Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters

Nature Communications - Tập 10 Số 1
Yong Gu Lee1, Haiyan Chu2, Yingjuan Lu2, Christopher P. Leamon2, Madduri Srinivasarao3, Karson S. Putt3, Philip S. Low3
1Department of Chemistry, Purdue University, West Lafayette, IN, 47907 USA
2Endocyte Inc., 3000 Kent Ave, West Lafayette, IN, 47906, USA
3Purdue Institute for Drug Discovery and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA

Tóm tắt

AbstractAlthough chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.

Từ khóa


Tài liệu tham khảo

Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73–95ra73 (2011).

Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients. J. Clin. Investig. 121, 1822–1826 (2011).

Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. New Engl. J. Med. 371, 1507–1517 (2014).

Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. New Engl. J. Med. 365, 725–733 (2011).

Bonifant, C. L., Jackson, H. J., Brentjens, R. J. & Curran, K. J. Toxicity and management in CAR T-cell therapy. Mol. Ther. Oncolytics. 3, 16011 (2016).

Morgan, R. A. et al. 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 (2010).

Fitzgerald, J. C. et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit. care Med. 45, e124–e131 (2017).

Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. (Sudbury, Mass) 20, 119 (2014).

Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).

Yokota, S. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371, 998–1006 (2008).

Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra225–224ra225 (2014).

Budde, L. E. et al. Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PloS one 8, e82742 (2013).

Tummers, Q. R. et al. Intraoperative imaging of folate receptor alpha positive ovarian and breast cancer using the tumor specific agent EC17. Oncotarget 7, 32144 (2016).

Dainty, L. A. et al. Overexpression of folate binding protein and mesothelin are associated with uterine serous carcinoma. Gynecol. Oncol. 105, 563–570 (2007).

Kelemen, L. E. The role of folate receptor α in cancer development, progression and treatment: cause, consequence or innocent bystander? Int. J. cancer 119, 243–250 (2006).

O’Shannessy, D. J., Somers, E. B., Maltzman, J., Smale, R. & Fu, Y.-S. Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. + 1, 22 (2012).

Toffoli, G. et al. Overexpression of folate binding protein in ovarian cancers. Int. J. cancer 74, 193–198 (1997).

Midelfort, K. et al. Substantial energetic improvement with minimal structural perturbation in a high affinity mutant antibody. J. Mol. Biol. 343, 685–701 (2004).

Kim, M. S. et al. Redirection of genetically engineered CAR-T cells using bifunctional small molecules. J. Am. Chem. Soc. 137, 2832–2835 (2015).

Lee, Y. G. et al. Use of a single CAR T cell and several bispecific adapters facilitates eradication of multiple antigenically different solid tumors. Cancer Res. 79, 387–396 (2019).

Giavridis, T. et al. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

Sentman, M.-L. et al. Mechanisms of Acute Toxicity in NKG2D Chimeric Antigen Receptor T Cell–Treated Mice. J. Immunol. 197, 4674–4685 (2016).

Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

van der Stegen, S. J. et al. Preclinical in vivo modeling of cytokine release syndrome induced by ErbB-retargeted human T cells: identifying a window of therapeutic opportunity? J. Immunol. 191, 4589–4598 (2013).

Wunderlich, M. et al. A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti–IL-6R treatment. JCI insight 1, e88181 (2016).

Kenderian S. S. et al. Ruxolitinib prevents cytokine release syndrome after CART cell therapy without impairing the anti-tumor effect in a xenograft model. Blood 128, 652 (2016).

Birn, H., Spiegelstein, O., Christensen, E. I. & Finnell, R. H. Renal tubular reabsorption of folate mediated by folate binding protein 1. J. Am. Soc. Nephrol. 16, 608–615 (2005).

Corrocher, R. et al. Differential binding of folates by rat renal cortex brush border and basolateral membrane preparations. Proc. Soc. Exp. Biol. Med. 178, 73–84 (1985).

Morshed, K. M., Ross, D. M. & McMartin, K. E. Folate transport proteins mediate the bidirectional transport of 5-methyltetrahydrofolate in cultured human proximal tubule cells. J. Nutr. 127, 1137–1147 (1997).

Turtle, C. J. et al. CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J. Clin. Investig. 126, 2123–2138 (2016).

Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682 (2006).

Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492 (2011).

Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy. Blood 130, 2295–2306 (2017).

Cao, Y. et al. Design of switchable chimeric antigen receptor T cells targeting breast cancer. Angew. Chem. 128, 7646–7650 (2016).

Lohmueller J. J., Ham J. D., Kvorjak M., Finn O. J. mSA2 affinity-enhanced biotin-binding CAR T cells for universal tumor targeting. Oncoimmunology 7, e1368604 (2017).

Ma, J. S. et al. Versatile strategy for controlling the specificity and activity of engineered T cells. Proc. Natl Acad. Sci. USA 113, E450–E458 (2016).

Rodgers, D. T. et al. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc. Natl Acad. Sci. USA 113, E459–E468 (2016).

Tamada, K. et al. Redirecting gene-modified T cells toward various cancer types using tagged antibodies. Clin. Cancer Res. 18, 6436–6445 (2012).

Urbanska, K. et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 72, 1844–1852 (2012).

Correia, I. Stability of IgG isotypes in serum. In: MAbs (ed^(eds). Taylor & Francis (2010).

Huang, L., Lu, J., Wroblewski, V. J., Beals, J. M. & Riggin, R. M. In vivo deamidation characterization of monoclonal antibody by LC/MS/MS. Anal. Chem. 77, 1432–1439 (2005).

Mankarious, S. et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J. Lab. Clin. Med. 112, 634–640 (1988).

Doyle, P. J., Lipetskaia, L., Duecy, E., Buchsbaum, G. & Wood, R. W. Sodium fluorescein use during intraoperative cystoscopy. Obstet. Gynecol. 125, 548–550 (2015).

Keerl, R., Weber, R. K., Draf, W., Wienke, A. & Schaefer, S. D. Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States. Laryngoscope 114, 266–272 (2004).

Leamon, C. P. et al. Impact of high and low folate diets on tissue folate receptor levels and antitumor responses toward folate-drug conjugates. J. Pharmacol. Exp. Ther. 327, 918–925 (2008).

Orellana, E. A. et al. FolamiRs: Ligand-targeted, vehicle-free delivery of microRNAs for the treatment of cancer. Sci. Transl. Med. 9, eaam9327 (2017).