Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy

Overview

Journal J Natl Cancer Inst

Publisher Oxford University Press

Specialty Oncology

Date 2016 Jan 29

PMID 26819347

Citations 141

Authors

Hanren Dai

Yao Wang

Xuechun Lu

Weidong Han

Affiliations

Soon will be listed here.

Abstract

The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.

Citing Articles

Immunotherapy in cervical cancer: an innovative approach for better treatment outcomes.

Dey T, Agrawal S Explor Target Antitumor Ther. 2025; 6:1002296.

PMID: 40061136 PMC: 11886377. DOI: 10.37349/etat.2025.1002296.

Novel immunotherapeutic approaches in gastric cancer.

Yang M, Lin W, Huang J, Mannucci A, Luo H Precis Clin Med. 2024; 7(4):pbae020.

PMID: 39397869 PMC: 11467695. DOI: 10.1093/pcmedi/pbae020.

The Art of Bioimmunogenomics (BIGs) 5.0 in CAR-T Cell Therapy for Lymphoma Management.

Anurogo D, Luthfiana D, Anripa N, Fauziah A, Soleha M, Rahmah L Adv Pharm Bull. 2024; 14(2):314-330.

PMID: 39206402 PMC: 11347730. DOI: 10.34172/apb.2024.034.

CD19 CAR T cells for B cell malignancies: a systematic review and meta-analysis focused on clinical impacts of CAR structural domains, manufacturing conditions, cellular product, doses, patient's age, and tumor types.

Montagna E, de Campos N, Porto V, da Silva G, Suarez E BMC Cancer. 2024; 24(1):1037.

PMID: 39174908 PMC: 11340198. DOI: 10.1186/s12885-024-12651-6.

Upregulated Nuclear Expression of Soluble Epoxide Hydrolase Predicts Poor Outcome in Breast Cancer Patients: Importance of the Digital Pathology Approach.

Montecillo-Aguado M, Soca-Chafre G, Antonio-Andres G, Morales-Martinez M, Tirado-Rodriguez B, Rocha-Lopez A Int J Mol Sci. 2024; 25(15).

PMID: 39125591 PMC: 11312095. DOI: 10.3390/ijms25158024.

References

Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J . Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010; 24(6):1160-70. PMC: 2888148. DOI: 10.1038/leu.2010.75. View

Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S . Multiplex Genome-Edited T-cell Manufacturing Platform for "Off-the-Shelf" Adoptive T-cell Immunotherapies. Cancer Res. 2015; 75(18):3853-64. DOI: 10.1158/0008-5472.CAN-14-3321. View

Recchia A, Bonini C, Magnani Z, Urbinati F, Sartori D, Muraro S . Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci U S A. 2006; 103(5):1457-62. PMC: 1360534. DOI: 10.1073/pnas.0507496103. View

Tamada K, Geng D, Sakoda Y, Bansal N, Srivastava R, Li Z . Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin Cancer Res. 2012; 18(23):6436-45. DOI: 10.1158/1078-0432.CCR-12-1449. View

Long A, Haso W, Shern J, Wanhainen K, Murgai M, Ingaramo M . 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015; 21(6):581-90. PMC: 4458184. DOI: 10.1038/nm.3838. View

Reshef R, Luger S, Hexner E, Loren A, Frey N, Nasta S . Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N Engl J Med. 2012; 367(2):135-45. PMC: 3568501. DOI: 10.1056/NEJMoa1201248. View

Letourneur F, Klausner R . T-cell and basophil activation through the cytoplasmic tail of T-cell-receptor zeta family proteins. Proc Natl Acad Sci U S A. 1991; 88(20):8905-9. PMC: 52619. DOI: 10.1073/pnas.88.20.8905. View

Li Y, Hayakawa K, Hardy R . The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J Exp Med. 1993; 178(3):951-60. PMC: 2191150. DOI: 10.1084/jem.178.3.951. View

Song D, Ye Q, Carpenito C, Poussin M, Wang L, Ji C . In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer Res. 2011; 71(13):4617-27. PMC: 4140173. DOI: 10.1158/0008-5472.CAN-11-0422. View

10.

Singh R, Paterson Y . Immunoediting sculpts tumor epitopes during immunotherapy. Cancer Res. 2007; 67(5):1887-92. DOI: 10.1158/0008-5472.CAN-06-3960. View

11.

Heslop H, Slobod K, Pule M, Hale G, Rousseau A, Smith C . Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2009; 115(5):925-35. PMC: 2817637. DOI: 10.1182/blood-2009-08-239186. View

12.

Kochenderfer J, Feldman S, Zhao Y, Xu H, Black M, Morgan R . Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009; 32(7):689-702. PMC: 2747302. DOI: 10.1097/CJI.0b013e3181ac6138. View

13.

Gattinoni L, Finkelstein S, Klebanoff C, Antony P, Palmer D, Spiess P . Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005; 202(7):907-12. PMC: 1397916. DOI: 10.1084/jem.20050732. View

14.

Kochenderfer J, Dudley M, Carpenter R, Kassim S, Rose J, Telford W . Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood. 2013; 122(25):4129-39. PMC: 3862276. DOI: 10.1182/blood-2013-08-519413. View

15.

Kowolik C, Topp M, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N . CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006; 66(22):10995-1004. DOI: 10.1158/0008-5472.CAN-06-0160. View

16.

Kahlon K, Brown C, Cooper L, Raubitschek A, Forman S, Jensen M . Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004; 64(24):9160-6. DOI: 10.1158/0008-5472.CAN-04-0454. View

17.

Scholler J, Brady T, Binder-Scholl G, Hwang W, Plesa G, Hege K . Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012; 4(132):132ra53. PMC: 4368443. DOI: 10.1126/scitranslmed.3003761. View

18.

Riviere I, Dunbar C, Sadelain M . Hematopoietic stem cell engineering at a crossroads. Blood. 2011; 119(5):1107-16. PMC: 3277348. DOI: 10.1182/blood-2011-09-349993. View

19.

Davila M, Riviere I, Wang X, Bartido S, Park J, Curran K . Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014; 6(224):224ra25. PMC: 4684949. DOI: 10.1126/scitranslmed.3008226. View

20.

Porter D, Levine B, Kalos M, Bagg A, June C . Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011; 365(8):725-33. PMC: 3387277. DOI: 10.1056/NEJMoa1103849. View