Modulation of chimeric antigen receptor surface expression by a small molecule switch
Tóm tắt
Engineered therapeutic cells have attracted a great deal of interest due to their potential applications in treating a wide range of diseases, including cancer and autoimmunity. Chimeric antigen receptor (CAR) T-cells are designed to detect and kill tumor cells that present a specific, predefined antigen. The rapid expansion of targeted antigen beyond CD19, has highlighted new challenges, such as autoactivation and T-cell fratricide, that could impact the capacity to manufacture engineered CAR T-cells. Therefore, the development of strategies to control CAR expression at the surface of T-cells and their functions is under intense investigations. Here, we report the development and evaluation of an off-switch directly embedded within a CAR construct (SWIFF-CAR). The incorporation of a self-cleaving degradation moiety controlled by a protease/protease inhibitor pair allowed the ex vivo tight and reversible control of the CAR surface presentation and the subsequent CAR-induced signaling and cytolytic functions of the engineered T-cells using the cell permeable Asunaprevir (ASN) small molecule. The strategy described in this study could, in principle, be broadly adapted to CAR T-cells development to circumvent some of the possible hurdle of CAR T-cell manufacturing. This system essentially creates a CAR T-cell with an integrated functional rheostat.
Tài liệu tham khảo
Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward. Nat Rev Clin Oncol. 2016;13(6):370–83.
Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31–46.
Mamonkin M, Mukherjee M, Srinivasan M, Sharma S, Gomes-Silva D, Mo F, Krenciute G, Orange JS, Brenner MK. Reversible transgene expression reduces fratricide and permits 4-1BB Costimulation of CAR T cells directed to T-cell malignancies. Cancer Immunol Res. 2018;6(1):47–58.
Png YT, Vinanica N, Kamiya T, Shimasaki N, Coustan-Smith E, Campana D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Adv. 2017;1(25):2348–60.
Duong CP, Westwood JA, Berry LJ, Darcy PK, Kershaw MH. Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer. Immunotherapy. 2011;3(1):33–48.
Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med. 2013;5(215):215ra172.
Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, Corder A, Schonfeld K, Koch J, Dotti G, et al. TanCAR: a novel bispecific chimeric antigen receptor for Cancer immunotherapy. Mol Ther Nucleic Acids. 2013;2:e105.
Juillerat A, Marechal A, Filhol JM, Valogne Y, Valton J, Duclert A, Duchateau P, Poirot L. An oxygen sensitive self-decision making engineered CAR T-cell. Sci Rep. 2017;7:39833.
Juillerat A, Marechal A, Filhol JM, Valton J, Duclert A, Poirot L, Duchateau P. Design of chimeric antigen receptors with integrated controllable transient functions. Sci Rep. 2016;6:18950.
Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med. 1998;188(4):619–26.
Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, Lim WA. Engineering customized cell sensing and response behaviors using synthetic notch receptors. Cell. 2016;164(4):780–91.
Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, Lim WA. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell. 2016;164(4):770–9.
Wilkie S, van Schalkwyk MC, Hobbs S, Davies DM, van der Stegen SJ, Pereira AC, Burbridge SE, Box C, Eccles SA, Maher J. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling. J Clin Immunol. 2012;32(5):1059–70.
Sakemura R, Terakura S, Watanabe K, Julamanee J, Takagi E, Miyao K, Koyama D, Goto T, Hanajiri R, Nishida T, et al. A Tet-on inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol Res. 2016;4(8):658–68.
Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015;350(6258):aab4077.
Viaud S, Ma JSY, Hardy IR, Hampton EN, Benish B, Sherwood L, Nunez V, Ackerman CJ, Khialeeva E, Weglarz M, et al. Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory. Proc Natl Acad Sci U S A. 2018;115(46):E10898–906.
Mata M, Gerken C, Nguyen P, Krenciute G, Spencer DM, Gottschalk S. Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov. 2017;7(11):1306–19.
Chung HK, Jacobs CL, Huo Y, Yang J, Krumm SA, Plemper RK, Tsien RY, Lin MZ. Tunable and reversible drug control of protein production via a self-excising degron. Nat Chem Biol. 2015;11(9):713–20.
Eley T, He B, Huang SP, Li W, Pasquinelli C, Rodrigues AD, Grasela DM, Bertz RJ. Pharmacokinetics of the NS3 protease inhibitor, Asunaprevir (ASV, BMS-650032), in phase I studies in subjects with or without chronic hepatitis C. Clin Pharmacol Drug Dev. 2013;2(4):316–27.
Pasquinelli C, McPhee F, Eley T, Villegas C, Sandy K, Sheridan P, Persson A, Huang SP, Hernandez D, Sheaffer AK, et al. Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C. Antimicrob Agents Chemother. 2012;56(4):1838–44.
McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G, Levine S, Chaniewski S, Yu F, Barry D, et al. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor Asunaprevir (BMS-650032). Antimicrob Agents Chemother. 2012;56(10):5387–96.
Xiao X, Ho M, Zhu Z, Pastan I, Dimitrov DS. Identification and characterization of fully human anti-CD22 monoclonal antibodies. MAbs. 2009;1(3):297–303.
Mihara K, Yanagihara K, Takigahira M, Imai C, Kitanaka A, Takihara Y, Kimura A. Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin lymphoma. J Immunother. 2009;32(7):737–43.
Arcangeli S, Rotiroti MC, Bardelli M, Simonelli L, Magnani CF, Biondi A, Biagi E, Tettamanti S, Varani L. Balance of anti-CD123 chimeric antigen receptor binding affinity and density for the targeting of acute myeloid leukemia. Mol Ther. 2017;25(8):1933–45.
Caruso HG, Hurton LV, Najjar A, Rushworth D, Ang S, Olivares S, Mi T, Switzer K, Singh H, Huls H, et al. Tuning sensitivity of CAR to EGFR density limits recognition of Normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75(17):3505–18.
Drent E, Themeli M, Poels R, de Jong-Korlaar R, Yuan H, de Bruijn J, Martens ACM, Zweegman S, van de Donk N, Groen RWJ, et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol Ther. 2017;25(8):1946–58.
Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, Lopomo P, Vigny M, Fry TJ, Orentas RJ, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25(9):2189–201.
Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8+ T cells. J Immunol. 2015;194(3):911–20.
Bonger KM, Chen LC, Liu CW, Wandless TJ. Small-molecule displacement of a cryptic degron causes conditional protein degradation. Nat Chem Biol. 2011;7(8):531–7.
Nishimura K, Fukagawa T, Takisawa H, Kakimoto T, Kanemaki M. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat Methods. 2009;6(12):917–22.
Pratt MR, Schwartz EC, Muir TW. Small-molecule-mediated rescue of protein function by an inducible proteolytic shunt. Proc Natl Acad Sci U S A. 2007;104(27):11209–14.
Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci U S A. 2001;98(15):8554–9.
Tae HS, Sundberg TB, Neklesa TK, Noblin DJ, Gustafson JL, Roth AG, Raina K, Crews CM. Identification of hydrophobic tags for the degradation of stabilized proteins. Chembiochem. 2012;13(4):538–41.
Lin MZ, Glenn JS, Tsien RY. A drug-controllable tag for visualizing newly synthesized proteins in cells and whole animals. Proc Natl Acad Sci U S A. 2008;105(22):7744–9.
Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, Odak A, Gonen M, Sadelain M. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.
Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJC, Giavridis T, Mansilla-Soto J, Eyquem J, Zhao Z, Whitlock BM, Miele MM, et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019;568(7750):112–6.
Drent E, Poels R, Mulders MJ, van de Donk N, Themeli M, Lokhorst HM, Mutis T. Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design. PLoS One. 2018;13(5):e0197349.
Valton J, Guyot V, Boldajipour B, Sommer C, Pertel T, Juillerat A, Duclert A, Sasu BJ, Duchateau P, Poirot L. A versatile safeguard for chimeric antigen receptor T-cell immunotherapies. Sci Rep. 2018;8(1):8972.
Marin V, Cribioli E, Philip B, Tettamanti S, Pizzitola I, Biondi A, Biagi E, Pule M. Comparison of different suicide-gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods. 2012;23(6):376–86.
Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, Potrel P, Bas C, Lemaire L, Galetto R, et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 2015;75(18):3853–64.
Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, Heslop HE, Spencer DM, Rooney CM. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105(11):4247–54.