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Engineering CAR-expressing natural killer cells with cytokine signaling and synthetic switch for an off-the-shelf cell-based cancer immunotherapy

Published online by Cambridge University Press:  27 March 2019

Yun Qu
Affiliation:
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
Elizabeth Siegler
Affiliation:
Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
Chumeng Cheng
Affiliation:
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA
Jiangyue Liu
Affiliation:
Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA 90089, USA
Gunce Cinay
Affiliation:
Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
Neelesh Bagrodia
Affiliation:
Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
Pin Wang
Affiliation:
Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA
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Abstract

Immune cells can be genetically engineered with a synthetic chimeric antigen receptor (CAR) to eliminate cancer cells, but clinical efficacy in solid tumors has been disappointing due in part to the immunosuppressive tumor microenvironment (TME). Additionally, the cost and logistical issues of personalized medicine necessitate the creation of an off-the-shelf CAR therapy. Synthetic biology tools were implemented in addressing these problems: an anti-mesothelin CAR, membrane-bound IL-15/IL-15Rα complex, and inducible caspase 9 “kill switch” were expressed in natural killer cells for tumor-targeting capabilities, immunostimulatory effects, and safety in treating a preclinical model of ovarian cancer with a renewable, allogenic cell therapy.

Type
Synthetic Biology Research Letter
Copyright
Copyright © Materials Research Society 2019 

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Footnotes

*

Authors contributed equally to this work.

References

1.Ho, P. and Chen, Y.: Mammalian synthetic biology in the age of genome editing and personalized medicine. Curr. Opin. Chem. Biol. 40, 57 (2017).CrossRefGoogle ScholarPubMed
2.Esensten, J., Bluestone, J., and Lim, W.: Engineering therapeutic T cells: from synthetic biology to clinical trials. Annu. Rev. Pathol. 12, 305 (2017).CrossRefGoogle ScholarPubMed
3.Sadelain, M., Brentjens, R., and Rivière, I.: The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388 (2013).CrossRefGoogle ScholarPubMed
4.Koneru, M., Purdon, T., Spriggs, D., Koneru, S., and Brentjens, R.: IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 23, e994446 (2015).CrossRefGoogle Scholar
5.Hurton, L., Singh, H., Najjar, A., Switzer, K., Mi, T., Maiti, S., Olivares, S., Rabinovich, B., Huls, H., Forget, M., Datar, V., Kebriaei, P., Lee, D., Champlin, R., and Cooper, L.: Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl. Acad. Sci. USA 113, 7788 (2016).CrossRefGoogle ScholarPubMed
6.Wu, C., Roybal, K., Puchner, E., Onuffer, J., and Lim, W.: Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015).CrossRefGoogle ScholarPubMed
7.Straathof, K., Pule, M., Yotnada, P., Dotti, G., Vanin, E., Brenner, M., Heslop, H., Spencer, D., and Rooney, C.: An inducible caspase 9 safety switch for T-cell therapy. Gene Ther. 105, 4247 (2005).Google ScholarPubMed
8.Diaconu, I., Ballard, B., Zhang, M., Chen, Y., West, J., Dott, G., and Savoldo, B.: Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol. Ther. 25, 580 (2017).CrossRefGoogle ScholarPubMed
9.Bonifant, C. L., Jackson, H. J., Brentjens, R. J., and Curran, K. J.: Toxicity and management in CAR T-cell therapy. Mol. Ther. Oncolytics 3, 16011 (2016).CrossRefGoogle ScholarPubMed
10.Rezvani, K. and Rouce, R. H.: The application of natural killer cell immunotherapy for the treatment of cancer. Front Immunol. 6, 578 (2015).CrossRefGoogle ScholarPubMed
11.Suck, G., Odendahl, M., Nowakowska, P., Seidl, C., Wels, W. S., Klingemann, H.G., and Tonn, T.: NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol. Immunother. 65, 485 (2016).CrossRefGoogle ScholarPubMed
12.Zhang, C., Oberoi, P., Oelsner, S., Waldmann, A., Linder, A., Tonn, T., and Wels, W.S.: Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 18, 533 (2017).CrossRefGoogle Scholar
13.Zhang, J., Sun, R., Wei, H., Zhang, J., and Tian, Z.: Characterization of interleukin-15 gene-modified human natural killer cells: implications for adoptive cellular immunotherapy. Haematologica 89, 338 (2004).Google ScholarPubMed
14.Sahm, C., Schönfeld, K., and Wels, W.: Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Cancer Immunol. Immunother. 61, 1451 (2012).CrossRefGoogle ScholarPubMed
15.Imamura, M., Shook, D., Kamiya, T., Shimasaki, N., Chai, S.M., Coustan-Smith, E., Imai, C., and Campana, D.: Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood 124, 1081 (2014).CrossRefGoogle ScholarPubMed
16.Sato, N., Patel, H. J., Waldmann, T. A., and Tagaya, Y.: The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc. Natl. Acad. Sci. USA 104, 588 (2007).CrossRefGoogle Scholar
17.Hassan, R., Bera, T., and Pastan, I.: Mesothelin: a new target for immunotherapy. Clin. Cancer Res. 10, 3937 (2004).CrossRefGoogle ScholarPubMed
18.Carpenito, C., Milone, M. C., Hassan, R., Simonet, J. C., Lakhal, M., Suhoski, M. M., Varela-Rohena, A., Haines, K. M., Heitjan, D. F., Albelda, S. M., Carroll, R. G., Riley, J. L., Pastan, I., and June, C. H.: Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl. Acad. Sci. USA 106, 3360 (2009).CrossRefGoogle Scholar
19.Han, X., Bryson, P., Zhao, Y., Cinay, G., Li, S., Guo, Y., Siriwon, N., and Wang, P.: Masked chimeric antigen receptor for tumor-specific activation. Mol. Ther. 25, 274 (2017).CrossRefGoogle ScholarPubMed
20.Tagaya, Y., Bamford, R., DeFilippis, A., and Waldmann, T.: IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4, 329 (1996).CrossRefGoogle ScholarPubMed
21.Guo, Y., Luan, L., Rabacal, W., Bohannon, J., Fensterheim, B., Hernandez, A., and Sherwood, E.: IL-15 superagonist-mediated immunotoxicity: role of NK cells and IFN-γ. J. Immunol. 195, 2353 (2015).CrossRefGoogle ScholarPubMed
22.Mah, A. and Cooper, M.: Metabolic Regulation of Natural Killer Cell IFN-γ Production. Crit. Rev. Immunol. 36, 131 (2016).CrossRefGoogle ScholarPubMed
23.Boissel, L., Betancur-Boissel, M., Lu, W., Krause, D., Van Etten, R., Wels, W., and Klingemann, H.: Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. OncoImmunology 2, e26527 (2013).CrossRefGoogle ScholarPubMed
24.Liu, Y., Fang, J., Kim, Y., Wong, M., and Wang, P.: Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Cell 167, 419 (2016).Google Scholar
25.Kloss, C., Condomines, M., Cartellieri, M., Bachmann, M., and Sadelain, M.: Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71 (2013).CrossRefGoogle ScholarPubMed
26.Zah, E., Lin, M., Silva-Benedict, A., Jensen, M., and Chen, Y.: T cells expressing CD19/CD20 bi-specific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498 (2016).CrossRefGoogle Scholar
27.Roybal, K., Williams, J., Morsut, M., Rupp, L., Kolinko, I., Choe, J., Walker, W., McNally, K., and Lim, W.: Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Mol. Pharm. 11, 1651 (2014).Google Scholar

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