zhuyong M, Patel K, Lopez-Terrada D, Ramos CA, Lulla P, Armaghany T, Grilley BJ, Gottschalk S, Dotti G, Metelitsa LS, Heslop HE, Brenner MK, Sumazin P, Heczey A. Interleukin-15-armored GPC3 CAR T cells for patients with solid cancers. Nature. 2025;637(8047):940-\u0080\u00936.","DOI":"10.1038\/s41586-024-08261-8"},{"key":"21","doi-asserted-by":"crossref","unstructured":"Chen N, Pu C, Zhao L, Li W, Wang C, Zhu R, Liang T, Niu C, Huang X, Tang H, Wang Y, Yang H, Jia B, Jiang X, Han G, Wang W, Chen D, Wang Y, Rowinsky EK, Kennedy E, Lu VX, Cui G, Wu Z, Xiao L, Cui J. Chimeric antigen receptor T cells targeting CD19 and GCC in metastatic colorectal cancer: A nonrandomized clinical trial. JAMA Oncol. 2024;10(11):1532-\u0080\u00936.","DOI":"10.1001\/jamaoncol.2024.3891"},{"key":"22","doi-asserted-by":"crossref","unstructured":"Hegde M, Navai S, DeRenzo C, Joseph SK, Sanber K, Wu M, Gad AZ, Janeway KA, Campbell M, Mullikin D, Nawas Z, Robertson C, Mathew PR, Zhang H, Mehta B, Bhat RR, Major A, Shree A, Gerken C, Kalra M, Chakraborty R, Thakkar SG, Dakhova O, Salsman VS, Grilley B, Lapteva N, Gee A, Dotti G, Bao R, Salem AH, Wang T, Brenner MK, Heslop HE, Wels WS, Hicks MJ, Gottschalk S, Ahmed N. Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: A phase 1 trial. Nat Cancer. 2024;5(6):880-\u0080\u009394.","DOI":"10.1038\/s43018-024-00749-6"},{"key":"23","doi-asserted-by":"crossref","unstructured":"Shah PD, Huang AC, Xu X, Orlowski R, Amaravadi RK, Schuchter LM, Zhang P, Tchou J, Matlawski T, Cervini A, Shea J, Gilmore J, Lledo L, Dengel K, Marshall A, Wherry EJ, Linette GP, Brennan A, Gonzalez V, Kulikovskaya I, Lacey SF, Plesa G, June CH, Vonderheide RH, Mitchell TC. Phase I trial of autologous RNA-electroporated cMET-directed CAR T Cells administered intravenously in patients with melanoma and breast carcinoma. Cancer Res Commun. 2023;3(5):821-\u0080\u00939.","DOI":"10.1158\/2767-9764.CRC-22-0486"},{"key":"24","doi-asserted-by":"crossref","unstructured":"Mackensen A, Haanen JBAG, Koenecke C, Alsdorf W, Wagner-Drouet E, Borchmann P, Heudobler D, Ferstl B, Klobuch S, Bokemeyer C, Desuki A, L\u00fcke F, Kutsch N, M\u00fcller F, Smit E, Hillemanns P, Karagiannis P, Wiegert E, He Y, Ho T, Kang-Fortner Q, Schlitter AM, Schulz-Eying C, Finlayson A, Flemmig C, K\u00fchlcke K, Preu\u00dfner L, Rengstl B, T\u00fcreci \u00d6\u0096, Sahin U. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: The phase 1 BNT211-01 trial. Nat Med. 2023;29(11):2844-\u0080\u009353.","DOI":"10.1038\/s41591-023-02612-0"},{"key":"25","doi-asserted-by":"crossref","unstructured":"Qi C, Liu C, Gong J, Liu D, Wang X, Zhang P, Qin Y, Ge S, Zhang M, Peng Z, Zhou J, Lu Z, Lu M, Cao Y, Yuan J, Wang Y, Wang Z, Xue R, Peng X, Wang Y, Yuan D, Li J, Zhang X, Shen L. Claudin18.2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial final results. Nat Med. 2024;30(8):2224-\u0080\u009334.","DOI":"10.1038\/s41591-024-03037-z"},{"key":"26","doi-asserted-by":"crossref","unstructured":"Botta GP, Kelly RJ, Jin Z, Ma H, Ku GY, Zhao D, Mehta R, Carnevale JC, Sierra G, Jia J, Baffa R, Li Z, Kim DW, Yoon HH. CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: Results of ELIMYN18.2 phase 1b clinical trial. J Clin Oncol. 2024;42(3):356. doi: 10.1200\/JCO.2024.42.3_suppl.356.","DOI":"10.1200\/JCO.2024.42.3_suppl.356"},{"key":"27","doi-asserted-by":"crossref","unstructured":"Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007;13(17):5144-\u0080\u00939.","DOI":"10.1158\/1078-0432.CCR-07-0869"},{"key":"28","doi-asserted-by":"crossref","unstructured":"Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL, Albelda SM, June CH. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 2010;70(22):9053-\u0080\u009361.","DOI":"10.1158\/0008-5472.CAN-10-2880"},{"key":"29","doi-asserted-by":"crossref","unstructured":"Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, Zhao Y, Kalos M, June CH. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1(1):26-\u0080\u009331.","DOI":"10.1158\/2326-6066.CIR-13-0006"},{"key":"30","doi-asserted-by":"crossref","unstructured":"Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, Chew A, Zhao Y, Levine BL, Albelda SM, Kalos M, June CH. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. 2014;2(2):112-\u0080\u009320.","DOI":"10.1158\/2326-6066.CIR-13-0170"},{"key":"31","doi-asserted-by":"crossref","unstructured":"Haas AR, Tanyi JL, O\u2019Hara MH, Gladney WL, Lacey SF, Torigian DA, Soulen MC, Tian L, McGarvey M, Nelson AM, Farabaugh CS, Moon E, Levine BL, Melenhorst JJ, Plesa G, June CH, Albelda SM, Beatty GL. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol Ther. 2019;27(11):1919-\u0080\u009329.","DOI":"10.1016\/j.ymthe.2019.07.015"},{"key":"32","doi-asserted-by":"crossref","unstructured":"Haas AR, Golden RJ, Litzky LA, Engels B, Zhao L, Xu F, Taraszka JA, Ramones M, Granda B, Chang WJ, Jadlowsky J, Shea KM, Runkle A, Chew A, Dowd E, Gonzalez V, Chen F, Liu X, Fang C, Jiang S, Davis MM, Sheppard NC, Zhao Y, Fraietta JA, Lacey SF, Plesa G, Melenhorst JJ, Mansfield K, Brogdon JL, Young RM, Albelda SM, June CH, Tanyi JL. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther. 2023;31(8):2309-\u0080\u009325.","DOI":"10.1016\/j.ymthe.2023.06.006"},{"key":"33","doi-asserted-by":"crossref","unstructured":"Shan Y, Ding B, Ji F, Lin H, Shi W, Wang E, Wang C, Shen Y. T cell receptor-\u0080\u0093like chimeric antigen receptor T cells targeting mesothelin: A first-in-human dose-escalation trial for platinum-resistant advanced ovarian cancer. Cancer. 2026;132(3):e70279.","DOI":"10.1002\/cncr.70279"},{"key":"34","doi-asserted-by":"crossref","unstructured":"Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, Naranjo A, Starr R, Wagner J, Wright C, Zhai Y, Bading JR, Ressler JA, Portnow J, D'Apuzzo M, Forman SJ, Jensen MC. Bioactivity and safety of IL-13R\u00ce\u00b12-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015;21(18):4062-\u0080\u009372.","DOI":"10.1158\/1078-0432.CCR-15-0428"},{"key":"35","doi-asserted-by":"crossref","unstructured":"Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, Harshbarger TL, D'Apuzzo M, Ressler JA, Jensen MC, Barish ME, Chen M, Portnow J, Forman SJ, Badie B. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561-\u0080\u00939.","DOI":"10.1056\/NEJMoa1610497"},{"key":"36","doi-asserted-by":"crossref","unstructured":"Li X, Shang X, Liu J, Zhang Y, Jia X, Li H, Wang Y, Gao J, Ma X, Zhang X, Rong X, Gan W, Zhang Y, Chen J, Wang L, Bao Z, He L, Yan X, Liu Y, Shao J, Xiao Z, Wang Z, Zhu H, Wang Z, Wu Y, Huang Y. Intrathecal CRISPR-edited allogeneic IL-13R\u00ce\u00b12 CAR T cells for recurrent high-grade glioma: Preclinical characterization and phase I trial. Nat Commun. 2026;17(1):1362.","DOI":"10.1038\/s41467-025-68112-6"},{"key":"37","doi-asserted-by":"crossref","unstructured":"Lee Y, Kim HS. Clinicopathological significance of claudin-6 immunoreactivity in low-grade, early-stage endometrioid endometrial carcinoma. In Vivo. 2025;39(1):367-\u0080\u009374.","DOI":"10.21873\/invivo.13837"},{"key":"38","doi-asserted-by":"crossref","unstructured":"Shi D, Shi Y, Kaseb AO, Qi X, Zhang Y, Chi J, Lu Q, Gao H, Jiang H, Wang H, Yuan D, Ma H, Wang H, Li Z, Zhai B. Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: Results of phase I trials. Clin Cancer Res. 2020;26(15):3979-\u0080\u009389.","DOI":"10.1158\/1078-0432.CCR-19-3259"},{"key":"39","doi-asserted-by":"crossref","unstructured":"Zhang Q, Fu Q, Cao W, Wang H, Xu X, Huang J, Zou A, Zhu J, Wan H, Yao Y, Tu E, Stone J, Bondanza A, Farsaci B, Liang T. Phase I study of C-CAR031, a GPC3-specific TGF\u00ce\u00b2RIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2024;42(16):4019.","DOI":"10.1200\/JCO.2024.42.16_suppl.4019"},{"key":"40","doi-asserted-by":"crossref","unstructured":"Fang W, Lu Z, Ge J, Zhang S, Zheng R, Yin W, Hao R, Sun M, Luo T. Preclinical development and a phase 1 trial of IMC001, an EpCAM-targeted CAR-T cell therapy, in patients with advanced gastric cancer. Mol Ther. 2025;33(11):5516-\u0080\u009329.","DOI":"10.1016\/j.ymthe.2025.08.014"},{"key":"41","doi-asserted-by":"crossref","unstructured":"Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, K\u00fcnkele A, Chang CA, Rawlings-Rhea S, Huang W, Seidel K, Albert CM, Pinto N, Gust J, Finn LS, Ojemann JG, Wright J, Orentas RJ, Baldwin M, Gardner RA, Jensen MC, Park JR. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: An interim analysis. Nat Med. 2021;27(9):1544-\u0080\u009352.","DOI":"10.1038\/s41591-021-01404-8"},{"key":"42","doi-asserted-by":"crossref","unstructured":"Heczey A, Louis CU, Savoldo B, Dakhova O, Durett A, Grilley B, Liu H, Wu MF, Mei Z, Gee A, Mehta B, Zhang H, Mahmood N, Tashiro H, Heslop HE, Dotti G, Rooney CM, Brenner MK. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol Ther. 2017;25(9):2214-\u0080\u009324.","DOI":"10.1016\/j.ymthe.2017.05.012"},{"key":"43","doi-asserted-by":"crossref","unstructured":"Straathof K, Flutter B, Wallace R, Jain N, Loka T, Depani S, Wright G, Thomas S, Cheung GWK, Gileadi T, Stafford S, Kokalaki E, Barton J, Marriott C, Rampling D, Ogunbiyi O, Akarca AU, Marafioti T, Inglott S, Gilmour K, Al-Hajj M, Day W, McHugh K, Biassoni L, Sizer N, Barton C, Edwards D, Dragoni I, Silvester J, Dyer K, Traub S, Elson L, Brook S, Westwood N, Robson L, Bedi A, Howe K, Barry A, Duncan C, Barone G, Pule M, Anderson J. Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Sci Transl Med. 2020;12(571):eabd6169.","DOI":"10.1126\/scitranslmed.abd6169"},{"key":"44","doi-asserted-by":"crossref","unstructured":"Liu Z, Zhou J, Yang X, Liu Y, Zou C, Lv W, Chen C, Cheng KK yip, Chen T, Chang LJ, Wu D, Mao J. Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Mol Cancer. 2023;22(1):3.","DOI":"10.1186\/s12943-022-01711-9"},{"key":"45","doi-asserted-by":"crossref","unstructured":"Yu L, Huang L, Lin D, Lai X, Wu L, Liao X, Liu J, Zeng Y, Liang L, Zhang G, Wang B, Wu Z, Tao S, Liu Y, Jiao C, Chang LJ, Yang L. GD2-specific chimeric antigen receptor-modified T cells for the treatment of refractory and\/or recurrent neuroblastoma in pediatric patients. J Cancer Res Clin Oncol. 2022;148(10):2643-\u0080\u009352.","DOI":"10.1007\/s00432-021-03839-5"},{"key":"46","doi-asserted-by":"crossref","unstructured":"Locatelli F, Pagliara D, De Ioris MA, Becilli M, Del Baldo G, Serra A, Mastronuzzi A, Cefalo MG, Li Pira G, Leone G, Bertaina V, Fabozzi F, Di Nardo M, Rosignoli C, D'\u0080\u0099Andrea ML, Crocoli A, Vennarini S, Sinibaldi M, Di Cecca S, Guercio M, Iaffaldano L, Lucarelli B, Algeri M, Merli P, Colafati GS, De Angelis B, Quintarelli C, del Bufalo F. GD2-targeting CAR T cells in high-risk neuroblastoma: A phase 1\/2 trial. Nat Med. 2025;31(11):3689-\u0080\u009399.","DOI":"10.1038\/s41591-025-03874-6"},{"key":"47","doi-asserted-by":"crossref","unstructured":"Majzner RG, Mackall CL. Tumor antigen escape from car t-cell therapy. Cancer Discov. 2018;8(10):1219-\u0080\u009326.","DOI":"10.1158\/2159-8290.CD-18-0442"},{"key":"48","doi-asserted-by":"crossref","unstructured":"Braig F, Brandt A, Goebeler M, Tony HP, Kurze AK, Nollau P, Bumm T, B\u00f6ttcher S, Bargou RC, Binder M. Resistance to anti-CD19\/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129(1):100-\u0080\u00934.","DOI":"10.1182\/blood-2016-05-718395"},{"key":"49","doi-asserted-by":"crossref","unstructured":"Rayes A, Mcmasters RL, O\u2019Brien MM. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr Blood Cancer. 2016;63(6):1113-\u0080\u00935.","DOI":"10.1002\/pbc.25953"},{"key":"50","doi-asserted-by":"crossref","unstructured":"Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H, Yang Y, Chien CD, Seif AE, Lei H, Song YK, Khan J, Lee DW, Mackall CL, Gardner RA, Jensen MC, Shern JF, Fry TJ. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun. 2016;7:12320.","DOI":"10.1038\/ncomms12320"},{"key":"51","doi-asserted-by":"crossref","unstructured":"Coorens THH, Collord G, Treger TD, Adams S, Mitchell E, Newman B, Getz G, Godfrey AL, Bartram J, Behjati S. Clonal origin of KMT2A wild-type lineage-switch leukemia following CAR-T cell and blinatumomab therapy. Nat Cancer. 2023;4(8):1095-\u0080\u0093101.","DOI":"10.1038\/s43018-023-00604-0"},{"key":"52","doi-asserted-by":"crossref","unstructured":"Ruella M, Xu J, Barrett DM, Fraietta JA, Reich TJ, Ambrose DE, Klichinsky M, Shestova O, Patel PR, Kulikovskaya I, Nazimuddin F, Bhoj VG, Orlando EJ, Fry TJ, Bitter H, Maude SL, Levine BL, Nobles CL, Bushman FD, Young RM, Scholler J, Gill SI, June CH, Grupp SA, Lacey SF, Melenhorst JJ. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med. 2018;24(10):1499-\u0080\u0093503.","DOI":"10.1038\/s41591-018-0201-9"},{"key":"53","doi-asserted-by":"crossref","unstructured":"O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV. 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(399):eaaa0984.","DOI":"10.1126\/scitranslmed.aaa0984"},{"key":"54","doi-asserted-by":"crossref","unstructured":"Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, Frank MJ, Shiraz P, Sahaf B, Craig J, Iglesias M, Younes S, Natkunam Y, Ozawa MG, Yang E, Tamaresis J, Chinnasamy H, Ehlinger Z, Reynolds W, Lynn R, Rotiroti MC, Gkitsas N, Arai S, Johnston L, Lowsky R, Majzner RG, Meyer E, Negrin RS, Rezvani AR, Sidana S, Shizuru J, Weng WK, Mullins C, Jacob A, Kirsch I, Bazzano M, Zhou J, Mackay S, Bornheimer SJ, Schultz L, Ramakrishna S, Davis KL, Kong KA, Shah NN, Qin H, Fry T, Feldman S, Mackall CL, Miklos DB. 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(8):1419-\u0080\u009331.","DOI":"10.1038\/s41591-021-01436-0"},{"key":"55","doi-asserted-by":"crossref","unstructured":"Zhang Y, Wang Y, Liu Y, Tong C, Wang C, Guo Y, Ti D, Yang Q, Qiao S, Wu Z, Han W. Long-term activity of tandem CD19\/CD20 CAR therapy in refractory\/relapsed B-cell lymphoma: A single-arm, phase 1-\u0080\u00932 trial. Leukemia. 2022;36(1):189-\u0080\u009396.","DOI":"10.1038\/s41375-021-01345-8"},{"key":"56","doi-asserted-by":"crossref","unstructured":"Shi X, Yan L, Shang J, Kang L, Yan Z, Jin S, Zhu M, Chang H, Gong F, Zhou J, Chen G, Pan J, Liu D, Zhu X, Tang F, Liu M, Liu W, Yao F, Yu L, Wu D, Fu C. Anti-CD19 and anti-BCMA CAR T cell therapy followed by lenalidomide maintenance after autologous stem-cell transplantation for high-risk newly diagnosed multiple myeloma. Am J Hematol. 2022;97(5):537-\u0080\u009347.","DOI":"10.1002\/ajh.26486"},{"key":"57","doi-asserted-by":"crossref","unstructured":"Liu Y, Deng B, Hu B, Zhang W, Zhu Q, Liu Y, Wang S, Zhang P, Yang Y, Yang J, Zheng Q, Yu X, Gao Z, Zhou C, Han W, Yang J, Jin L, Tong C, Chang AH, Zhang Y. Sequential different B-cell antigen-targeted CAR T cell therapy for pediatric refractory\/relapsed Burkitt lymphoma. Blood Adv. 2022;6(3):717-\u0080\u009330.","DOI":"10.1182\/bloodadvances.2021004557"},{"key":"58","doi-asserted-by":"crossref","unstructured":"Gu J, Li J, Xu Y, Zhang G, Xie J, Jia R, Chen W, Lu Z, Chang C, Wen H, Chang LJ, Ma H, Cai Q. Preliminary exploration of PSMA CAR-T combined with GD2 CAR-T for the treatment of refractory\/relapsed gliomas. J Transl Med. 2025;23(1):591.","DOI":"10.1186\/s12967-025-06523-1"},{"key":"59","doi-asserted-by":"crossref","unstructured":"Bagley SJ, Desai AS, Fraietta JA, Silverbush D, Chafamo D, Freeburg NF, Gopikrishna GK, Rech AJ, Nabavizadeh A, Bagley LJ, Park J, Jarocha D, Martins R, Sarmiento N, Maloney E, Lledo L, Stein C, Marshall A, Leskowitz RM, Jadlowsky JK, Mackey S, Christensen S, Oner BS, Plesa G, Brennan A, Gonzalez V, Chen F, Barrett D, Colbourn R, Nasrallah MP, Mourelatos Z, Hwang WT, Alanio C, Siegel DL, June CH, Hexner EO, Binder ZA, O'Rourke DM. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13R\u00ce\u00b12 in recurrent glioblastoma: A phase 1 trial. Nat Med. 2025;31(8):2778-\u0080\u009387.","DOI":"10.1038\/s41591-025-03745-0"},{"key":"60","doi-asserted-by":"crossref","unstructured":"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(23):6436-\u0080\u009345.","DOI":"10.1158\/1078-0432.CCR-12-1449"},{"key":"61","doi-asserted-by":"crossref","unstructured":"Rataj F, Jacobi SJ, Stoiber S, Asang F, Ogonek J, Tokarew N, Cadilha BL, van Puijenbroek E, Heise C, Duewell P, Endres S, Klein C, Kobold S. High-affinity CD16-polymorphism and Fc-engineered antibodies enable activity of CD16-chimeric antigen receptor-modified T cells for cancer therapy. Br J Cancer. 2019;120(1):79-\u0080\u009387.","DOI":"10.1038\/s41416-018-0341-1"},{"key":"62","doi-asserted-by":"crossref","unstructured":"Cartellieri M, Feldmann A, Koristka S, Arndt C, Loff S, Ehninger A, von Bonin M, Bejestani EP, Ehninger G, Bachmann MP. Switching CAR T cells on and off: A novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J. 2016;6(8):e458.","DOI":"10.1038\/bcj.2016.61"},{"key":"63","doi-asserted-by":"crossref","unstructured":"Feldmann A, Hoffmann A, Bergmann R, Koristka S, Berndt N, Arndt C, Rodrigues Loureiro L, Kittel-Boselli E, Mitwasi N, Kegler A, Lamprecht C, Gonz\u00e1lez Soto KE, Bachmann M. Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy. Oncoimmunology. 2020;9(1):1785608.","DOI":"10.1080\/2162402X.2020.1785608"},{"key":"64","doi-asserted-by":"crossref","unstructured":"Cho JH, Collins JJ, Wong WW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell. 2018;173(6):1426-\u0080\u009338.e11.","DOI":"10.1016\/j.cell.2018.03.038"},{"key":"65","doi-asserted-by":"crossref","unstructured":"Lajoie MJ, Boyken SE, Salter AI, Bruffey J, Rajan A, Langan RA, Olshefsky A, Muhunthan V, Bick MJ, Gewe M, Quijano-Rubio A, Johnson JL, Lenz G, Nguyen A, Pun S, Correnti CE, Riddell SR, Baker D. Designed protein logic to target cells with precise combinations of surface antigens. Science. 2020;369(6511):1637-\u0080\u009343.","DOI":"10.1126\/science.aba6527"},{"key":"66","doi-asserted-by":"crossref","unstructured":"Lanitis E, Poussin M, Klattenhoff AW, Song D, Sandaltzopoulos R, June CH, Powell DJ. Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol Res. 2013;1(1): 43-\u0080\u009353.","DOI":"10.1158\/2326-6066.CIR-13-0008"},{"key":"67","doi-asserted-by":"crossref","unstructured":"Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, McNally KA, Lim WA. Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell. 2016;167(2): 419-\u0080\u009332.","DOI":"10.1016\/j.cell.2016.09.011"},{"key":"68","doi-asserted-by":"crossref","unstructured":"Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Sch\u00f6nfeld K, Koch J, Dotti G, Heslop HE, Gottschalk S, Wels WS, Baker ML, Ahmed N. TanCAR: A novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids. 2013;2(7):e105.","DOI":"10.1038\/mtna.2013.32"},{"key":"69","doi-asserted-by":"crossref","unstructured":"Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol. 2013;31(1):71-\u0080\u00935.","DOI":"10.1038\/nbt.2459"},{"key":"70","doi-asserted-by":"crossref","unstructured":"Tousley AM, Rotiroti MC, Labanieh L, Rysavy LW, Kim WJ, Lareau C, Sotillo E, Weber EW, Rietberg SP, Dalton GN, Yin Y, Klysz D, Xu P, de la Serna EL, Dunn AR, Satpathy AT, Mackall CL, Majzner RG. Co-opting signaling molecules enables logic-gated control of CAR T cells. Nature. 2023;615(7952):507-\u0080\u009316.","DOI":"10.1038\/s41586-023-05778-2"},{"key":"71","doi-asserted-by":"crossref","unstructured":"Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med. 2013;5(215):215ra172.","DOI":"10.1126\/scitranslmed.3006597"},{"key":"72","doi-asserted-by":"crossref","unstructured":"Mock JY, Winters A, Riley TP, Bruno R, Naradikian MS, Sharma S, Jette CA, Elshimali R, Gahrs C, Toledo-Warshaviak D, West AP, Kamb A, Hamburger AE. HLAA-\u0088\u0097 02-gated safety switch for cancer therapy has exquisite specificity for its allelic target antigen. Mol Ther Oncolytics. 2022;27:157-\u0080\u009366.","DOI":"10.1016\/j.omto.2022.09.010"},{"key":"73","doi-asserted-by":"crossref","unstructured":"Moon O, Hartley J, Deng S, Kueberuwa G, Hawkins RE, Bridgeman JS, Bao L. 232 CARKeyTM -\u0080\u0093 a tri-specific, dual receptor, CAR T cell therapy platform to overcome solid tumor antigen heterogeneity. 2025; J Immunother Cancer. 2025;13(Suppl 2):232. doi: 10.1136\/jitc-2025-sitc2025.0232.","DOI":"10.1136\/jitc-2025-SITC2025.0232"},{"key":"74","doi-asserted-by":"crossref","unstructured":"Hwang MS, Mog BJ, Douglass J, Pearlman AH, Hsiue EHC, Paul S, DiNapoli SR, Konig MF, Pardoll DM, Gabelli SB, Bettegowda C, Papadopoulos N, Vogelstein B, Zhou S, Kinzler KW. Targeting loss of heterozygosity for cancer-specific immunotherapy. Proc Natl Acad Sci U S A. 2021;118(12) ):e2022410118.","DOI":"10.1073\/pnas.2022410118"},{"key":"75","doi-asserted-by":"crossref","unstructured":"Bangayan NJ, Wang L, Sojo GB, Noguchi M, Cheng D, Ta L, Gunn D, Mao Z, Liu S, Yin Q, Riedinger M, Li K, Wu AM, Stoyanova T, Witte ON. Dual-inhibitory domain iCARs improve the efficiency of the AND-NOT gate CAR T strategy. Proc Natl Acad Sci U S A. 2023;120(47):e2312374120.","DOI":"10.1073\/pnas.2312374120"},{"key":"76","doi-asserted-by":"crossref","unstructured":"Funk MA, Heller G, Waidhofer-S\u00f6llner P, Leitner J, Steinberger P. Inhibitory CARs fail to protect from immediate T cell cytotoxicity. Mol Ther. 2024;32(4):982-\u0080\u009399.","DOI":"10.1016\/j.ymthe.2024.02.022"}],"container-title":["Critical Reviews\u2122 in Oncogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.dl.begellhouse.com\/download\/article\/4dd5f75467bd4c30\/CRO-64031.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T20:34:56Z","timestamp":1785011696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.dl.begellhouse.com\/journals\/439f422d0783386a,5a518e4904bba712,4dd5f75467bd4c30.html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":76,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1615\/critrevoncog.2026064031","relation":{},"ISSN":["0893-9675"],"issn-type":[{"value":"0893-9675","type":"print"}],"subject":[],"published":{"date-parts":[[2026]]}}}