Abrantes and Forcados et al. generated and characterized AM52.1, a pan-carcinoma antibody with exclusive specificity for a truncated O-glycan structure Sialyl-Tn antigen (STn), which is found on various epithelial tumors, but not healthy tissues, and is associated with adverse outcomes. AM52.1 CAR T cells efficiently targeted STn-expressing cell lines and patient-derived organoids, and significantly extended survival in preclinical models of gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases. AM52.1 CAR T cells eradicated STn-positive tumor cells, even at low antigen density, with no evidence of toxicity.
Contributed by Katherine Turner
ABSTRACT: Accurate identification of tumor-specific markers is vital for developing chimeric antigen receptor (CAR)-based therapies. While cell surface antigens are seldom cancer-restricted, their post-translational modifications (PTMs), particularly aberrant carbohydrate structures, offer attractive alternatives. Among these, the sialyl-Tn (STn) antigen stands out for its prevalent presence in various epithelial tumors. Although monoclonal antibodies (mAbs) against STn have been developed, their clinical application has been hindered by concerns regarding specificity. Herein, we describe AM52.1, a mAb with unprecedented specificity for STn and lack of reactivity with healthy tissues. The single-chain variable fragment (scFv) of AM52.1 was assembled into a second-generation CAR scaffold. AM52.1CAR T cells efficiently targeted STn-expressing cancer cell lines and patient-derived organoids (PDOs), while sparing STn-negative cells. In further preclinical models, AM52.1CAR T cells robustly controlled gastric and tubo-ovarian tumors, as well as colorectal cancer mucinous peritoneal metastases, highlighting their strong therapeutic potential for targeting and managing complex solid tumors.
Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Mole
Author Info: (1) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (2) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (3) Department of Medical Biochemistry, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (4) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (5) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway. (6) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (7) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. (8) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway. (9) ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; Department of Pathology & Cancer Biology and Epigenetics Group - Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (P.CCC), Rua Dr. Antnio Bernardino de Almeida, 4200-072 Porto, Portugal. (10) Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (11) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (12) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (13) Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Hematology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. (14) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (15) Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway; Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (16) Department of Immunology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (17) CCBIO - Centre for Cancer Biomarkers, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Department of Clinical Medicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway; Gade Laboratory for Pathology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway. (18) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (19) Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Department of Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Ullernchaussen 70, 0379 Oslo, Norway; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 9, 0372 Oslo, Norway. (20) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal. (21) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. (22) i3S - Instituto de Investigao e Inovao em Sade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Jlio Amaral de Carvalho 45, 4200-135 Porto, Portugal; ICBAS - Instituto de Cincias Biomdicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal; FMUP - Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hernni Monteiro, 4200-319 Porto, Portugal. Electronic address: celsor@i3s.up.pt. (23) Translational Research Unit, Department of Cellular Therapy, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway. Electronic address: sebastw@ous-hf.no.
