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Targeting of Tumor-Associated Glycoforms of MUC1 with CAR T Cells

2016; Cell Press; Volume: 45; Issue: 5 Linguagem: Inglês

10.1016/j.immuni.2016.10.014

1097-4180

John Maher, Scott Wilkie, David M. Davies, Sefina Arif, Gianfranco Picco, Sylvain Julien, Julie Foster, Joy Burchell, Joyce Taylor‐Papadimitriou,

Immune Cell Function and Interaction

We read with interest the manuscript by June and colleagues published recently in Immunity in which they describe targeting of aberrantly glycosylated tumor-associated cell membrane mucin MUC1 using chimeric antigen receptor-engineered human T cells (Posey et al., 2016Posey Jr., A.D. Schwab R.D. Boesteanu A.C. Steentoft C. Mandel U. Engels B. Stone J.D. Madsen T.D. Schreiber K. Haines K.M. et al.Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.Immunity. 2016; 44: 1444-1454Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). In that study, the authors used a second generation 4-1BB costimulatory-molecule-based chimeric antigen receptor (CAR) (Imai et al., 2004Imai C. Mihara K. Andreansky M. Nicholson I.C. Pui C.H. Geiger T.L. Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.Leukemia. 2004; 18: 676-684Crossref PubMed Scopus (540) Google Scholar) in which targeting was achieved using a single-chain variable fragment (scFv) derived from the 5E5 antibody. This CAR selectively binds MUC1 that carries the Tn or sialyl (S)Tn glycan. Both of these truncated glycans are aberrantly expressed on the MUC1 glycoprotein in a spectrum of malignancies and consequently represent attractive targets for immunotherapeutic exploitation. We read with interest the manuscript by June and colleagues published recently in Immunity in which they describe targeting of aberrantly glycosylated tumor-associated cell membrane mucin MUC1 using chimeric antigen receptor-engineered human T cells (Posey et al., 2016Posey Jr., A.D. Schwab R.D. Boesteanu A.C. Steentoft C. Mandel U. Engels B. Stone J.D. Madsen T.D. Schreiber K. Haines K.M. et al.Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.Immunity. 2016; 44: 1444-1454Abstract Full Text Full Text PDF PubMed Scopus (366) Google Scholar). In that study, the authors used a second generation 4-1BB costimulatory-molecule-based chimeric antigen receptor (CAR) (Imai et al., 2004Imai C. Mihara K. Andreansky M. Nicholson I.C. Pui C.H. Geiger T.L. Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia.Leukemia. 2004; 18: 676-684Crossref PubMed Scopus (540) Google Scholar) in which targeting was achieved using a single-chain variable fragment (scFv) derived from the 5E5 antibody. This CAR selectively binds MUC1 that carries the Tn or sialyl (S)Tn glycan. Both of these truncated glycans are aberrantly expressed on the MUC1 glycoprotein in a spectrum of malignancies and consequently represent attractive targets for immunotherapeutic exploitation. We would like to draw the attention of readers to an earlier publication that established for the first time the principle that underglycosylated (tumor-associated) glycoforms of MUC1 could be targeted using CAR-engineered T cells (Wilkie et al., 2008Wilkie S. Picco G. Foster J. Davies D.M. Julien S. Cooper L. Arif S. Mather S.J. Taylor-Papadimitriou J. Burchell J.M. Maher J. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor.J. Immunol. 2008; 180: 4901-4909Crossref PubMed Scopus (252) Google Scholar). A panel of eight CARs was engineered using scFvs derived from SM3 and HMFG2 antibodies. Although these antibodies recognize epitopes within the peptide core of MUC1, the binding of both antibodies to their epitopes is critically dependent on the underglycosylation of MUC1. SM3 and HMFG2 scFvs and derived CARs were shown to bind to a range of tumor-associated MUC1 glycoforms, including MUC1 Tn, STn, T, and ST, as well as unglycosylated MUC1. The SM3 antibody in particular demonstrates exquisite tumor selectivity in that it fails to bind MUC1 when it is physiologically expressed at high levels in the mammary gland during lactation (Burchell et al., 1987Burchell J. Gendler S. Taylor-Papadimitriou J. Girling A. Lewis A. Millis R. Lamport D. Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin.Cancer Res. 1987; 47: 5476-5482PubMed Google Scholar). By way of caveat, however, we now know that MUC1 can also be detected on the surface of at least a subset of activated T cells using both HMFG2 and SM3. We are currently evaluating 5E5 in this regard in a panel of donors. We congratulate June and colleagues for publishing this outstanding paper, which validates the concept we had proposed and developed in our earlier work. Although it is especially pleasing to see that the recent work on CAR targeting of MUC1 was published in Immunity, omitting the reference to our 2008 paper might give the erroneous impression that the underlying concept was novel. An accompanying editorial published in the same issue of Immunity does allude to our earlier paper (Blidner et al., 2016Blidner A.G. Mariño K.V. Rabinovich G.A. Driving CARs into Sweet Roads: Targeting Glycosylated Antigens in Cancer.Immunity. 2016; 44: 1248-1250Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). The authors state that "limitations were encountered that were associated with MUC-1-imposed steric hindrance, antigenic heterogeneity and possible undesired effects, precluding the immediate translation of MUC1-CAR T cells to clinical settings." To avoid misunderstandings on the part of the readership, we felt that further clarification of these points was also warranted. It is indeed correct that steric hindrance proved to be a major issue with CARs targeted using SM3, a limitation that was partially mitigated by inclusion of an extended hinge in the CAR. This was less of an issue with HMFG2-based CARs, which bind to several tumor-associated glycoforms of MUC1 (including MUC1-Tn and MUC1-STn) with higher affinity. We did not encounter problems with antigenic heterogeneity in our models because binding by HMFG2 was uniformly observed in the tumor models we studied. Furthermore, we did not observe toxicity following infusion of MUC1 re-targeted CAR T cells, using a mouse model in which we later established that cytokine release syndrome could be induced following the infusion of human CAR T cells (van der Stegen et al., 2013van der Stegen S.J. Davies D.M. Wilkie S. Foster J. Sosabowski J.K. Burnet J. Whilding L.M. Petrovic R.M. Ghaem-Maghami S. Mather S. 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. 2013; 191: 4589-4598Crossref PubMed Scopus (93) Google Scholar). In order to initiate a clinical CAR T cell program for solid tumors at King's College London, we elected to prioritize an ErbB CAR that was engineered in parallel (van Schalkwyk et al., 2013van Schalkwyk M.C. Papa S.E. Jeannon J.P. Guerrero Urbano T. Spicer J.F. Maher J. Design of a phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer.Hum. Gene Ther. Clin. Dev. 2013; 24: 134-142Crossref PubMed Scopus (101) Google Scholar). We made this decision primarily because of the greater potency of that CAR in pre-clinical studies, mindful in particular of the disappointing clinical results reported by several investigators using CAR-engineered T cells for patients with solid tumors. We are pleased to report that this dose-escalation Phase 1 trial commenced 12 months ago and that we have treated seven patients with head and neck cancer to date (https://clinicaltrials.gov/ct2/show/NCT01818323). Related research is supported by the Experimental Cancer Medicine Centre at King's College London and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Distinguishing Truncated and Normal MUC1 Glycoform Targeting from Tn-MUC1-Specific CAR T Cells: Specificity Is the Key to SafetyPosey et al.ImmunityNovember 15, 2016In BriefGenetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate potent clinical antitumor effects in a variety of blood cancers. However, clinical activity in solid tumors has been disappointing and toxicity has been a serious concern (Lamers et al., 2013; Morgan et al., 2010). We recently found that a CAR specific for the Tn-glycoform of MUC1 had potent activity in preclinical models of blood cancer and adenocarcinoma (Posey et al., 2016). Full-Text PDF Open Archive