Precision Targeting and Genetically Modified T Cells for Targeting Cancer Cells

Authors

  • Dr Ammar A. Razzak Mahmood Dept. of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad. Bab Al-Mouadam,10001. Baghdad Iraq.
  • Sudhakar Srinivasan Tutor, Department of Biochemistry, Annapoorna Medical College and Hospital, Salem, India.
  • Challaraj Emmanuel E. S Department of Life Sciences, Kristu Jayanti College (Autonomous), K Narayanapura, Kothanur Post, Bengaluru-560077, Karnataka, India

DOI:

https://doi.org/10.22376/ijtos.2023.2.1.1-9

Keywords:

Precision Targeting, Genetically Modified T Cells, Targeting, Precision Medicine, Immunotherapy, Cancer Cells

Abstract

In this review cancer treatment, despite notable progress, challenges persist globally. Traditional methods like surgery, chemotherapy, and radiotherapy, while effective, often compromise patients' overall quality of life due to side effects. Immunotherapeutic strategies, especially Chimeric Antigen Receptor T cells, show promise by leveraging the immune system to target tumors independently of certain immune escape mechanisms. However, CAR-T cells' specificity to surface antigens limits their applicability. Precise cancer management demands ongoing research to refine and broaden these therapies. Employing CAR or T-cell receptor therapies, genetic engineering enhances T-cell antigenic specificity, optimizing cancer immunotherapy precision. CARs, synthetic receptors engineered for tumor antigen recognition, represent a groundbreaking approach, intertwining immunotherapy, gene therapy, and cancer therapy. The human immune system's ability to discern self from non-self-entities forms the basis of immunotherapy, fostering innovative modalities that selectively target cancer cells. CAR-T therapy, with FDA approval for leukemia and lymphoma, holds transformative potential but faces safety and efficacy challenges. Advances, including mitigating cytotoxicity and enhancing therapeutic efficacy, show promise. Utilizing genetic alteration, CARs have shown efficacy in the treatment of hematologic malignancies, particularly CD19 CARs in B cell blood cancers. Current study is investigating the potential uses of CAR-T cell treatment in patients with lymphoma and myeloma.

References

Zhang JP, Zhang R, Tsao ST, Liu YC, Chen X, Lu DP et al. Sequential allogeneic and autologous CAR-T–cell therapy to treat an immune-compromised leukemic patient. Blood Adv. 2018 Jul 24;2(14):1691-5. doi: 10.1182/bloodadvances.2018017004, PMID 30026294.

Akatsuka Y. TCR-like CAR-T cells targeting MHC-bound minor histocompatibility antigens. Front Immunol. 2020 Feb 28;11:257. doi: 10.3389/fimmu.2020.00257, PMID 32184779.

Majzner RG, Mackall CL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 2018 Oct 1;8(10):1219-26. doi: 10.1158/2159-8290.CD-18-0442, PMID 30135176.

June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018 Mar 23;359(6382):1361-5. doi: 10.1126/science.aar6711, PMID 29567707.

Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020 Oct 12;38(4):473-88. doi: 10.1016/j.ccell.2020.07.005, PMID 32735779.

Benmebarek MR, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019 Mar 14;20(6):1283. doi: 10.3390/ijms20061283, PMID 30875739.

Feng J, Xu H, Cinquina A, Wu Z, Chen Q, Zhang P et al. Treatment of aggressive T cell lymphoblastic lymphoma/leukemia using anti-CD5 CAR T cells. Stem Cell Rev Rep. 2021 Apr;17(2):652-61. doi: 10.1007/s12015-020-10092-9, PMID 33410096.

Benjamini O, Shimoni A, Besser M, Shem-Tov N, Danylesko I, Yerushalmi R et al. Safety and efficacy of CD19-CAR T cells in Richter’s transformation after targeted therapy for chronic lymphocytic leukemia. Blood. 2020 Nov 5;136;Suppl 1:40. doi: 10.1182/blood-2020-138904.

Caratelli S, Sconocchia T, Arriga R, Coppola A, Lanzilli G, Lauro D et al. FCγ chimeric receptor-engineered T cells: methodology, advantages, limitations, and clinical relevance. Front Immunol. 2017 Apr 27;8:457. doi: 10.3389/fimmu.2017.00457, PMID 28496440.

Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016 Aug 1;126(8):3130-44. doi: 10.1172/JCI83092, PMID 27454297.

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E. CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. The Journal of clinical investigation. 2016 Jun 1;126(6):2123-38.

Korell F, Laier S, Sauer S, Veelken K, Hennemann H, Schubert ML et al. Current challenges in providing good leukapheresis products for manufacturing of CAR-T cells for patients with relapsed/refractory NHL or ALL. Cells. 2020 May 15;9(5):1225. doi: 10.3390/cells9051225, PMID 32429189.

Liu H, Xu Y, Xiang J, Long L, Green S, Yang Z et al. Targeting alpha-fetoprotein (AFP)–MHC complex with CAR T-cell therapy for liver cancer. Clin Cancer Res. 2017 Jan 15;23(2):478-88. doi: 10.1158/1078-0432.CCR-16-1203, PMID 27535982.

Eisenberg V, Hoogi S, Shamul A, Barliya T, Cohen CJ. T-cells ”à la CAR-T (e)”–Genetically engineering T-cell response against cancer. Adv Drug Deliv Rev. 2019 Feb 15;141:23-40. doi: 10.1016/j.addr.2019.01.007, PMID 30653988.

Zheng PP, Kros JM, Li J. Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov Today. 2018 Jun 1;23(6):1175-82. doi: 10.1016/j.drudis.2018.02.012, PMID 29501911.

Hutt D, Bielorai B, Baturov B, Z’orbinski I, Ilin N, Adam E et al. Feasibility of leukapheresis for CAR T-cell production in heavily pre-treated pediatric patients. Transfus Apher Sci. 2020 Aug 1;59(4):102769. doi: 10.1016/j.transci.2020.102769, PMID 32414613.

Truong NTH, Gargett T, Brown MP, Ebert LM. Effects of chemotherapy agents on circulating leukocyte populations: potential implications for the success of CAR-T cell therapies. Cancers. 2021 May 6;13(9):2225. doi: 10.3390/cancers13092225, PMID 34066414.

Mi JQ, Xu J, Zhou J, Zhao W, Chen Z, Melenhorst JJ et al. CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies. Front Med. 2021 Dec 18;15(6):783-804. doi: 10.1007/s11684-021-0904-z, PMID 34921673.

Liu B, Yan L, Zhou M. Target selection of CAR T cell therapy in accordance with the TME for solid tumors. Am J Cancer Res. 2019;9(2):228-41. PMID 30906625.

Han D, Xu Z, Zhuang Y, Ye Z, Qian Q. Current progress in CAR-T cell therapy for hematological malignancies. J Cancer. 2021;12(2):326-34. doi: 10.7150/jca.48976, PMID 33391429.

Watanabe K, Nishikawa H. Engineering strategies for broad application of TCR-T-and CAR-T-cell therapies. Int Immunol. 2021 Nov 1;33(11):551-62. doi: 10.1093/intimm/dxab052, PMID 34374779.

Gross G, Eshhar Z. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annu Rev Pharmacol Toxicol. 2016 Jan 6;56:59-83. doi: 10.1146/annurev-pharmtox-010814-124844, PMID 26738472.

Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, Van Leeuwen DG, Drakes DJ et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018 Oct;36(9):847-56. doi: 10.1038/nbt.4195, PMID 30102295.

Bupha-Intr O, Haeusler G, Chee L, Thursky K, Slavin M, Teh B. CAR-T cell therapy and infection: a review. Expert Rev Anti-Infect Ther. 2021 Jun 3;19(6):749-58. doi: 10.1080/14787210.2021.1855143, PMID 33249873.

Zheng PP, Kros JM, Li J. Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov Today. 2018 Jun 1;23(6):1175-82. doi: 10.1016/j.drudis.2018.02.012, PMID 29501911.

Mohanty R, Chowdhury CR, Arega S, Sen P, Ganguly P, Ganguly N. CAR T cell therapy: A new era for cancer treatment (Review). Oncol Rep. 2019 Dec 1;42(6):2183-95. doi: 10.3892/or.2019.7335, PMID 31578576.

Bartoló-Ibars A, Uribe-Herranz M, Muñoz-Sánchez G, Arnaldos-Pérez C, Ortiz-Maldonado V, Urbano-Ispizua Á et al. CAR-T after stem cell transplantation in B-cell lymphoproliferative disorders: are they really autologous or allogenic cell therapies? Cancers. 2021 Sep 17;13(18):4664. doi: 10.3390/cancers13184664, PMID 34572890.

Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M et al. CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res Ther. 2021 Dec;12(1):1.

Zhang XW, Wu YS, Xu TM, Cui MH. CAR-T cells in the treatment of ovarian cancer: A promising cell therapy. Biomolecules. 2023 Mar 2;13(3):465. doi: 10.3390/biom13030465, PMID 36979400.

Cheever A, Townsend M, O’Neill K. Tumor microenvironment immunosuppression: a roadblock to CAR T-cell advancement in solid tumors. Cells. 2022 Nov 16;11(22):3626.

Razavi AS, Loskog A, Razi S, Rezaei N. The signaling and the metabolic differences of various CAR T cell designs. Int Immunopharmacol. 2023 Jan 1;114:109593. doi: 10.1016/j.intimp.2022.109593, PMID 36700773.

Vasic D, Lee JB, Leung Y, Khatri I, Na Y, Abate-Daga D et al. Allogeneic double-negative CAR-T cells inhibit tumor growth without off-tumor toxicities. Sci Immunol. 2022 Apr 22;7(70):eabl3642. doi: 10.1126/sciimmunol.abl3642, PMID 35452255.

Al-Haideri M, Tondok SB, Safa SH, Maleki AH, Rostami S, Jalil AT et al. CAR-T cell combination therapy: the next revolution in cancer treatment. Cancer Cell Int. 2022 Nov 24;22(1):365. doi: 10.1186/s12935-022-02778-6, PMID 36419058.

Foeng J, Comerford I, McColl SR. Harnessing the chemokine system to home CAR-T cells into solid tumors. Cell Rep Med. 2022 Mar 15;3(3):100543. doi: 10.1016/j.xcrm.2022.100543, PMID 35492880.

White LG, Goy HE, Rose AJ, McLellan AD. Controlling cell trafficking: addressing failures in CAR T and NK cell therapy of solid tumours. Cancers. 2022 Feb 15;14(4):978. doi: 10.3390/cancers14040978, PMID 35205725.

Al-Haideri M, Tondok SB, Safa SH, Maleki AH, Rostami S, Jalil AT et al. CAR-T cell combination therapy: the next revolution in cancer treatment. Cancer Cell Int. 2022 Nov 24;22(1):365. doi: 10.1186/s12935-022-02778-6, PMID 36419058.

Taromi S, Firat E, Simonis A, Braun LM, Apostolova P, Elze M et al. Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer. Cancer Lett. 2022 Jul 10;538:215697. doi: 10.1016/j.canlet.2022.215697, PMID 35487310.

Liu X, Onda M, Watson N, Hassan R, Ho M, Bera TK et al. Highly active CAR T cells that bind to a juxtamembrane region of mesothelin and are not blocked by shed mesothelin. Proc Natl Acad Sci USA. 2022 May 10;119(19):e2202439119. doi: 10.1073/pnas.2202439119.

Li H, Zhou X, Wang G, Hua D, Li S, Xu T et al. CAR-T cells targeting TSHR demonstrate safety and potent preclinical activity against differentiated thyroid cancer. J Clin Endocrinol Metab. 2022 Apr 1;107(4):1110-26. doi: 10.1210/clinem/dgab819, PMID 34751400.

Meister H, Look T, Roth P, Pascolo S, Sahin U, Lee S et al. Multifunctional mRNA-based CAR T cells display promising antitumor activity against glioblastoma. Clin Cancer Res. 2022 Nov 1;28(21):4747-56. doi: 10.1158/1078-0432.CCR-21-4384, PMID 36037304.

Sengsayadeth S, Savani BN, Oluwole O, Dholaria B. Overview of approved CAR‐T therapies, ongoing clinical trials, and its impact on clinical practice. EJHaem. 2022 Jan;3;Suppl 1:6-10. doi: 10.1002/jha2.338, PMID 35844299.

Zhang X, Zhu L, Zhang H, Chen S, Xiao Y. CAR-T cell therapy in hematological malignancies: current opportunities and challenges. Front Immunol. 2022 Jun 10;13:927153. doi: 10.3389/fimmu.2022.927153, PMID 35757715.

Chen S, Zhang Y, Fang C, Zhang N, Wang Y, Chen R et al. Donor-derived and off-the-shelf allogeneic anti-CD19 CAR T-cell therapy for R/R ALL and NHL: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2022 Sep 7;179:103807. doi: 10.1016/j.critrevonc.2022.103807, PMID 36087853.

Jain MD, Smith M, Shah NN. How I treat refractory CRS and ICANS after CAR T-cell therapy. Blood. The J Am Soc Hematol. 2023 May 18;141(20):2430-42.

Ghassemi S, Durgin JS, Nunez-Cruz S, Patel J, Leferovich J, Pinzone M et al. Rapid manufacturing of nonactivated potent CAR T.

Si X, Gu T, Liu L, Huang Y, Han Y, Qian P et al. Hematologic cytopenia post CAR T cell therapy: etiology, potential mechanisms and perspective. Cancer Lett. 2022 Sep 17;550:215920. doi: 10.1016/j.canlet.2022.215920, PMID 36122628.

Xu N, Yang XF, Xue SL, Tan JW, Li MH, Ye J et al. Ruxolitinib reduces severe CRS response by suspending CAR-T cell function instead of damaging CAR-T cells. Biochem Biophys Res Commun. 2022 Mar 5;595:54-61. doi: 10.1016/j.bbrc.2022.01.070, PMID 35101664.

Beyar-Katz O, Perry C, On YB, Amit O, Gutwein O, Wolach O et al. Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells—single-center experience. Ann Hematol. 2022 Aug;101(8):1769-76. doi: 10.1007/s00277-022-04889-6, PMID 35731278.

Cook MR, Dorris CS, Makambi KH, Luo Y, Munshi PN, Donato M et al. Toxicity and efficacy of CAR T-cell therapy in primary and secondary CNS lymphoma: a meta-analysis of 128 patients. Blood Adv. 2023 Jan 10;7(1):32-9. doi: 10.1182/bloodadvances.2022008525, PMID 36260735.

Tang JP, Peters CW, Quiros C, Wang X, Klomhaus AM, Yamada RE et al. Hypophosphatemia due to increased effector cell metabolic activity is associated with neurotoxicity symptoms in CD19-targeted CAR T-cell therapy. Cancer Immunol Res. 2022 Dec 2;10(12):1433-40. doi: 10.1158/2326-6066.CIR-22-0418, PMID 36259217.

Pan K, Farrukh H, Chittepu VC, Xu H, Pan CX, Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022 Dec;41(1):1-2.

Zhang Q, Zu C, Jing R, Feng Y, Zhang Y, Zhang M et al. Incidence, clinical characteristics and prognosis of tumor lysis syndrome following B-cell maturation antigen-targeted chimeric antigen receptor-T cell therapy in relapsed/refractory multiple myeloma. Front Immunol. 2023 May 4;14:1125357. doi: 10.3389/fimmu.2023.1125357, PMID 37215107.

Patel A, Levenson J, Huang J, Agha M, Dorritie K. Prevalence of orthostatic hypotension or frank hypotension after car-T hospitalization. J Am Coll Cardiol. 2021 May 11;77(18):3289-. doi: 10.1016/S0735-1097(21)04643-X.

Smith AJ, Oertle J, Warren D, Prato D. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: summary and perspective. J Cell Immunother. 2016 Nov 1;2(2):59-68. doi: 10.1016/j.jocit.2016.08.001.

Geltink RIK, Kyle RL, Pearce EL. Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol. 2018 Apr 26;36:461-88. doi: 10.1146/annurev-immunol-042617-053019, PMID 29677474.

Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, Van Leeuwen DG, Drakes DJ et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018 Oct;36(9):847-56. doi: 10.1038/nbt.4195, PMID 30102295.

Mao R, Kong W, He Y. The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: moderate is better. Front Immunol. 2022 Oct 17;13:1032403. doi: 10.3389/fimmu.2022.1032403, PMID 36325345.

Sadelain MCd. CD19 Car T cells. Cell. 2017 Dec 14;171(7):1471. doi: 10.1016/j.cell.2017.12.002, PMID 29245005.

Dabiri H, Safarzadeh Kozani P, Habibi Anbouhi M, Mirzaee Godarzee M, Haddadi MH, Basiri M et al. Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies. Biomark Res. 2023 Jul 4;11(1):67. doi: 10.1186/s40364-023-00509-1, PMID 37403182.

Published

05-01-2024

How to Cite

A. Razzak Mahmood, D. A., S. Srinivasan, and C. Emmanuel E. S. “Precision Targeting and Genetically Modified T Cells for Targeting Cancer Cells”. International Journal of Trends in OncoScience, vol. 2, no. 1, Jan. 2024, pp. 1-9, doi:10.22376/ijtos.2023.2.1.1-9.

Issue

Section

Review Articles