CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies
The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20–100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.
Key Wordsommuno-oncology CAR T cell lymphoma One Health
All authors (JPM, SE, CJ, AJ, KA, ABM, MK, SB WW, AKL, SSK) have contributed to the writing of the manuscript. JPM was responsible for the final production of the commentary. All authors have read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
JPM, SE, CJ, AJ, KA, WW, and SSK are founders of LifEngine Animal Health Laboratories, Inc. SSK is inventor on patents in the CAR T cell therapy field that are licensed to Novartis. This work was partially supported (AKL) by the Intramural Program of the National Cancer Institute, NIH (Z01-BC006161).
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.
- 31.Advances in aggressive lymphoma from the 2017 American Society of Hematology Annual Meeting and Exposition. Clin Adv Hematol Oncol. 2018;16(Suppl 5(2)):1–24.Google Scholar
- 32.News in Brief. Value in Using CAR T-cells for DLBCL. Cancer Discov. 2018;8(2):131–2.Google Scholar
- 43.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. J Clin Oncol. 2015;33(6):540–9.PubMedCrossRefPubMedCentralGoogle Scholar
- 53.Richards KL, Motsinger-Reif AA, Chen HW, Fedoriw Y, Fan C, Nielsen DM, et al. Gene profiling of canine B-cell lymphoma reveals germinal center and post-germinal center subtypes with different survival times, modeling human DLBCL. Cancer Res. 2013;73(16):5029–39.PubMedPubMedCentralCrossRefGoogle Scholar
- 61.Ramanayake S, Bilmon I, Bishop D, Dubosq MC, Blyth E, Clancy L, et al. Low-cost generation of good manufacturing practice-grade CD19-specific chimeric antigen receptor-expressing T-cells using piggyBac gene transfer and patient-derived materials. Cytotherapy. 2015;17(9):1251–67.PubMedCrossRefGoogle Scholar
- 63.Wierson WA, Welker JM, Almeida MP, Mann CM, Webster DA, Weiss TJ, Torrie ME, Vollbrecht MK, Lan M, McKeighan KC, Ming Z, Wehmeier A, Mikelson CS, Haltom JA, Kwan KM, Chien CB, Balciunas D, Ekker SC, Clark KJ, Webber BR, Moriarity B, Solin SL, Carlson DF, Dobbs DL, McGrail M, Essner JJ. GeneWeld: a method for efficient targeted integration directed by short homology http://biorxiv.org/content/early/2018/10/03/431627.
- 64.National Cancer Policy Forum, Board on Health Care Services, Institute of Medicine, National Academies of Sciences, Engineering, and Medicine. The role of clinical studies for pets with naturally occurring tumors in translational cancer research: workshop summary. Washington (DC): National Academies Press (US); 2015.Google Scholar
- 70.Bon C, Toutain PL, Concordet D, Gehring R, Martin-Jimenez T, Smith J, et al. Mathematical modeling and simulation in animal health. Part III: using nonlinear mixed-effects to characterize and quantify variability in drug pharmacokinetics. J Vet Pharmacol Ther. 2018;41(2):171–83.PubMedCrossRefPubMedCentralGoogle Scholar
- 71.Berger EP, Johannes CM, Jergens AE, Allenspach K, Powers BE, Du Y, et al. Retrospective evaluation of toceranib phosphate (Palladia®) use in the treatment of gastrointestinal stromal tumors of dogs. J Vet Intern Med. 2018;32(6):2045–53. https://doi.org/10.1111/jvim.15335.CrossRefPubMedPubMedCentralGoogle Scholar
- 81.Burton JH, Mazcko C, LeBlanc A, Covey JM, Ji J, Kinders RJ, et al. NCI comparative oncology program testing of non-camptothecin indenoisoquinoline topoisomerase I inhibitors in naturally occurring canine lymphoma. Clin Cancer Res. 2018;24(23):5830–40. https://doi.org/10.1158/1078-0432.CCR-18-1498.CrossRefPubMedGoogle Scholar
- 84.Gaurnier-Hausser A, Patel R, Baldwin AS, May MJ, Mason NJ. NEMO-binding domain peptide inhibits constitutive NF-κB activity and reduces tumor burden in a canine model of relapsed, refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2011;17(14):4661–71.PubMedPubMedCentralCrossRefGoogle Scholar
- 85.Habineza Ndikuyeze G, Gaurnier-Hausser A, Patel R, Baldwin AS, May MJ, Flood P, et al. A phase I clinical trial of systemically delivered NEMO binding domain peptide in dogs with spontaneous activated B-cell like diffuse large B-cell lymphoma. PLoS One. 2014;9(5):e95404.PubMedPubMedCentralCrossRefGoogle Scholar
- 86.Ito D, Frantz AM, Williams C, Thomas R, Burnett RC, Avery AC, et al. CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies. Leuk Lymphoma. 2012;53(7):1390–8.PubMedPubMedCentralCrossRefGoogle Scholar