High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells
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Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-γ and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.
Keywordscytokine-activated T cells high-affinity T cell receptor cancer immunotherapy TCR-CAT
This study was supported by the Sciences and Technology Program of Guangzhou (No. 201504010016); the National Key R&D program (No. 2016YFC1303404); and the Sciences and Technology Program of Guangzhou (No. 201704020220). The study was also sponsored by the CAS-TWAS President’s PhD Fellowship Program awarded to Synat Kang.
- 1.Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006; 314(5796): 126–129CrossRefGoogle Scholar
- 2.Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, Dudley ME, Feldman SA, Yang JC, Sherry RM, Phan GQ, Hughes MS, Kammula US, Miller AD, Hessman CJ, Stewart AA, Restifo NP, Quezado MM, Alimchandani M, Rosenberg AZ, Nath A, Wang T, Bielekova B, Wuest SC, Akula N, McMahon FJ, Wilde S, Mosetter B, Schendel DJ, Laurencot CM, Rosenberg SA. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36(2): 133–151CrossRefGoogle Scholar
- 3.Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 2011; 29(7): 917–924CrossRefGoogle Scholar
- 4.Tan MP, Dolton GM, Gerry AB, Brewer JE, Bennett AD, Pumphrey NJ, Jakobsen BK, Sewell AK. Human leucocyte antigen class Iredirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells. Clin Exp Immunol 2017; 187(1): 124–137CrossRefGoogle Scholar
- 5.Lanier LL, Yu G, Phillips JH. Analysis of Fc?RIII (CD16) membrane expression and association with CD3? and Fc epsilon RI-? by site-directed mutation. J Immunol 1991; 146(5): 1571–1576Google Scholar
- 7.Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, Hassan NJ, Gavarret J, Bianchi FC, Pumphrey NJ, Ladell K, Gostick E, Sewell AK, Lissin NM, Harwood NE, Molloy PE, Li Y, Cameron BJ, Sami M, Baston EE, Todorov PT, Paston SJ, Dennis RE, Harper JV, Dunn SM, Ashfield R, Johnson A, McGrath Y, Plesa G, June CH, Kalos M, Price DA, Vuidepot A, Williams DD, Sutton DH, Jakobsen BK. Monoclonal TCR-redirected tumor cell killing. Nat Med 2012; 18 (6): 980–987CrossRefGoogle Scholar
- 8.Zhao Y, Bennett AD, Zheng Z, Wang QJ, Robbins PF, Yu LY, Li Y, Molloy PE, Dunn SM, Jakobsen BK, Rosenberg SA, Morgan RA. High-affinity TCRs generated by phage display provide CD4+ T cells with the ability to recognize and kill tumor cell lines. J Immunol 2007; 179(9): 5845–5854CrossRefGoogle Scholar
- 9.Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, June CH. NY-ESO-1-specific TCRengineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 2015; 21(8): 914–921CrossRefGoogle Scholar
- 10.Robbins PF, Kassim SH, Tran TL, Crystal JS, Morgan RA, Feldman SA, Yang JC, Dudley ME, Wunderlich JR, Sherry RM, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Li YF, El-Gamil M, Rosenberg SA. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res 2015; 21 (5): 1019–1027CrossRefGoogle Scholar
- 11.Schmidt-Wolf IG, Lefterova P, Mehta BA, Fernandez LP, Huhn D, Blume KG, Weissman IL, Negrin RS. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol 1993; 21(13): 1673–1679Google Scholar
- 14.Mesiano G, Todorovic M, Gammaitoni L, Leuci V, Giraudo Diego L, Carnevale-Schianca F, Fagioli F, Piacibello W, Aglietta M, Sangiolo D. Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin Biol Ther 2012; 12(6): 673–684CrossRefGoogle Scholar
- 16.Todorovic M, Mesiano G, Gammaitoni L, Leuci V, Giraudo Diego L, Cammarata C, Jordaney N, Carnevale-Schianca F, Gallo S, Fagioli F, Piacibello W, Elia AR, Pignochino Y, Dell’aglio C, Grignani G, Cignetti A, Aglietta M, Sangiolo D. Ex vivo allogeneic stimulation significantly improves expansion of cytokine-induced killer cells without increasing their alloreactivity across HLA barriers. J Immunother 2012; 35(7): 579–586CrossRefGoogle Scholar
- 25.Robbins PF, Li YF, El-Gamil M, Zhao Y, Wargo JA, Zheng Z, Xu H, Morgan RA, Feldman SA, Johnson LA, Bennett AD, Dunn SM, Mahon TM, Jakobsen BK, Rosenberg SA. Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions. J Immunol 2008; 180(9): 6116–6131CrossRefGoogle Scholar
- 26.White SM, Renda M, Nam NY, Klimatcheva E, Zhu Y, Fisk J, Halterman M, Rimel BJ, Federoff H, Pandya S, Rosenblatt JD, Planelles V. Lentivirus vectors using human and simian immunodeficiency virus elements. J Virol 1999; 73(4): 2832–2840Google Scholar
- 28.Elia AR, Circosta P, Sangiolo D, Bonini C, Gammaitoni L, Mastaglio S, Genovese P, Geuna M, Avolio F, Inghirami G, Tarella C, Cignetti A. Cytokine-induced killer cells engineered with exogenous T-cell receptors directed against melanoma antigens: enhanced efficacy of effector cells endowed with a double mechanism of tumor recognition. Hum Gene Ther 2015; 26(4): 220–231CrossRefGoogle Scholar
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