CAR-T CELL THERAPY FOR CHRONIC LYMPHOCYTIC LEUKEMIA: A PROMISING IMMUNOTHERAPY APPROACH

Authors

  • ZA KHAN Department Of Medicine, Bolan Medical College Quetta, Pakistan
  • T ABAID Department Of Medicine, Ali Fatima Hospital Lahore, Pakistan
  • J KHAN Department Of Medicine, Bolan Medical College Quetta, Pakistan
  • W AHMAD Department Of Health Sciences Technology, National Skills University Islamabad, Pakistan
  • M USMAN Department Of Medical Lab Technology, University Of Haripur, Pakistan
  • A BABAR Department Of Biological and Allied Health Sciences, Pak-Austria Fachhochschule Institute of Applied Sciences and Technology Haripur Khyber Pakhtunkhwa, Pakistan
  • M NAEEM Department Of Biological Science, Superior University Lahore, Pakistan

DOI:

https://doi.org/10.54112/bcsrj.v2024i1.1378

Keywords:

Hronic Lymphocytic Leukemia Chimeric Antigen Receptor T-Cells Hematologic Neoplasms Immunotherapy Antigens, Neoplasm

Abstract

Chronic Lymphocytic Leukemia (CLL) is a prevalent hematological malignancy with limited curative options, necessitating innovative and effective therapeutic approaches. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a transformative treatment modality, leveraging genetically modified T cells for targeted antitumor activity. This study explores the advancements in CAR T cell therapy for CLL, emphasizing its clinical potential, key manufacturing processes, structural design, therapeutic mechanisms, safety considerations, and strategies for optimizing efficacy. A comprehensive analysis of current literature and clinical data was conducted to examine CAR T cell manufacturing processes, including T cell source selection, activation, genetic modification, and expansion. Detailed evaluation of CAR T cell structural components and generational developments provided insights into their design and functionality. Additionally, therapeutic mechanisms, antigen selection strategies, and toxicity management approaches were critically reviewed. Key findings highlight the iterative advancements across four generations of CAR T cells, enhancing their antitumor efficacy, targeting specificity, and safety profile. Optimal target antigen selection and refinement of structural components, such as the ectodomain, transmembrane domain, and endodomain, significantly contributed to improved functionality. While CAR T cell therapy demonstrated robust antitumor activity in CLL, associated toxicities remain a challenge. Ongoing efforts focus on mitigating adverse events and optimizing clinical outcomes. CAR T cell therapy represents a promising paradigm shift in CLL treatment, combining precision targeting with potent antitumor effects. Continued advancements in design, manufacturing, and safety strategies underscore its transformative potential to improve patient outcomes and revolutionize CLL therapeutics. Further clinical trials and research are warranted to fully realize its therapeutic promise.

Downloads

Download data is not yet available.

References

Todorovic Z, Todorovic D, Markovic V, Ladjevac N, Zdravkovic N, Djurdjevic P, et al. CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings. Current Oncology. 2022;29(5):3647-57.

Mancikova V, Smida M. Current state of car T-cell therapy in chronic lymphocytic leukemia. International journal of molecular sciences. 2021;22(11):5536.

Lemal R, Tournilhac O. State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019. Journal for ImmunoTherapy of Cancer. 2019;7(1):202.

Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann C, Kater A, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2021;32(1):23-33.

Rozman C, Montserrat E. Chronic Lymphocytic Leukemia. New England Journal of Medicine. 1995;333(16):1052-7.

Bewarder M, Stilgenbauer S, Thurner L, Kaddu-Mulindwa D. Current treatment options in CLL. Cancers. 2021;13(10):2468.

Reis M, Ogonek J, Qesari M, Borges NM, Nicholson L, Preußner L, et al. Recent developments in cellular immunotherapy for HSCT-associated complications. Frontiers in Immunology. 2016;7:500.

Barrett DM, Grupp SA, June CH. Chimeric Antigen Receptor– and TCR-Modified T Cells Enter Main Street and Wall Street. The Journal of Immunology. 2015;195(3):755-61.

Abken H, Chmielewski M, Hombach A. Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells. Frontiers in Immunology. 2013;4.

Srivastava S, Riddell SR. Engineering CAR-T cells: design concepts. Trends in immunology. 2015;36(8):494-502.

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia. New England Journal of Medicine. 2011;365(8):725-33.

Scheuermann RH, Racila E. CD19 Antigen in Leukemia and Lymphoma Diagnosis and Immunotherapy. Leukemia & Lymphoma. 1995;18(5-6):385-97.

Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022;602(7897):503-9.

Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817-28.

Yee C. The use of endogenous T cells for adoptive transfer. Immunological reviews. 2014;257(1):250-63.

Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer discovery. 2013;3(4):388-98.

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. New England Journal of Medicine. 2013;368(16):1509-18.

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. Journal of clinical oncology. 2015;33(6):540.

Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Science translational medicine. 2014;6(224):224ra25-ra25.

Brentjens R, Davila M, Riviere I, Park J, Wang X, Cowell L. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013 Mar 20.5 (177): 177ra38. Epub 2013/03/22. eng; 2013.

Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. The Lancet. 2015;385(9967):517-28.

Smith JW. Apheresis techniques and cellular immunomodulation. Therapeutic Apheresis. 1997;1(3):203-6.

Karafin MS, Graminske S, Erickson P, Walters MC, Scott EP, Carter S, et al. Evaluation of the Spectra Optia apheresis system for mononuclear cell (MNC) collection in G‐CSF mobilized and nonmobilized healthy donors: results of a multicenter study. Journal of clinical apheresis. 2014;29(5):273-80.

Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, et al. Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. Journal of Immunology (Baltimore, Md: 1950). 1997;159(12):5921-30.

Levine B. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells. Cancer gene therapy. 2015;22(2):79-84.

Brentjens RJ, Latouche J-B, Santos E, Marti F, Gong MC, Lyddane C, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nature medicine. 2003;9(3):279-86.

Naldini L, Blömer U, Gallay P, Ory D, Mulligan R, Gage FH, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263-7.

Hollyman D, Stefanski J, Przybylowski M, Bartido S, Borquez-Ojeda O, Taylor C, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. Journal of Immunotherapy (Hagerstown, Md: 1997). 2009;32(2):169.

Zhang C, Liu J, Zhong JF, Zhang X. Engineering car-t cells. Biomarker research. 2017;5(1):1-6.

Tasian SK, Gardner RA. CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Therapeutic advances in hematology. 2015;6(5):228-41.

Brocker T. Chimeric Fv-ζ or Fv-ε receptors are not sufficient to induce activation or cytokine production in peripheral T cells. Blood, The Journal of the American Society of Hematology. 2000;96(5):1999-2001.

Finney HM, Lawson AD, Bebbington CR, Weir ANC. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. The Journal of Immunology. 1998;161(6):2791-7.

Park TS, Rosenberg SA, Morgan RA. Treating cancer with genetically engineered T cells. Trends in biotechnology. 2011;29(11):550-7.

Marin V, Pizzitola I, Agostoni V, Attianese GMPG, Finney H, Lawson A, et al. Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors. Haematologica. 2010;95(12):2144.

Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert opinion on biological therapy. 2015;15(8):1145-54.

Wei J, Han X, Bo J, Han W. Target selection for CAR-T therapy. Journal of hematology & oncology. 2019;12:1-9.

Tan Su Yin E, Hu YX, Huang H. The breakthrough and the future: CD20 chimeric antigen receptor T‐cell therapy for hematologic malignancies. ImmunoMedicine. 2022;2(1):e1039.

Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nature medicine. 2020;26(10):1569-75.

Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C, et al. T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood. 2006;108(12):3890-7.

Ranganathan R, Shou P, Ahn S, Sun C, West J, Savoldo B, et al. CAR T cells targeting human immunoglobulin light chains eradicate mature B-cell malignancies while sparing a subset of normal B cells. Clinical Cancer Research. 2021;27(21):5951-60.

Hudecek M, Schmitt TM, Baskar S, Lupo-Stanghellini MT, Nishida T, Yamamoto TN, et al. The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood, The Journal of the American Society of Hematology. 2010;116(22):4532-41.

Scarfò I, Ormhøj M, Frigault MJ, Castano AP, Lorrey S, Bouffard AA, et al. Anti-CD37 chimeric antigen receptor T cells are active against B-and T-cell lymphomas. Blood, The Journal of the American Society of Hematology. 2018;132(14):1495-506.

Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer discovery. 2016;6(6):664-79.

Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T-cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. American Society of Clinical Oncology Educational Book. 2019;39:433-44.

Turtle CJ, Hay KA, Hanafi L-A, Li D, Cherian S, Chen X, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure of ibrutinib. Journal of Clinical Oncology. 2017;35(26):3010.

Gauthier J, Hirayama AV, Hay KA, Li D, Lymp J, Sheih A, et al. Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and/or refractory CLL. Blood. 2018;132(Supplement 1):299-.

Buie LW, Pecoraro JJ, Horvat TZ, Daley RJ. Blinatumomab: a first-in-class bispecific T-cell engager for precursor B-cell acute lymphoblastic leukemia. Annals of pharmacotherapy. 2015;49(9):1057-67.

Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. The Lancet Oncology. 2015;16(1):57-66.

Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. The journal of gene medicine. 2012;14(6):405-15.

Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clinical cancer research. 2006;12(20):6106-15.

Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biology of blood and marrow transplantation. 2010;16(9):1245-56.

Mammadova-Bach E, Ollivier V, Loyau S, Schaff M, Dumont B, Favier R, et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood, The Journal of the American Society of Hematology. 2015;126(5):683-91.

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 immunology research. 2013;1(1):26-31.

Fransson M, Piras E, Burman J, Nilsson B, Essand M, Lu B, et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. Journal of neuroinflammation. 2012;9:1-12.

Hombach A, Kofler D, Rappl G, Abken H. Redirecting human CD4+ CD25+ regulatory T cells from the peripheral blood with pre-defined target specificity. Gene therapy. 2009;16(9):1088-96.

Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179-84.

Ali A, Kitchen SG, Chen IS, Ng HL, Zack JA, Yang OO. HIV-1-specific chimeric antigen receptors based on broadly neutralizing antibodies. Journal of virology. 2016;90(15):6999-7006.

Mirzaei HR, Mirzaei H, Namdar A, Rahmati M, Till BG, Hadjati J. Predictive and therapeutic biomarkers in chimeric antigen receptor T‐cell therapy: A clinical perspective. Journal of Cellular Physiology. 2019;234(5):5827-41.

Paietta E. Immunobiology of acute leukemia. Neoplastic diseases of the blood. 2018:237-79.

Zah E, Lin M-Y, Jensen MC, Silva-Benedict A, Chen YY. Abstract IA12: Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy. Cancer Immunology Research. 2017;5(3_Supplement):IA12-IA.

Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer discovery. 2018;8(10):1219-26.

Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. The Journal of clinical investigation. 2016;126(8):3036-52.

Schneider D, Xiong Y, Wu D, Nӧlle V, Schmitz S, Haso W, et al. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. Journal for immunotherapy of cancer. 2017;5(1):1-17.

Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Molecular Therapy-Nucleic Acids. 2013;2.

Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clinical cancer research. 2013;19(19):5300-9.

Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences. 2010;107(9):4275-80.

Hodi FS, O'day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. 2010;363(8):711-23.

Shi H, Sun M, Liu L, Wang Z. Chimeric antigen receptor for adoptive immunotherapy of cancer: latest research and future prospects. Molecular cancer. 2014;13:1-8.

Liu L, Sun M, Wang Z. Adoptive T-cell therapy of B-cell malignancies: conventional and physiological chimeric antigen receptors. Cancer letters. 2012;316(1):1-5.

Minutolo NG, Hollander EE, Powell Jr DJ. The emergence of universal immune receptor T cell therapy for cancer. Frontiers in oncology. 2019;9:176.

Zhao J, Lin Q, Song Y, Liu D. Universal CARs, universal T cells, and universal CAR T cells. Journal of hematology & oncology. 2018;11:1-9.

Downloads

Published

2024-12-18

How to Cite

KHAN , Z., ABAID , T., KHAN , J., AHMAD , W., USMAN , M., BABAR , A., & NAEEM , M. (2024). CAR-T CELL THERAPY FOR CHRONIC LYMPHOCYTIC LEUKEMIA: A PROMISING IMMUNOTHERAPY APPROACH. Biological and Clinical Sciences Research Journal, 2024(1), 1378. https://doi.org/10.54112/bcsrj.v2024i1.1378

Most read articles by the same author(s)

1 2 3 4 > >>