The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer - PubMed (original) (raw)
The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer
Daniel W Lee et al. Clin Cancer Res. 2012.
Erratum in
- Correction: The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer.
[No authors listed] [No authors listed] Clin Cancer Res. 2017 Jan 15;23(2):611. doi: 10.1158/1078-0432.CCR-16-2684. Clin Cancer Res. 2017. PMID: 28093489 No abstract available.
Abstract
Improved outcomes for children with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, gene therapy, and cell-processing technologies have paved the way for clinical applications of chimeric antigen receptor-based therapies. This is a new form of targeted immunotherapy that merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity, potential for expansion, and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B-cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. In pediatric oncology, CD19 and GD2 are compelling antigens that have already been identified for targeting pre-B acute lymphoblastic leukemia and neuroblastoma, respectively, with this approach, but it is likely that other antigens expressed in a variety of childhood cancers will also soon be targeted using this therapy. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of childhood cancer.
©2012 AACR.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Figures
Figure 1
Current CAR design allows for MHC-independent antigen recognition and incorporates costimulatory signal (s) endowing the transduced T cell with potent cytotoxic activity. In contrast to the TCR, which recognizes peptide in the context of MHC and provides signal 1, CARs interact in an MHC-independent manner. All CARs must provide signal 1 in the form of the TCR z activating subunit (first-generation), but the addition of one (second-generation) or 2 (third-generation) costimulatory signals (CD28, 4-1BB, or OX40) provides the CAR-transduced T cell with both signals 1 and 2, leading to full activation, proliferation, and cytotoxicity.
Figure 2
General schema for the preparation, transduction, and infusion of CAR-modified T cells. A, apheresed T cells from a patient or an allogeneic donor are activated. Three accepted methods are illustrated: (i) stimulation with the activating CD3 antibody, OKT3, in the presence of IL-2; (ii) stimulation with anti-CD3– and anti-CD28–coated paramagnetic beads in the presence of IL-2; and (iii) stimulation with aAPC (expressing 4-1BBL and an Fc receptor) with OKT3 and IL-2. Activated cells are then transduced with the CAR using a retro- or lentiviral platform. Because the CAR is integrated into the T-cell genome, all daughter cells that are generated (a mix of CD4+ [Th1/Th2/TH17/Treg] and CD8+ T cells) during this expansion also express the CAR. CAR T cells are then infused into the patient after preparative chemotherapy. B, generation of CAR-expressing T cells generally results in a several-hundred-fold expansion over 14 days. Such extensive proliferation may generate predominantly TEFF cells, which have cytotoxic capabilities but limited proliferative potential compared with T-effector and TCM cells. C, less intense stimulation and/or modulation of stimulation methods may produce more naïve T cells or T–central memory cells, which have an increased likelihood of persistence.
Figure 3
Lymphodepleting preparatory regimens can enhance the efficacy of adoptive cell therapy. Proposed mechanisms include (i) a reduction in endogenous lymphocytes, leading to accumulation of IL-7 and IL-15 (homeostatic cytokines that support cell expansion and persistence); (ii) a transient reduction in the number and frequency of Tregs, thereby diminishing suppression; and (iii) induction of gut damage, which can lead to the systemic release of bacterial byproducts [e.g., lipopolysaccharide (LPS)] that activate the innate immune system.
Similar articles
- Chimeric antigen receptor therapy for cancer.
Barrett DM, Singh N, Porter DL, Grupp SA, June CH. Barrett DM, et al. Annu Rev Med. 2014;65:333-47. doi: 10.1146/annurev-med-060512-150254. Epub 2013 Nov 20. Annu Rev Med. 2014. PMID: 24274181 Free PMC article. Review. - At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies.
Oluwole OO, Davila ML. Oluwole OO, et al. J Leukoc Biol. 2016 Dec;100(6):1265-1272. doi: 10.1189/jlb.5BT1115-524R. Epub 2016 Jun 27. J Leukoc Biol. 2016. PMID: 27354412 Review. - CAR T Cell Therapy in Acute Lymphoblastic Leukemia and Potential for Chronic Lymphocytic Leukemia.
Singh N, Frey NV, Grupp SA, Maude SL. Singh N, et al. Curr Treat Options Oncol. 2016 Jun;17(6):28. doi: 10.1007/s11864-016-0406-4. Curr Treat Options Oncol. 2016. PMID: 27098534 Review. - Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.
Mihara K, Yanagihara K, Takigahira M, Kitanaka A, Imai C, Bhattacharyya J, Kubo T, Takei Y, Yasunaga S, Takihara Y, Kimura A. Mihara K, et al. Br J Haematol. 2010 Oct;151(1):37-46. doi: 10.1111/j.1365-2141.2010.08297.x. Epub 2010 Jul 30. Br J Haematol. 2010. PMID: 20678160 - Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies.
Biagi E, Marin V, Giordano Attianese GM, Dander E, D'Amico G, Biondi A. Biagi E, et al. Haematologica. 2007 Mar;92(3):381-8. doi: 10.3324/haematol.10873. Haematologica. 2007. PMID: 17339188 Review.
Cited by
- CAR-T cells for pediatric malignancies: Past, present, future and nursing implications.
Callahan C, Haas L, Smith L. Callahan C, et al. Asia Pac J Oncol Nurs. 2023 Aug 3;10(11):100281. doi: 10.1016/j.apjon.2023.100281. eCollection 2023 Nov. Asia Pac J Oncol Nurs. 2023. PMID: 38023730 Free PMC article. Review. - Lenalidomide improves NKG2D-based CAR-T cell activity against colorectal cancer cells invitro.
Zarei M, Abdoli S, Farazmandfar T, Shahbazi M. Zarei M, et al. Heliyon. 2023 Sep 27;9(10):e20460. doi: 10.1016/j.heliyon.2023.e20460. eCollection 2023 Oct. Heliyon. 2023. PMID: 37790973 Free PMC article. - Computational Methods in Immunology and Vaccinology: Design and Development of Antibodies and Immunogens.
Guarra F, Colombo G. Guarra F, et al. J Chem Theory Comput. 2023 Aug 22;19(16):5315-5333. doi: 10.1021/acs.jctc.3c00513. Epub 2023 Aug 1. J Chem Theory Comput. 2023. PMID: 37527403 Free PMC article. Review. - Walking a Fine Germline: Synthesizing Public Opinion and Legal Precedent to Develop Policy Recommendations for Heritable Gene-Editing.
Benston S. Benston S. J Bioeth Inq. 2022 Sep;19(3):421-431. doi: 10.1007/s11673-022-10186-8. Epub 2022 Apr 19. J Bioeth Inq. 2022. PMID: 35438443 - Identification of the Predictive Models for the Treatment Response of Refractory/Relapsed B-Cell ALL Patients Receiving CAR-T Therapy.
Gu J, Liu S, Cui W, Dai H, Cui Q, Yin J, Li Z, Kang L, Qiu H, Han Y, Miao M, Chen S, Xue S, Wang Y, Jin Z, Zhu X, Yu L, Wu D, Tang X. Gu J, et al. Front Immunol. 2022 Mar 17;13:858590. doi: 10.3389/fimmu.2022.858590. eCollection 2022. Front Immunol. 2022. PMID: 35371098 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical