Abstract
Recent progress in chimeric antigen receptor-modified T-cell (CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment (scFv) sequence specifically targeting the MUC1 antigen and co-expressing interleukin (IL) 12 (named SM3-CAR). The other CAR-T cell line carried the SM3 scFv sequence modified to improve its binding to MUC1 antigen (named pSM3-CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1+ seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that pSM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.
Article PDF
Similar content being viewed by others
References
Abken, H. (2015). Adoptive therapy with CAR redirected T cells: the challenges in targeting solid tumors. Immunotherapy 7, 535–544.
Acres, B., Lacoste G., and Limacher J.M. (2015). Targeted immunotherapy designed to treat MUC1-expressing solid tumour. Curr Top Microbiol Immunol doi: 10.1007/82_2015_429.
Acres, B., and Limacher, J.M. (2005). MUC1 as a target antigen for cancer immunotherapy. Expert Rev Vaccines 4, 493–502.
Barnd, D.L., Lan, M.S., Metzgar, R.S., and Finn, O.J. (1989). Specific, major histocompatibility complex-unrestricted recognition of tumor- associated mucins by human cytotoxic T cells. Proc Natl Acad Sci USA 86, 7159–7163.
Barrett, D.M., Teachey, D.T., and Grupp S.A. (2014). Toxicity management for patients receiving novel T-cell engaging therapies. Curr Opin Pediatr 26, 43–49.
Beatson, R., Maurstad G., Picco G., Arulappu A., Coleman J., Wandell, H. H., Clausen, H., Mandel, U., Taylor-Papadimitriou, J., Sletmoen, M., and Burchell J.M. (2015). The breast cancer-associated glycoforms of MUC1, MUC1-Tn and sialyl-Tn, are expressed in COSMC wild-type cells and bind the C-type lectin MGL. PLoS One 10, e0125994.
Beatson, R.E., Taylor-Papadimitriou, J., and Burchell, J.M. (2010). MUC1 immunotherapy. Immunotherapy 2, 305–327.
Blixt, O., Bueti, D., Burford, B., Allen, D., Julien, S., Hollingsworth, M., Gammerman, A., Fentiman, I., Taylor-Papadimitriou, J., and Burchell J. M. (2011). Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis. Breast Cancer Res 13, R25.
Burchell, J., and Taylor-Papadimitriou, J. (1993). Effect of modification of carbohydrate side chains on the reactivity of antibodies with core-protein epitopes of the MUC1 gene product. Epithelial Cell Biol 2, 155–162.
Chinnasamy, D., Yu, Z., Kerkar, S.P., Zhang, L., Morgan, R.A., Restifo, N.P., and Rosenberg, S.A. (2012). Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin Cancer Res 18, 1672–1683.
Chmielewski, M., and Abken, H. (2015). TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther 15, 1145–1154.
Chmielewski, M., Hombach, A.A., and Abken H. (2014). Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev 257, 83–90.
Condomines, M., Arnason, J., Benjamin R., Gunset G., Plotkin, J., and Sadelain, M. (2015). Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition. PLoS One 10, e0130518.
Correa, I., Plunkett T., Vlad, A., Mungul, A., Candelora-Kettel, J., Burchell, J.M., Taylor-Papadimitriou, J., and Finn, O.J. (2003). Form and pattern of MUC1 expression on T cells activated in vivo or in vitro suggests a function in T-cell migration. Immunology 108, 32–41.
Craddock, J.A., Lu, A., Bear, A., Pule, M., Brenner, M.K., Rooney, C.M., and Foster, A.E. (2010). Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 33, 780–788.
Dalziel, M., Whitehouse, C., McFarlane, I., Brockhausen, I., Gschmeissner, S., Schwientek, T., Clausen, H., Burchell, J.M., and Taylor-Papadimitriou, J. (2001). The relative activities of the C2GnT1 and ST3Gal-I glycosyltransferases determine O-glycan structure and expression of a tumor-associated epitope on MUC1. J Biol Chem 276, 11007–11015.
Davila, M.L., and Brentjens, R. (2013). Chimeric antigen receptor therapy for chronic lymphocytic leukemia: what are the challenges–Hematol Oncol Clin North Am 27, 341–353.
Dhani, N., Fyles, A., Hedley, D., and Milosevic, M. (2015). The clinical significance of hypoxia in human cancers. Semin Nucl Med 45, 110–121.
Gendler, S.J., Spicer, A.P., Lalani, E.N., Duhig, T., Peat, N., Burchell, J., Pemberton, L., Boshell, M., and Taylor-Papadimitriou, J. (1991). Structure and biology of a carcinoma-associated mucin, MUC1. Am Rev Respir Dis 144, S42–S47.
Gheybi, E., Amani, J., Salmanian, A.H., Mashayekhi, F., and Khodi, S. (2014). Designing a recombinant chimeric construct contain MUC1 and HER2 extracellular domain for prediagnostic breast cancer. Tumour Biol 35, 11489–11497.
Granowska, M., Britton, K.E., Mather, S.J., Lowe, D.G., Ellison, D., Bomanji, J., Burchell, J., Taylor-Papadimitriou, J., Hudson, C.R., and Shepherd, J.H. (1993). Radioimmunoscintigraphy with technetium- 99m-labelled monoclonal antibody, SM3, in gynaecological cancer. Eur J Nucl Med 20, 483–489.
Granowska, M., Mather, S.J., Jobling, T., Naeem, M., Burchell, J., Taylor-Papadimitriou, J., Shepherd, J., and Britton, K.E. (1990). Radiolabelled stripped mucin, SM3, monoclonal antibody for immunoscintigraphy of ovarian tumours. Int J Biol Markers 5, 89–96.
Gross, T., Wagner, A., Ugurel, S., Tilgen, W., and Reinhold, U. (2001). Identification of TIA-1+ and granzyme B+ cytotoxic T cells in lichen sclerosus et atrophicus. Dermatology 202, 198–202.
Grupp, S.A., Kalos, M., Barrett, D., Aplenc, R., Porter, D.L., Rheingold, S.R., Teachey, D.T., Chew, A., Hauck, B., Wright, J.F., Milone, M.C., Levine, B.L., and June, C.H. (2013). Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368, 1509–1518.
Hillerdal, V., and Essand, M. (2015). Chimeric antigen receptor-engineered T cells for the treatment of metastatic prostate cancer. BioDrugs 29, 75–89.
Jensen, M.C., and Riddell, S.R. (2014). Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunol Rev 257, 127–144.
Jonckheere, N., and van Seuningen, I. (2010). The membrane-bound mucins: from cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie 92, 1–11.
Jonnalagadda, M., Mardiros, A., Urak, R., Wang, X., Hoffman, L.J., Bernanke, A., Chang, W.C., Bretzlaff, W., Starr, R., Priceman, S., Ostberg, J.R., Forman, S.J., and Brown, C.E. (2015). Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther 23, 757–768.
Kakarla, S., and Gottschalk, S. (2014). CAR T cells for solid tumors: armed and ready to go–Cancer J 20, 151–155.
Kimura, T., and Finn, O.J. (2013). MUC1 immunotherapy is here to stay. Expert Opin Biol Ther 13, 35–49.
Koehler, H., Kofler, D., Hombach, A., and Abken, H. (2007). CD28 costimulation overcomes transforming growth factor-beta-mediated repression of proliferation of redirected human CD4+ and CD8+ T cells in an antitumor cell attack. Cancer Res 67, 2265–2273.
Kofler, D.M., Chmielewski, M., Rappl, G., Hombach, A., Riet, T., Schmidt, A., Hombach, A. A., Wendtner, C.M., and Abken, H. (2011). CD28 costimulation Impairs the efficacy of a redirected T-cell antitumor attack in the presence of regulatory T cells which can be overcome by preventing Lck activation. Mol Ther 19, 760–767.
Kruger, W., Kroger, N., and Zander, A.R. (2000). MUC1 expression in hemopoietic tissues. J Hematother Stem Cell Res 9, 409–410.
Lamers, C.H., Sleijfer, S., van Steenbergen, S., van Elzakker, P., van Krimpen, B., Groot, C., Vulto, A., den Bakker, M., Oosterwijk, E., Debets, R., and Gratama, J.W. (2013). Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther 21, 904–912.
Lamers, C.H., van Steenbergen-Langeveld, S., van Brakel, M., Groot-van Ruijven, C.M., van Elzakker, P.M., van Krimpen, B., Sleijfer, S., and Debets, R. (2014). T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. Hum Gene Ther Methods 25, 345–357.
Lutschg, V., Boucke, K., Hemmi, S., and Greber, U.F. (2011). Chemotactic antiviral cytokines promote infectious apical entry of human adenovirus into polarized epithelial cells. Nat Commun 2, 391.
Madsen, C.B., Wandall, H.H., and Pedersen, A.E. (2013). Potential for novel MUC1 glycopeptide-specific antibody in passive cancer immunotherapy. Immunopharmacol Immunotoxicol 35, 649–652.
Maher, J., and Wilkie, S. (2009). CAR mechanics: driving T cells into the MUC of cancer. Cancer Res 69, 4559–4562.
Maude, S.L., Frey, N., Shaw, P.A., Aplenc, R., Barrett, D.M., Bunin, N. J., Chew, A., Gonzalez,V.E., Zheng Z.,, Lacey, S.F., Mahnke,Y.D., Melenhorst, J.J., Rheingold, S.R., Shen, A., Teachey, D.T., Levine, B.L., June, C.H., Porter, D.L., and Grupp, S.A. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371,1507–1517.
Maude, S.L., Shpall, E.J., and Grupp, S.A. (2014). Chimeric antigen receptor T-cell therapy for ALL. Hematology Am Soc Hematol Educ Program 2014, 559–564.
Maude, S.L., Teachey, D.T., Porter, D.L., and Grupp, S.A. (2015). CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125, 4017–4023.
Morgan, R.A., Yang, J.C., Kitano, M., Dudley, M.E., Laurencot, C.M. and Rosenberg, S.A. (2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18, 843–851.
Mungul, A., Cooper, L., Brockhausen, I., Ryder, K., Mandel, U., Clausen, H., Rughetti, A., Miles, D.W., Taylor-Papadimitriou, J., and Burchell, J.M. (2004). Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice. Int J Oncol 25, 937–943.
Oleinika, K., Nibbs, R.J., Graham, G.J., and Fraser, A.R. (2013). Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol 171, 36–45.
Peat, N., Gendler, S.J., Lalani, N., Duhig, T., and Taylor-Papadimitriou, J. (1992). Tissue-specific expression of a human polymorphic epithelial mucin (MUC1) in transgenic mice. Cancer Res 52, 1954–1960.
Pegram, H.J., Lee, J.C., Hayman, E.G., Imperato, G.H., Tedder, T.F., Sadelain, M., and Brentjens, R.J. (2012). Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141.
Pegram, H.J., Park, J.H., and Brentjens, R.J. (2014). CD28z CARs and armored CARs. Cancer J 20, 127–133.
Pegram, H.J., Purdon, T.J., van Leeuwen, D.G., Curran, K.J., Giralt, S.A., Barker, J.N., and Brentjens, R.J. (2015). IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422.
Porter, D.L., Levine, B.L., Kalos, M., Bagg, A., and June, C.H. (2011). Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365, 725–733.
Sakaguchi, S., Ono, M., Setoguchi, R., Yagi, H., Hori, S., Fehervari, Z., Shimizu, J., Takahashi, T., and Nomura, T. (2006). Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212, 8–27.
Tang, C.K., and Apostolopoulos, V. (2008). Strategies used for MUC1 immunotherapy: preclinical studies. Expert Rev Vaccines 7, 951–962.
Tang, C.K., Katsara, M., and Apostolopoulos, V. (2008). Strategies used for MUC1 immunotherapy: human clinical studies. Expert Rev Vaccines 7, 963–975.
Tarp, M.A., Sorensen, A.L., Mandel, U., Paulsen, H., Burchell, J., Taylor-Papadimitriou, J., and Clausen, H. (2007). Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat. Glycobiology 17, 197–209.
Taylor-Papadimitriou, J., Burchell, J.M., Plunkett, T., Graham, R., Correa, I., Miles, D., and Smith, M. (2002). MUC1 and the immunobiology of cancer. J Mammary Gland Biol Neoplasia 7, 209–221.
Taylor-Papadimitriou, J., D’Souza, B., Burchell, J., Kyprianou, N., and Berdichevsky, F. (1993). The role of tumor-associated antigens in the biology and immunotherapy of breast cancer. Ann N YA cad Sci 698, 31–47.
Turtle, C.J. (2014). Chimeric antigen receptor modified T cell therapy for B cell malignancies. Int J Hematol 99, 132–140.
Wilkie, S., Picco, G., Foster, J., Davies, D.M., Julien, S., Cooper, L., Arif, S., Mather, S.J., Taylor-Papadimitriou, J.
Burchell, J.M., and Maher, J. (2008). Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol 180, 4901-4909.
Yang, E., Hu, X.F., and Xing P.X. (2007). Advances of MUC1 as a target for breast cancer immunotherapy. Histol Histopathol 22, 905–922.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
You, F., Jiang, L., Zhang, B. et al. Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci. China Life Sci. 59, 386–397 (2016). https://doi.org/10.1007/s11427-016-5024-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-016-5024-7