Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated BBB opening: A novel combinatorial immunotherapy regimen for gliomas.

التفاصيل البيبلوغرافية
العنوان:	Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated BBB opening: A novel combinatorial immunotherapy regimen for gliomas.
المؤلفون:	Kim KS; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Habashy K; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Gould A; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Zhao J; Department of Systems Biology, Columbia University, New York, NY, USA.; Program for Mathematical Genomics, Department of Systems Biology.; Department of Biomedical Informatics, Columbia University, New York, NY, USA., Najem H; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Amidei C; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Saganty R; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Arrieta VA; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Dmello C; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Chen L; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Zhang DY; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Castro B; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Billingham L; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Levey D; Agenus Inc., Lexington, MA, USA., Huber O; Agenus Inc., Lexington, MA, USA., Marques M; Agenus Inc., Lexington, MA, USA., Savitsky DA; Agenus Inc., Lexington, MA, USA., Morin BM; Agenus Inc., Lexington, MA, USA., Muzzio M; Life Science Group, IIT Research Institute (IITRI), Chicago, IL, USA., Canney M; CarThera, Lyon, France., Horbinski C; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA.; Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Zhang P; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Miska J; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Padney S; Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Zhang B; Department of Medicine, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Rabadan R; Department of Systems Biology, Columbia University, New York, NY, USA.; Program for Mathematical Genomics, Department of Systems Biology.; Department of Biomedical Informatics, Columbia University, New York, NY, USA., Phillips JJ; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.; Department of Pathology, University of California San Francisco, San Francisco, CA, USA., Butowski N; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA., Heimberger AB; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Hu J; Department of Cancer Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX., Stupp R; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA.; Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Division of Hematology/Oncology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA., Chand D; Agenus Inc., Lexington, MA, USA., Lee-Chang C; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA., Sonabend AM; Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.; Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA.
المصدر:	Neuro-oncology [Neuro Oncol] 2024 Jul 19. Date of Electronic Publication: 2024 Jul 19.
Publication Model:	Ahead of Print
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Oxford University Press Country of Publication: England NLM ID: 100887420 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1523-5866 (Electronic) Linking ISSN: 15228517 NLM ISO Abbreviation: Neuro Oncol Subsets: MEDLINE
أسماء مطبوعة:	Publication: 2010- : Oxford : Oxford University Press Original Publication: 1999-<2002> : Charlottesville, VA : Carden Jennings Pub.,
مستخلص:	Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers. Method: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor associated macrophages/microglia (TAMs). Results: FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4 mediated selective depletion of intra-tumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. Conclusion: Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534). (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
فهرسة مساهمة:	Keywords: BBB; Fc-enhanced anti-CTLA-4; Glioblastoma; doxorubicin; immunotherapy
سلسلة جزيئية:	ClinicalTrials.gov NCT05864534
تواريخ الأحداث:	Date Created: 20240719 Latest Revision: 20240719
رمز التحديث:	20240720
DOI:	10.1093/neuonc/noae135
PMID:	39028616
قاعدة البيانات:	MEDLINE

Full Text Finder

الوصف
تدمد:	1523-5866
DOI:	10.1093/neuonc/noae135