The AAPS Journal

, 21:50 | Cite as

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies

  • Jonathan P. MochelEmail author
  • Stephen C. Ekker
  • Chad M. Johannes
  • Albert E. Jergens
  • Karin Allenspach
  • Agnes Bourgois-Mochel
  • Michael Knouse
  • Sebastien Benzekry
  • Wesley Wierson
  • Amy K. LeBlanc
  • Saad S. Kenderian
Commentary Theme: Precision Medicine: Implications for the Pharmaceutical Sciences
Part of the following topical collections:
  1. Theme: Precision Medicine: Implications for the Pharmaceutical Sciences


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 Words

ommuno-oncology CAR T cell lymphoma One Health 


Author Contributions

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.


  1. 1.
    Kaiser J, Couzin-Frankel J. Cancer immunotherapy sweeps Nobel for medicine. Science. 2018;362(6410):13.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Kenderian SS, Ruella M, Gill S, Kalos M. Chimeric antigen receptor T-cell therapy to target hematologic malignancies. Cancer Res. 2014;74(22):6383–9.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Yoon DH, Osborn MJ, Tolar J, Kim CJ. Incorporation of immune checkpoint blockade into chimeric antigen receptor T-cells (CAR-Ts): combination or built-in CAR-T. Int J Mol Sci. 2018;19(2):E340.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Collins FS, Gottlieb S. The next phase of human gene-therapy oversight. N Engl J Med. 2018;379(15):1393–5.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Seelig DM, Avery AC, Ehrhart EJ, Linden MA. The comparative diagnostic features of canine and human lymphoma. Vet Sci. 2016;3(2):11.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Bromberek JL, Rout ED, Agnew MR, Yoshimoto J, Morley PS, Avery AC. Breed distribution and clinical characteristics of B cell chronic lymphocytic leukemia in dogs. J Vet Intern Med. 2016;30(1):215–22.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kosti P, Maher J, Arnold JN. Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front Immunol. 2018;9:1104.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T-cells. Sci Transl Med. 2016;8(355):355ra116.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    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. Lancet. 2015;385(9967):517–28.PubMedCrossRefGoogle Scholar
  12. 12.
    Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T-cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14(11):1264–70.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T-cells. Blood. 2008;112(6):2261–71.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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. Clin Cancer Res. 2006;12(20 Pt 1):6106–15.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T-cells in lymphoma patients. J Clin Invest. 2011;121(5):1822–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol. 2003;3(7):544–56.PubMedCrossRefGoogle Scholar
  18. 18.
    Boomer JS, Green JM. An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol. 2010;2(8):a002436.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Sperling AI, Auger JA, Ehst BD, Rulifson IC, Thompson CB, Bluestone JA. CD28/B7 interactions deliver a unique signal to naive T-cells that regulates cell survival but not early proliferation. J Immunol. 1996;157(9):3909–17.PubMedGoogle Scholar
  20. 20.
    Zhang H, Snyder KM, Suhoski MM, Maus MV, Kapoor V, June CH, et al. 4-1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy. J Immunol. 2007;179(7):4910–8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, et al. Control of large, established tumor xenografts with genetically retargeted human T-cells containing CD28 and CD137 domains. Proc Natl Acad Sci U S A. 2009;106(9):3360–5.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T-cell-mediated tumor eradication. Mol Ther. 2010;18(2):413–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944–50.PubMedCrossRefGoogle Scholar
  24. 24.
    Tavernier E, Boiron JM, Huguet F, Bradstock K, Vey N, Kovacsovics T, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Gökbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Hüttmann A, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120(10):2032–41.PubMedCrossRefGoogle Scholar
  26. 26.
    Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T-cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.PubMedCrossRefGoogle Scholar
  27. 27.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T-cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T-cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010;116(19):3875–86.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Roberts ZJ, Better M, Bot A, Roberts MR, Ribas A. Axicabtagene ciloleucel, a first-in-class CAR T-cell therapy for aggressive NHL. Leuk Lymphoma. 2018;59(8):1785–96.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 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. 32.
    News in Brief. Value in Using CAR T-cells for DLBCL. Cancer Discov. 2018;8(2):131–2.Google Scholar
  33. 33.
    Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T-cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Rasche L, Weinhold N, Morgan GJ, van Rhee F, Davies FE. Immunologic approaches for the treatment of multiple myeloma. Cancer Treat Rev. 2017;55:190–9.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Jin Z, Xiang R, Qing K, Li X, Zhang Y, Wang L, et al. The severe cytokine release syndrome in phase I trials of CD19-CAR-T-cell therapy: a systematic review. Ann Hematol. 2018;97:1327–35. Scholar
  36. 36.
    Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Liu D, Zhao J. Cytokine release syndrome: grading, modeling, and new therapy. J Hematol Oncol. 2018;11(1):121.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    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. Sci Transl Med. 2014;6(224):224ra25.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T-cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    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 Discov. 2016;6(6):664–79.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T-cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–8.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–71.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 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
  44. 44.
    Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T-cells. Cancer Discov. 2017;7(12):1404–19.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Hoyos V, Savoldo B, Quintarelli C, Mahendravada A, Zhang M, Vera J, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Schiffman JD, Breen M. Comparative oncology: what dogs and other species can teach us about humans with cancer. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370(1673):20140231.CrossRefGoogle Scholar
  48. 48.
    Gruntzig K, Graf R, Boo G, et al. Swiss Canine Cancer Registry 1955-2008: occurrence of the most common tumour diagnoses and influence of age, breed, body size, sex and neutering status on tumour development. J Comp Pathol. 2016;155(2–3):156–70.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Dobson JM, Samuel S, Milstein H, Rogers K, Wood JLN. Canine neoplasia in the UK: estimates of incidence rates from a population of insured dogs. J Small Anim Pract. 2002;43(6):240–6.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Richards KL, Suter SE. Man’s best friend: what can pet dogs teach us about non-Hodgkin lymphoma? Immunol Rev. 2015;263(1):173–91.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Marconato L, Gelain ME, Comazzi S. The dog as a possible animal model for human non-Hodgkin lymphoma: a review. Hematol Oncol. 2013;31(1):1–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Ito D, Frantz AM, Modiano JF. Canine lymphoma as a comparative model for human non-Hodgkin lymphoma: recent progress and applications. Vet Immunol Immunopathol. 2014;159(3–4):192–201.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 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
  54. 54.
    Chun R. Lymphoma: which chemotherapy protocol and why? Top Companion Anim Med. 2009;24(3):157–62.PubMedCrossRefGoogle Scholar
  55. 55.
    Frimberger AE, Moore AS, Rassnick KM, Cotter SM, O’Sullivan JL, Quesenberry PJ. A combination chemotherapy protocol with dose intensification and autologous bone marrow transplant (VELCAP-HDC) for canine lymphoma. J Vet Intern Med. 2006;20(2):355–64.PubMedCrossRefGoogle Scholar
  56. 56.
    Jubala CM, Wojcieszyn JW, Valli VE, et al. CD20 expression in normal canine B cells and in canine non-Hodgkin lymphoma. Vet Pathol. 2005;42(4):488–76.CrossRefGoogle Scholar
  57. 57.
    Impellizeri JA, Howell K, McKeever KP, Crow SE. The role of rituximab in the treatment of canine lymphoma: an ex vivo evaluation. Vet J. 2006;171(3):556–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Panjwani MK, Smith JB, Schutsky K, Gnanandarajah J, O’Connor CM, Powell DJ Jr, et al. Feasibility and safety of RNA-transfected CD20-specific chimeric antigen receptor T-cells in dogs with spontaneous B cell lymphoma. Mol Ther. 2016;24(9):1602–14.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Sharma P, King GT, Shinde SS, Purev E, Jimeno A. Axicabtagene ciloleucel for the treatment of relapsed/refractory B-cell non-Hodgkin’s lymphomas. Drugs Today (Barc). 2018;54(3):187–98.CrossRefGoogle Scholar
  60. 60.
    Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using sleeping beauty to generate CD19-specific CAR T-cells. J Clin Invest. 2016;126(9):3363–76.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 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
  62. 62.
    Roth TL, Puig-Saus C, Yu R, Shifrut E, Carnevale J, Li PJ, et al. Reprogramming human T-cell function and specificity with non-viral genome targeting. Nature. 2018;559(7714):405–9.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 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
  64. 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
  65. 65.
    Schneider B, Balbas-Martinez V, Jergens AE, Troconiz IF, Allenspach K, Mochel JP. Model-based reverse translation between veterinary and human medicine: the one health initiative. CPT Pharmacometrics Syst Pharmacol. 2018;7(2):65–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Mochel JP, Gabrielsson J, Collard W, Fink M, Gehring R, Laffont C, et al. Animal Health Modeling & Simulation Society: a new society promoting model-based approaches in veterinary pharmacology. J Vet Pharmacol Ther. 2013;36:417–9. Scholar
  67. 67.
    Mochel JP, Fink M, Peyrou M, Soubret A, Giraudel JM, Danhof M. Pharmacokinetic/pharmacodynamic modeling of renin-angiotensin aldosterone biomarkers following angiotensin-converting enzyme (ACE) inhibition therapy with benazepril in dogs. Pharm Res. 2015;32(6):1931–46.PubMedCrossRefGoogle Scholar
  68. 68.
    Mochel JP, Danhof M. Chronobiology and pharmacologic modulation of the renin-angiotensin-aldosterone system in dogs: what have we learned? Rev Physiol Biochem Pharmacol. 2015;169:43–69.PubMedCrossRefGoogle Scholar
  69. 69.
    Riviere JE, Gabrielsson J, Fink M, Mochel J. Mathematical modeling and simulation in animal health. Part I: moving beyond pharmacokinetics. J Vet Pharmacol Ther. 2016;39(3):213–23.PubMedCrossRefGoogle Scholar
  70. 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. 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. Scholar
  72. 72.
    Gordon I, Paoloni M, Mazcko C, Khanna C. The Comparative Oncology Trials Consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med. 2009;6(10):e1000161.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Paoloni M, Khanna C. Translation of new cancer treatments from pet dogs to humans. Nat Rev Cancer. 2008;8(2):147–56.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Breen M, Modiano JF. Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans--man and his best friend share more than companionship. Chromosom Res. 2008;16(1):145–54.CrossRefGoogle Scholar
  75. 75.
    Jacob JA. Researchers turn to canine clinical trials to advance cancer therapies. JAMA. 2016;315(15):1550–2.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Khanna C, London C, Vail D, Mazcko C, Hirschfeld S. Guiding the optimal translation of new cancer treatments from canine to human cancer patients. Clin Cancer Res. 2009;15(18):5671–7.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Tsoi MS, Weiden PL, Storb R. Lymphocyte reactivity to autochthonous tumor cells in dogs with spontaneous malignancies. Cell Immunol. 1974;13(3):431–9.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Weiden PL, Storb R, Lerner KG, Kao GF, Graham TC, Thomas ED. Treatment of canine malignancies by 1200 R total body irradiation and autologous marrow grafts. Exp Hematol. 1975;3(2):124–34.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Benjamini E, Theilen GH, Torten M, Fong S, Crow S, Henness AM. Tumor vaccines for immunotherapy of canine lymphosarcoma. Ann N Y Acad Sci. 1976;277(00):305–12.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Paoloni MC, Tandle A, Mazcko C, Hanna E, Kachala S, Leblanc A, et al. Launching a novel preclinical infrastructure: comparative oncology trials consortium directed therapeutic targeting of TNFalpha to cancer vasculature. PLoS One. 2009;4(3):e4972.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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. Scholar
  82. 82.
    Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194(12):1861–74.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol. 2002;3(3):221–7.PubMedCrossRefGoogle Scholar
  84. 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. 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. 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
  87. 87.
    LeBlanc AK, Breen M, Choyke P, Dewhirst M, Fan TM, Gustafson DL, et al. Perspectives from man’s best friend: National Academy of Medicine’s Workshop on Comparative Oncology. Sci Transl Med. 2016;8(324):324ps5.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    LeBlanc AK, Mazcko CN, Khanna C. Defining the value of a comparative approach to cancer drug development. Clin Cancer Res. 2016;22(9):2133–8.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Paoloni M, Mazcko C, Selting K, Lana S, Barber L, Phillips J, et al. Defining the pharmacodynamic profile and therapeutic index of NHS-IL12 immunocytokine in dogs with malignant melanoma. PLoS One. 2015;10(6):e0129954.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Lampreht U, Kamensek U, Stimac M, Sersa G, Tozon N, Bosnjak M, et al. Gene electrotransfer of canine interleukin 12 into canine melanoma cell lines. J Membr Biol. 2015;248(5):909–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Lampreht Tratar U, Kos S, Kamensek U, Ota M, Tozon N, Sersa G, et al. Antitumor effect of antibiotic resistance gene-free plasmids encoding interleukin-12 in canine melanoma model. Cancer Gene Ther. 2018;25(9–10):260–73.PubMedCrossRefGoogle Scholar
  92. 92.
    Paoloni M, Lana S, Thamm D, Mazcko C, Withrow S. The creation of the comparative oncology trials consortium pharmacodynamic core: infrastructure for a virtual laboratory. Vet J. 2010;185(1):88–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Shin B, Kress RL, Kramer PA, Darley-Usmar VM, Bellis SL, Harrington LE. Effector CD4 T-cells with progenitor potential mediate chronic intestinal inflammation. J Exp Med. 2018;215(7):1803–12.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Otoni CC, Heilmann RM, García-Sancho M, Sainz A, Ackermann MR, Suchodolski JS, et al. Serologic and fecal markers to predict response to induction therapy in dogs with idiopathic inflammatory bowel disease. J Vet Intern Med. 2018;32(3):999–1008.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ruella M, Kenderian SS. Next-generation chimeric antigen receptor T-cell therapy: going off the shelf. BioDrugs. 2017;31(6):473–81.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jaspers JE, Brentjens RJ. Development of CAR T-cells designed to improve antitumor efficacy and safety. Pharmacol Ther. 2017;178:83–91.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Jonathan P. Mochel
    • 1
    • 2
    Email author
  • Stephen C. Ekker
    • 3
  • Chad M. Johannes
    • 4
  • Albert E. Jergens
    • 4
  • Karin Allenspach
    • 4
  • Agnes Bourgois-Mochel
    • 4
  • Michael Knouse
    • 1
  • Sebastien Benzekry
    • 5
  • Wesley Wierson
    • 6
  • Amy K. LeBlanc
    • 7
  • Saad S. Kenderian
    • 8
    • 9
  1. 1.Department of Biomedical SciencesIowa State UniversityAmesUSA
  2. 2.Iowa State University College of Vet. MedicineAmesUSA
  3. 3.Mayo Clinic Cancer Center Department of Biochemistry and Molecular BiologyRochesterUSA
  4. 4.Department of Veterinary Clinical SciencesIowa State UniversityAmesUSA
  5. 5.Team MONCInstitut National de Recherche en Informatique et en AutomatiqueBordeauxFrance
  6. 6.Department of Genetics, Development, and Cell BiologyIowa State UniversityAmesUSA
  7. 7.Comparative Oncology ProgramCenter for Cancer Research National Cancer InstituteBethesdaUSA
  8. 8.Department of MedicineMayo Clinic Division of HematologyRochesterUSA
  9. 9.Department of ImmunologyMayo ClinicRochesterUSA

Personalised recommendations