Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition
| العنوان: | Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition |
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| المؤلفون: | Nina Eißler, Peter Ruf, Horst Lindhofer, Nina Deppisch, Ralph Mocikat |
| المصدر: | Oncotarget Oncotarget 8, 4520-4529 (2017) |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, CD4-Positive T-Lymphocytes, medicine.medical_treatment, Catumaxomab, Melanoma, Experimental, 03 medical and health sciences, Mice, 0302 clinical medicine, Cancer immunotherapy, Cell Line, Tumor, Antibodies, Bispecific, T-cell activation, medicine, melanoma, Animals, CTLA-4 Antigen, cancer immunotherapy, biology, business.industry, Melanoma, Immunotherapy, medicine.disease, Ipilimumab, Xenograft Model Antitumor Assays, Immune checkpoint, Tumor antigen, Up-Regulation, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, CTLA-4, 030220 oncology & carcinogenesis, Immunology, biology.protein, tumor antigen, Antibody, business, Immunologic Memory, Spleen, medicine.drug, Research Paper |
| الوصف: | // Nina Deppisch 1 , Peter Ruf 2 , Nina Eisler 1 , Horst Lindhofer 2 , Ralph Mocikat 1, 3 1 Institut fur Molekulare Immunologie, Helmholtz-Zentrum Munchen, Germany 2 Trion Research GmbH, Martinsried, Germany 3 AG Translationale Molekulare Immunologie, Helmholtz-Zentrum Munchen, Germany Correspondence to: Ralph Mocikat, email: Mocikat@helmholtz-muenchen.de Keywords: tumor antigen, T-cell activation, melanoma, CTLA-4, cancer immunotherapy Received: July 25, 2016 Accepted: December 05, 2016 Published: December 10, 2016 ABSTRACT Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo . This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4 + memory T cells found in the spleens. |
| وصف الملف: | application/pdf |
| تدمد: | 1949-2553 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::628cc857597013665278c7375a3f58de https://pubmed.ncbi.nlm.nih.gov/27966460 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....628cc857597013665278c7375a3f58de |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
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