Research Article

Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin-15Rα Signaling

Author(s): Sushmita Nair, Jing-Bo Wang, Shih-Ting Tsao, Yuchen Liu, Wei Zhu, William B. Slayton, Jan S. Moreb, Lujia Dong and Lung-Ji Chang*

Volume 19, Issue 1, 2019

Page: [40 - 53] Pages: 14

DOI: 10.2174/1566523218666181116093857


Introduction: Recent studies on CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved costimulatory signals in the CAR design.

Methods: Here, we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Rα. These novel CARs were functionally assessed based on a simple target cell killing assay.

Results: The results showed that the CD28/IL-15Rα co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-γ, TNFα and IL-2 upon interaction with the target cells.

Conclusion: In a follow-up clinical study, an acute lymphoblastic leukemia (ALL) patient, who experienced multiple relapses of central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Rα-modified CART cells in cancer patients.

Keywords: IL-15 receptor, chimeric antigen receptor, immunotherapy, acute B lymphoblastic leukemia, lentiviral vector, CNS leukemia.

Graphical Abstract
Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA 1993; 90(2): 720-4.
Kowolik CM, Topp MS, Gonzalez S, et al. 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.
Hwu P, Yang JC, Cowherd R, et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res 1995; 55(15): 3369-73.
Savoldo B, Ramos CA, Liu E, 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.
Song DG, Ye Q, Carpenito C, et al. 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.
Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA 2009; 106(9): 3360-5.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365(8): 725-33.
Brentjens RJ, Davila ML, Riviere I, et al. CD19-Targeted T Cells Rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5(177): 177ra138.
Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified t cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509-18.
Cruz CR, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: A phase 1 study. Blood 2013; 122(17): 2965-73.
Brentjens RJ, Riviere I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011; 118(18): 4817-28.
Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 2013; 122(25): 4129-39.
Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014; 123(17): 2625-35.
Turtle CJ. Chimeric antigen receptor modified T cell therapy for B cell malignancies. Int J Hematol 2014; 99(2): 132-40.
Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci 2012; 33(1): 35-41.
Munger W, DeJoy SQ, Jeyaseelan R, et al. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: Comparison with interleukin-2. Cell Immunol 1995; 165(2): 289-93.
Marks-Konczalik J, Dubois S, Losi JM, et al. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci USA 2000; 97(21): 11445-50.
Jakobisiak M, Golab J, Lasek W. Interleukin 15 as a promising candidate for tumor immunotherapy. Cytokine Growth Factor Rev 2011; 22(2): 99-108.
Budagian V, Bulanova E, Paus R, Bulfone-Paus S. IL-15/IL-15 receptor biology: A guided tour through an expanding universe. Cytokine Growth Factor Rev 2006; 17(4): 259-80.
Okada S, Han S, Patel ES, Yang LJ, Chang LJ. STAT3 signaling contributes to the high effector activities of interleukin-15-derived dendritic cells. Immunol Cell Biol 2015; 93(5): 461-71.
Zhang JP, Zhang R, Tsao ST, et al. Sequential allogeneic and autologous CAR-T-cell therapy to treat an immune-compromised leukemic patient. Blood Adv 2018; 2(14): 1691-5.
Chang L-J, Zhang C. Infection and replication of Tat-minus human immunodeficiency viruses: Genetic analyses of LTR and tat mutants in primary and long-term human lymphoid cells. Virology 1995; 211: 157-69.
Chang L-J, Liu X, He J. Lentiviral siRNAs targeting multiple highly conserved RNA sequences of human immunodeficiency virus type 1. Gene Ther 2005; 12: 1133-44.
Wang B, He J, Liu C, Chang LJ. An effective cancer vaccine modality: Lentiviral modification of dendritic cells expressing multiple cancer-specific antigens. Vaccine 2006; 24: 3477-89.
Zhang G, Gurtu V, Kain SR, Yan G. Early detection of apoptosis using a fluorescent conjugate of annexin V. Biotechniques 1997; 23(3): 525-31.
Nicholson IC, Lenton KA, Little DJ, et al. Construction and characterisation of a functional CD19 specific single chain Fv fragment for immunotherapy of B lineage leukaemia and lymphoma. Mol Immunol 1997; 34(16-17): 1157-65.
Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 2009; 32(7): 689-702.
Chang L-J, He J. Retroviral vectors for gene therapy of AIDS and cancer. Curr Opin Mol Ther 2001; 3(5): 468-75.
Chang LJ, Zaiss AK. Methods for the preparation and use of lentivirus vectors. Methods Mol Med 2002; 69: 303-18.
Brunner KT, Mauel J, Cerottini JC, Chapuis B. Quantitative assay of the lytic action of immune lymphoid cells on 51-Cr-labelled allogeneic target cells in vitro; inhibition by isoantibody and by drugs. Immunology 1968; 14(2): 181-96.
Henderson MA, Yong CS, Duong CP, et al. Chimeric antigen receptor-redirected T cells display multifunctional capacity and enhanced tumor-specific cytokine secretion upon secondary ligation of chimeric receptor. Immunotherapy 2013; 5(6): 577-90.
Trapani JA, Smyth MJ. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2002; 2(10): 735-47.
Betts MR, Koup RA. Detection of T-cell degranulation: CD107a and b. Methods Cell Biol 2004; 75: 497-512.
Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181(10): 6738-46.
Tao Q, Chen T, Tao L, et al. IL-15 improves the cytotoxicity of cytokine-induced killer cells against leukemia cells by upregulating CD3+CD56+ cells and downregulating regulatory T cells as well as IL-35. J Immunother 2013; 36(9): 462-7.
Hoyos V, Savoldo B, Quintarelli C, 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.
Mishra A, Liu S, Sams GH, et al. Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation. Cancer Cell 2012; 22(5): 645-55.
Williams MT, Yousafzai Y, Cox C, et al. Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia. Blood 2014; 123(20): 3116-27.
Steinway SN, Loughran TP. Targeting IL-15 in large granular lymphocyte leukemia. Expert Rev Clin Immunol 2013; 9(5): 405-8.

© 2022 Bentham Science Publishers | Privacy Policy