Abstract
T cell malignancies are aggressive diseases with no standard treatment available, often resulting in poor patient outcomes. Lately, the recent FDA approval of a CD19 CAR T cell therapy for B cell acute lymphoblastic leukemia has earned nationwide attention, leading to the possibility that success of CD19 CAR therapy can be extended to T cell malignancies. However, the impact of T cell depletion due to a shared antigen pool remains an issue to be resolved. Here, we describe a CD4CAR capable of eliminating CD4-positive T cell acute lymphoblastic leukemia in a systemic mouse model, with CAMPATH (alemtuzumab) as a natural safety switch to deplete the infused CD4CAR T cells to prevent toxicities associated with CD4 cell aplasia. Our data support the potential use of CD4CAR T cells for the treatment of CD4-postive T-cell acute lymphoblastic leukemia malignancies or refractory disease in clinical settings.
Abbreviations
- CAR :
-
Chimeric antigen receptor
- FDA :
-
Food and Drug Administration
- B-ALL :
-
B cell acute lymphoblastic leukemia
- T-ALL :
-
T cell acute lymphoblastic leukemia
- CAMPATH :
-
Alemtuzumab
- I.P. :
-
Intraperitoneal injection
References
Maude, S. L., Teachey, D. T., Porter, D. L., & Grupp, S. A. (2015). CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood, 125, 4017–4023.
Ramos, C. A., Savoldo, B., & Dotti, G. (2014). CD19-CAR trials. Cancer Journal, 20, 112–118.
Lindsey, J. W., Hodgkinson, S., Mehta, R., Siegel, R. C., Mitchell, D. J., Lim, M., Piercy, C., Tram, T., Dorfman, L., Enzmann, D., & Steinman, L. (1994). Phase 1 clinical trial of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology, 44, 413–419.
Nicolas, J. F., Chamchick, N., Thivolet, J., Wijdenes, J., Morel, P., & Revillard, J. P. (1991). CD4 antibody treatment of severe psoriasis. Lancet, 338, 321.
Gottlieb, A. B., Lebwohl, M., Shirin, S., Sherr, A., Gilleaudeau, P., Singer, G., Solodkina, G., Grossman, R., Gisoldi d, E., Phillips, S., Neisler, H. M., & Krueger, J. G. (2000). Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis vulgaris: Results of a pilot, multicenter, multiple-dose, placebo-controlled study. Journal of the American Academy of Dermatology, 43, 595–604.
Kalos, M., Levine, B. L., Porter, D. L., et al. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Science Translational Medicine, 3, 95ra73.
Lee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., Fry, T. J., Orentas, R., Sabatino, M., Shah, N. N., Steinberg, S. M., Stroncek, D., Tschernia, N., Yuan, C., Zhang, H., Zhang, L., Rosenberg, S. A., Wayne, A. S., & Mackall, C. L. (2015). T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. Lancet, 385, 517–528.
Pinz, K., Liu, H., Golightly, M., Jares, A., Lan, F., Zieve, G. W., Hagag, N., Schuster, M., Firor, A. E., Jiang, X., & Ma, Y. (2016). Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells. Leukemia, 30, 701–707.
Chen, K. H., Wada, M., Firor, A. E., Pinz, K. G., Jares, A., Liu, H., Salman, H., Golightly, M., Lan, F., Jiang, X., & Ma, Y. (2016). Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget, 7, 56219–56232.
Chen K. H., Wada M., Pinz K. G., et al. (2017). A compound chimeric antigen receptor strategy for targeting multiple myeloma. Leukemia.
Acknowledgements
The authors thank Todd Rueb and Rebecca Connor at the Stony Brook University flow cytometry lab for conducting analysis of samples. We also thank Laurie Levine and Joan Pashinsky at the animal facility at Stony Brook University for assistance with animal care.
Funding
This work was supported by iCell Gene Therapeutics.The KentuckyOne Health Foundations (WT).
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GM, AS, KP and WT wrote the manuscript. MW designed and performed experiments. GM, KP and AS performed the experiments.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The acquisition of donor T cells adhered to a protocol approved by the Institutional Review Board of Stony Brook University. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Animal studies were approved by the Institutional Review Board at Stony Brook University.
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The authors declare that they have no competing interests.
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Ma, G., Shen, J., Pinz, K. et al. Targeting T Cell Malignancies Using CD4CAR T-Cells and Implementing a Natural Safety Switch. Stem Cell Rev and Rep 15, 443–447 (2019). https://doi.org/10.1007/s12015-019-09876-5
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DOI: https://doi.org/10.1007/s12015-019-09876-5