Efficient CAR T cell targeting of the CA125 extracellular repeat domain of MUC16.

Autor:	Casey NP; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Kleinmanns K; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway., Forcados C; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Gelebart PF; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway., Joaquina S; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Lode M; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway., Benard E; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Kaveh F; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Caulier B; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Center for Cancer Cell Reprogramming (CanCell), Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Helgestad Gjerde C; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway., García de Jalón E; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway., Warren DJ; Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway., Lindemann K; Department of Gynecologic Oncology, Oslo University Hospital, Oslo, Norway.; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway., Rokkones E; Department of Gynecologic Oncology, Oslo University Hospital, Oslo, Norway., Davidson B; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway., Myhre MR; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Kvalheim G; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Bjørge L; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway., McCormack E; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.; Centre for Pharmacy, Department of Clinical Science, University of Bergen, Bergen, Norway.; Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway., Inderberg EM; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway., Wälchli S; Translational Research Unit, Section of Cellular Therapy, Department of Oncology, Oslo University Hospital, Oslo, Norway sebastw@rr-research.no.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Apr 11; Vol. 12 (4). Date of Electronic Publication: 2024 Apr 11.
DOI:	10.1136/jitc-2023-008179
Abstrakt:	Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy. Methods: We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct. Results: We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain. Conclusions: Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies. Competing Interests: Competing interests: SW, EMI, DJW, NPC and EB have filled a patent application on chimeric antigen receptor for ovarian cancer. The other authors declare no conflict of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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