Design and development of CAR-T cells for cancer therapy

authors:

avatar Shafieeh Mansoori , avatar Monireh Gholizadeh , avatar Shahriyar Abdoli , avatar Sohiela Ajdari , avatar Mohammad Ali Shokrgozar , avatar Mohsen Basiri ORCID , avatar Zahra Sharifzadeh , *

Koomesh: Vol.25, issue 1; 1-15
published online: March 02, 2023
article type: issue_documents_importer
received: August 01, 2021
accepted: October 02, 2022

how to cite: Mansoori S, Gholizadeh M, Abdoli S, Ajdari S, Shokrgozar M A, et al. Design and development of CAR-T cells for cancer therapy. koomesh. 2023;25(1):e152796. 

Abstract

Introduction: Today, treatment with CAR-T cells is accepted as an effective treatment for blood malignancies. CAR-T cells are autologous T cells that are engineered by gene transfer techniques to express a chimeric antigen receptor (CAR). Despite the promising results and the approval of six CAR-T cell products; these products have not yet been approved for solid tumors. In addition, the high cost of treatment with CAR-T cells has limited patients' access to these life-saving drugs. Therefore, key considerations in the design and development of CAR-T cells should be defined and methods of reducing the cost of this treatment method should be investigated. Materials and Methods: This study was performed based on an accurate bibliography through research databases such as PubMed, Scopus, Web of Science, and Google Scholar search engine, as well as the websites of pharmaceutical companies. Results: CAR synthetic receptors contain an antigen-recognizing extracellular region that connects to the space-forming, transmembrane and intracellular messenger regions. Each part of the CAR structure affects some functions of CAR, including target recognition, activation and cell lysis. So far, five generations of CAR-T cells have been developed to improve the messaging capacity of these cells. In addition, gene transfer systems such as electroporation, transposon and genome editing systems have been introduced as an alternative to viral vectors to produce safe and affordable CAR-T cells. Also, the development of ready-to-use products, product production in places far from the place of consumption, new pricing platforms and methods, and health insurance system initiatives have been suggested as ways to reduce prices. Conclusion: In this article, an overview of how to develop CAR-T cells, important factors in the design of chimeric receptors, different methods of gene transfer and solutions to reduce the cost of this treatment were discussed. By using these strategies, the potential of CAR-T cells in cancer immunotherapy can be fully utilized.

References

  • 1.

    Global Cancer Observatory [cited 2021 Feb 26]. Available from: https://gco.iarc.fr/.

  • 2.

    Zamani F, Oraee-Yazdani S, Langroudi L, Hashemi SM. Role of mesenchymal stem cells in growth and progression of cancer and prospective potentials in cancer therapy. Koomesh 2022; 24: 1-25. (Persian).

  • 3.

    Global Cancer Observatory. Available from: https://gco.iarc.fr/.##.

  • 4.

    Jiang X, Xu J, Liu M, Xing H, Wang Z, Huang L, et al. Adoptive CD8+ T cell therapy against cancer: Challenges and opportunities. Cancer Lett 2019; 462: 23-32.

  • 5.

    Hartmann J, SchlerLenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 2017; 9: 1183-1197.

  • 6.

    Wang M, Yin B, Wang HY, Wang RF. Current advances in T-cell-based cancer immunotherapy. Immunotherapy 2014; 6: 1265-1278.

  • 7.

    Sarkar I, Pati S, Dutta A, Basak U, Sa G. T-memory cells against cancer: remembering the enemy. Cell Immunol 2019; 338: 27-31.

  • 8.

    Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 1986; 233: 1318-1321.

  • 9.

    June C, Rosenberg SA, Sadelain M, Weber JS. T-cell therapy at the threshold. Nat Biotechnol 2012; 30: 611-614.

  • 10.

    Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res 2015; 21: 1019-1027.

  • 11.

    Eckle SB, Turner SJ, Rossjohn J, McCluskey J. Predisposed T cell antigen receptor recognition of MHC and MHC-I like molecules? Curr Opin Immunol 2013; 25: 653-659.

  • 12.

    Shao H, Zhang W, Hu Q, Wu F, Shen H, Huang S. TCR mispairing in genetically modified T cells was detected by fluorescence resonance energy transfer. Mol Biol Rep 2010; 37: 3951-3956.

  • 13.

    Bendle GM, Linnemann C, Hooijkaas AI, Bies L, de Witte MA, Jorritsma A, et al. Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med 2010; 16: 565-570.

  • 14.

    van Loenen MM, de Boer R, Amir AL, Hagedoorn RS, Volbeda GL, Willemze R, et al. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci U S A 2010; 107: 10972-10977.

  • 15.

    GomesSilva D, Ramos CA. Cancer immunotherapy using CART cells: from the research bench to the assembly line. Biotechnology 2018; 13: 1700097.

  • 16.

    Rohaan MW, Wilgenhof S, Haanen JB. Adoptive cellular therapies: the current landscape. Virchows Arch 2019; 474: 449-461.

  • 17.

    Kansagra A, Farnia S, Majhail N. Expanding access to chimeric antigen receptor T-cell therapies: challenges and opportunities. Am Soc Clin Oncol Educ Book 2020; 40: e27-e34.

  • 18.

    Guo Y, Feng K, Tong C, Jia H, Liu Y, Wang Y, et al. Efficiency and side effects of anti-CD38 CAR T cells in an adult patient with relapsed B-ALL after failure of bi-specific CD19/CD22 CAR T cell treatment. Cell Mol Immunol 2020; 17: 430-432.

  • 19.

    Castelletti L, Yeo D, van Zandwijk N, Rasko JE. Anti-Mesothelin CAR T cell therapy for malignant mesothelioma. Biomark Res 2021; 9: 1-13.

  • 20.

    Nukala U, Rodriguez Messan M, Yogurtcu ON, Wang X, Yang H. A systematic review of the efforts and hindrances of modeling and simulation of CAR T-cell therapy. AAPS J 2021; 23: 1-20.

  • 21.

    Chong EA, Alanio C, Svoboda J, Nasta SD, Landsburg DJ, Lacey SF, et al. Pembrolizumab for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. Blood 2022; 139: 1026-1038.

  • 22.

    Baird JH, Frank MJ, Craig J, Patel S, Spiegel JY, Sahaf B, et al. CD22-Directed CAR T-cell therapy mediates durable complete responses in adults with relapsed or refractory large B-cell lymphoma after failure of CD19-directed CAR T-cell therapy and high response rates in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. Blood 2020; 136: 28-29.##https://doi.org/10.1182/blood-2020-139087.

  • 23.

    Bastos-Oreiro M, de las Heras A, Presa M, Casado MA, Pardo C, Martn-Escudero V, et al. Cost-Effectiveness analysis of axicabtagene ciloleucel vs. tisagenlecleucel for the management of relapsed/refractory diffuse large B-Cell lymphoma in spain. Cancers 2022; 14: 538.

  • 24.

    Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 2013; 39: 49-60.

  • 25.

    Rahimi Jamnani F, Shokrgozar MA, Mahboudi F, Ahmadvand D, Sharifzadeh Z, Parhamifar L, Moghimi SM. T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: towards tumor-directed oligoclonal T cell therapy. Biochim Biophys Acta 2014; 1840: 378-386.

  • 26.

    Plckthun A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu Rev Pharmacol Toxicol 2015; 55: 489-511.

  • 27.

    Wagner DL, Fritsche E, Pulsipher MA, Ahmed N, Hamieh M, Hegde M, et al. Immunogenicity of CAR T cells in cancer therapy. Nat Rev Clin Oncol 2021; 18: 379-393.

  • 28.

    Davies DM, Foster J, Van Der Stegen SJ, Parente-Pereira AC, Chiapero-Stanke L, Delinassios GJ, et al. Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Mol Med 2012; 18: 565-576.

  • 29.

    Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res 2015; 75: 3596-3607.

  • 30.

    Zah E, Lin M-Y, Silva-Benedict A, Jensen MC, Chen YY. ADDENDUM: T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res 2016; 4: 639-641.

  • 31.

    Sharifzadeh Z, Rahbarizadeh F, Shokrgozar MA, Ahmadvand D, Mahboudi F, Jamnani FR, et al. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents. Cancer Lett 2013; 334: 237-244.

  • 32.

    Cheadle E, Rothwell D, Bridgeman J, Sheard V, Hawkins R, Gilham D. Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells. Gene Ther 2012; 19: 1114-1120.

  • 33.

    Lanitis E, Poussin M, Klattenhoff AW, Song D, Sandaltzopoulos R, June CH, et al. 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: 43-53.

  • 34.

    Kim DW, Cho JY. Recent advances in allogeneic CAR-T cells. Biomolecules 2020; 10: 263.

  • 35.

    Bagheri S, Safaie Qamsari E, Yousefi M, Riazi-Rad F, Sharifzadeh Z. Targeting the 4-1BB costimulatory molecule through single chain antibodies promotes the human T-cell response. Cell Mol Biol Lett 2020; 25: 1-13.

  • 36.

    Sukumaran S, Watanabe N, Bajgain P, Raja K, Mohammed S, Fisher WE, et al. Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discover 2018; 8: 972-987.

  • 37.

    Mir MA. editor T-Cell Costimulation and Its Applications in Diseases 2015.##https://doi.org/10.1016/B978-0-12-802585-7.00006-6.

  • 38.

    Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L, Pohl C, et al. Tumor-specific T cell activation by recombinant immunoreceptors: CD3 signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 signaling receptor molecule. J Immunol 2001; 167: 6123-6131.

  • 39.

    Stoiber S, Cadilha BL, Benmebarek MR, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells 2019; 8: 472.

  • 40.

    Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC, Gunset G, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 2015; 28: 415-428.

  • 41.

    Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Nat Acad Sci 2009; 106: 3360-3365.

  • 42.

    Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009; 17: 1453-1464.

  • 43.

    Feucht J, Sun J, Eyquem J, Ho YJ, Zhao Z, Leibold J, et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat Med 2019; 25: 82-88.

  • 44.

    Helsen CW, Hammill JA, Lau VW, Mwawasi KA, Afsahi A, Bezverbnaya K, et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun 2018; 9: 1-13.

  • 45.

    Xu Y, Yang Z, Horan LH, Zhang P, Liu L, Zimdahl B, et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov 2018; 4: 1-13.

  • 46.

    Han S, Latchoumanin O, Wu G, Zhou G, Hebbard L, George J, et al. Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors. Cancer Lett 2017; 390: 188-200.

  • 47.

    Barde I, Salmon P, Trono D. Production and titration of lentiviral vectors. Curr Protoc Neurosci 2010; 53.##https://doi.org/10.1002/0471142301.ns0421s53.

  • 48.

    Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 2012; 4: 132ra53.

  • 49.

    Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, et al. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol 2006; 24: 687-696.

  • 50.

    MacLeod DT, Antony J, Martin AJ, Moser RJ, Hekele A, Wetzel KJ, et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther 2017; 25: 949-961.

  • 51.

    Hackett PB, Largaespada DA, Switzer KC, Cooper LJ. Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Translat Res 2013; 161: 265-283.

  • 52.

    Yant SR, Wu X, Huang Y, Garrison B, Burgess SM, Kay MA. High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 2005; 25: 2085-2094.

  • 53.

    Singh H, Huls H, Kebriaei P, Cooper LJ. A new approach to gene therapy using Sleeping Beauty to genetically modify clinicalgrade T cells to target CD 19. Immunol Rev 2014; 257: 181-190.

  • 54.

    Manuri PV, Wilson MH, Maiti SN, Mi T, Singh H, Olivares S, et al. piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies. Human Gene Ther 2010; 21: 427-437.

  • 55.

    Nakazawa Y, Huye LE, Salsman VS, Leen AM, Ahmed N, Rollins L, et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol Ther 2011; 19: 2133-2143.

  • 56.

    Zhang Y, Zhang Z, Ding Y, Fang Y, Wang P, Chu W, et al. Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J Cancer Res Clin Oncol 2021; 147: 3725-3734.

  • 57.

    Yoon S, Lee J, Cho H, Kim E, Kim H, Park M, et al. Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model. Cancer Gene Ther 2009; 16: 489-497.

  • 58.

    Beatty GL, Haas AR, Maus MV, Torigian DA, Soulen MC, Plesa G, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol Res 2014; 2: 112-120.

  • 59.

    Hajari Taheri F, Hassani M, Sharifzadeh Z, Behdani M, Arashkia A, Abolhassani M. T cell engineered with a novel nanobodybased chimeric antigen receptor against VEGFR2 as a candidate for tumor immunotherapy. IUBMB Life 2019; 71: 1259-1267.

  • 60.

    Hassani M, Hajari Taheri F, Sharifzadeh Z, Arashkia A, Hadjati J, van Weerden WM, et al. Construction of a chimeric antigen receptor bearing a nanobody against prostate a specific membrane antigen in prostate cancer. J Cell Biochem 2019; 120: 10787-10795.

  • 61.

    Hassani M, Taheri FH, Sharifzadeh Z, Arashkia A, Hadjati J, van Weerden WM, et al. Engineered jurkat cells for targeting prostate-specific membrane antigen on prostate cancer cells by nanobody-based chimeric antigen receptor. Iran Biomed J 2020; 24: 81.

  • 62.

    Delhove JM, Qasim W. Genome-edited T cell therapies. Curr Stem Cell Rep 2017; 3: 124-136.

  • 63.

    Ren J, Zhao Y. Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9. Protein Cell 2017; 8: 634-643.

  • 64.

    Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M, Gate RE, et al. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. Proc Natl Acad Sci U S A 2015; 112: 10437-10442.

  • 65.

    Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, et al. Multiplex genome-edited T-cell manufacturing platform for "off-the-shelf" adoptive T-cell immunotherapies. Cancer Res 2015; 75: 3853-3864.

  • 66.

    Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Translat Med 2017; 9: 2013.

  • 67.

    Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci Translat Med 2016; 8: 320ra3.##https://doi.org/10.1126/scitranslmed.aad5222.

  • 68.

    Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 2017; 543: 113-117.

  • 69.

    Global Cell And Gene Therapy Market [cited 2021 Mar 28]. Available from: https://www.thebusinessresearchcompany.com/report/cell-and-gene-therapy-global-market-report-2020-30-covid-19-growth-and-change.

  • 70.

    Global Car-T Therapy Pipeline Analysis Market Data And Industry Growth Analysis [cited 2021 March 28]. Available from: https://www.thebusinessresearchcompany.com/report/car-t-therapy-pipeline-analysis-global-market-report.

  • 71.

    Morrison C. Fresh from the biotech pipeline--2017. Nat Biotechnol 2018; 36: 131-137.

  • 72.

    T-cell Therapy Market Size & Share Report, 2021-2028 [cited 2021 April 7]. Available from: https://www.grandviewresearch.com/industry-analysis/t-cell-therapy-market.##.

  • 73.

    Mullard A. FDA approves fourth CAR-T cell therapy. Nat Rev Drug Discov 2021; 20: 166-167.

  • 74.

    Highlights of prescribing Information, Kymriah [cited 2020 July 7]. Available from: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf.

  • 75.

    Highlights of prescribing information, Yescarta [cited 2020 July 7]. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdf.

  • 76.

    U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma [press release]. July 24 2020.

  • 77.

    Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2020; 382: 1331-1342.

  • 78.

    Romero D. KTE-X19 active in MCL. Nat Rev Clin Oncol 2020; 17: 336.

  • 79.

    Slater H. FDA Will Not Complete Review of BLA for Lisocabtagene Maraleucel By PDUFA Date 2020 [cited 2021 Feb 26]. Available from: https://www.cancernetwork.com/view/fda-will-not-complete-review-of-bla-for-lisocabtagene-maraleucel-by-pdufa-date.

  • 80.

    Sternberg A. Liso-cel Receives FDA Approval for the Treatment of R/R Large B-Cell Lymphoma cancer network [cited 2021 Feb 26]. Available from: https://www.cancernetwork.com/view/liso-cel-receives-fda-approval-for-the-treatment-of-r-r-large-b-cell-lymphoma.

  • 81.

    Romero D. Initial results with liso-cel. Nat Rev Clin Oncol 2020; 17: 654.

  • 82.

    Roex G, Feys T, Beguin Y, Kerre T, Poir X, Lewalle P, et al. Chimeric antigen receptor-T-cell therapy for B-cell hematological malignancies: an update of the pivotal clinical trial data. Pharmaceutics 2020; 12: 194.

  • 83.

    Sharma P, Kanapuru B, George B, Lin X, Xu Z, Bryan WW, et al. FDA approval summary: idecabtagene vicleucel for relapsed or refractory multiple myeloma. Clin Cancer Res 2022.

  • 84.

    VICLEUCEL I. BCMA-Directed CAR T cells in relapsed refractory multiple myeloma: highlights from SOHO 2021. J Adv Pract Oncol 2022; 13: 23-25.

  • 85.

    Yip A, Webster RM. The market for chimeric antigen receptor T cell therapies. Nat Rev Drug Discov 2018; 17: 161-162.

  • 86.

    Nosrati M, Hasanzad M, Nikfar S. A review on precision medicine and conducting pharmacogenetics tests of drugs. Koomesh 2022; 24: 230-236. (Persian).

  • 87.

    Bristol Myers finally wins FDA approval for cancer cell therapy BiopharmaDive [cited 2021 Mar 29]. Available from: https://www.biopharmadive.com/news/bristol-myers-liso-cel-fda-approval-car-t/594660/.

  • 88.

    Prasad V. Tisagenlecleucel-the first approved CAR-T-cell therapy: implications for payers and policy makers. Nat Rev Clin Oncol 2018; 15: 11-12.

  • 89.

    Court E. Novartis' CAR-T gene therapy, the first approved by FDA, to cost $475,000 MarketWatch [cited 2020 July 11]. Available from: https://www.marketwatch.com/story/novartis-car-t-gene-therapy-the-first-approved-by-fda-to-be-priced-based-on-cancer-patients-outcomes-2017-08-30.

  • 90.

    Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD. Cost effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma. J Clin Oncol 2019; 37: 2105-2119.

  • 91.

    Schultz L, Mackall C. Driving CAR T cell translation forward. Sci Translat Med 2019; 11: eaaw2127.

  • 92.

    Harrison RP, Zylberberg E, Ellison S, Levine BL. Chimeric antigen receptor-T cell therapy manufacturing: modelling the effect of offshore production on aggregate cost of goods. Cytotherapy 2019; 21: 224-233.

  • 93.

    Geethakumari PR, Dhakal B, Ramasamy DP, Kansagra AJ. CAR T-Cell therapy: current practice and future solutions to optimize patient access. J Clin Pathways 2021; 7: 54-62.##https://doi.org/10.25270/jcp.2021.03.00002.

  • 94.

    Cao J, Wang G, Cheng H, Wei C, Qi K, Sang W, et al. Potent antileukemia activities of humanized CD19targeted Chimeric antigen receptor T (CART) cells in patients with relapsed/refractory acute lymphoblastic leukemia. Am J Hematol 2018; 93: 851-858.

  • 95.

    Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest 2016; 126: 2123-2138.

  • 96.

    Drent E, Poels R, Ruiter R, van de Donk NW, Zweegman S, Yuan H, et al. Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells. Clin Cancer Res 2019; 25: 4014-4025.

  • 97.

    Iri-Sofla FJ, Rahbarizadeh F, Ahmadvand D, Rasaee MJ. Nanobody-based chimeric receptor gene integration in Jurkat cells mediated by PhiC31 integrase. Exp Cell Res 2011; 317: 2630-2641.

  • 98.

    Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu X, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 2013; 1: 26-31.

  • 99.

    Lamers CH, Willemsen R, van Elzakker P, van Steenbergen-Langeveld S, Broertjes M, Oosterwijk-Wakka J, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood 2011; 117: 72-82.

  • 100.

    Caserta S, Kleczkowska J, Mondino A, Zamoyska R. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J Immunol 2010; 185: 6545-6554.

  • 101.

    Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18: 843-851.

  • 102.

    Drent E, Themeli M, Poels R, de Jong-Korlaar R, Yuan H, de Bruijn J, et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther 2017; 25: 1946-1958.

  • 103.

    Hudecek M, Lupo-Stanghellini MT, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin Cancer Res 2013; 19: 3153-3164.

  • 104.

    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.

  • 105.

    Ramos CA, Rouce R, Robertson CS, Reyna A, Narala N, Vyas G, et al. In vivo fate and activity of second-versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin's lymphomas. Mol Ther 2018; 26: 2727-2737.

  • 106.

    Knkele A, Johnson AJ, Rolczynski LS, Chang CA, Hoglund V, Kelly-Spratt KS, et al. Functional tuning of CARs reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due to cell Fas-FasL-dependent AICD. Cancer Immunol Res 2015; 3: 368-379.

  • 107.

    Zhao Y, Wang QJ, Yang S, Kochenderfer JN, Zheng Z, Zhong X, et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol 2009; 183: 5563-5574.

  • 108.

    Guedan S, Madar A, Casado-Medrano V, Shaw C, Wing A, Liu F, et al. Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability. J Clin Invest 2020; 130: 3087-3097.

  • 109.

    Boucher JC, Li G, Shrestha B, Cabral M, Morrissey D, Guan L, et al. Mutation of the CD28 costimulatory domain confers decreased CAR T cell exhaustion. Blood 2018; 132: 966.##https://doi.org/10.1182/blood-2018-99-110645.

  • 110.

    Ellis J. Silencing and variegation of gammaretrovirus and lentivirus vectors. Human Gene Ther 2005; 16: 1241-1246.

  • 111.

    Liu J, Zhou G, Zhang L, Zhao Q. Building potent chimeric antigen receptor T cells with CRISPR genome editing. Front Immunol 2019; 10: 456.

  • 112.

    cell trial data [cited 2020 July 12]. Available from: https://celltrials.org/maps-cell-and-gene-therapy/cellular-immunotherapy-companies.