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P02.05 Investigation of a syngeneic a-PD-1 antibody to treat murine 4T1 mammary carcinoma

Journal for immunotherapy of cancer, 2020-10, Vol.8 (Suppl 2), p.A21-A22 [Peer Reviewed Journal]

2020 Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ. ;EISSN: 2051-1426 ;DOI: 10.1136/jitc-2020-ITOC7.40

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  • Title:
    P02.05 Investigation of a syngeneic a-PD-1 antibody to treat murine 4T1 mammary carcinoma
  • Author: Pedersen, I Skandorff ; Orfin, K ; Nielsen, K N ; Holst, P J
  • Subjects: Employment
  • Is Part Of: Journal for immunotherapy of cancer, 2020-10, Vol.8 (Suppl 2), p.A21-A22
  • Description: Background Many cancers acquire mechanisms to evade immunosurveillance by activating immune checkpoint pathways, which suppress the antitumor immune responses. Monoclonal antibodies (ab’s) targeting immune checkpoints, such as CTLA-4 and PD-1, have shown excellent results in several cancers and are currently being investigated in clinical trials for various malignancies. The clinically tested a-CTLA-4 (Ipilimumab) and a-PD-1 (Nivolumab and Pembrolizumab) ab’s are fully human or humanized ab’s, respectively. However, most studies conducted in mice utilize a xenogeneic a-PD-1 ab originating from rat, IgG2a RMP1-14 clone. This has been proposed to cause adverse effects in the commonly used 4T1 mammary carcinoma model of triple negative breast cancer (TNBC). Repeated administration of xenogeneic a-PD-1 ab’s in this model results in fatal hypersensitivity reactions in tumor bearing mice, and unlike human TNBC, the 4T1 cell line is generally poorly responsive to immune checkpoint inhibitors. Recently, a semi-syngeneic recombinant a-PD-1 ab has been developed by transferring the variable regions of RMP1-14 onto a murine IgG1e3 constant region. Materials and Methods Testing xenogeneic and semi-syngeneic a-PD-1 ab with and without a-CTLA-4 ab in BALB/c mice carrying 4T1 luciferase positive tumors. Results In this study, we compared a semi-syngeneic recombinant a-PD-1 ab to the original xenogeneic RMP1-14 clone for treatment of luciferase positive 4T1 carcinomas. Surprisingly, the semi-syngeneic a-PD-1 ab was not able to circumvent the fatal hypersensitivity reactions. Still, the combination therapy of a-CTLA-4 and the semi-syngeneic a-PD-1 ab significantly reduced tumor volume in 4T1-luciferase tumor bearing mice compared to isotype control-treated mice already from day 16 post tumor inoculation (day 8 post treatment-initiation). In contrast, xenogeneic a-PD-1/a-CTLA-4 treated mice did not show significant difference from the control group until 24 days post tumor inoculation and never to the same degree. Furthermore, analysis of the T cell responses towards the murine tumor-associated antigen AH-1, revealed that treatment with syngeneic a-PD-1/a-CTLA-4 ab gave a significantly stronger CD8+ T cell response over both control mice and mice treated with xenogeneic a-PD-1/a-CTLA-4 ab. Conclusions These studies indicate that the semi-syngeneic a-PD-1 IgG1e3 ab might be a more efficient and translatable a-PD-1 ab for preclinical in vivo studies, which is important for the future investigation of immune checkpoint inhibitor therapy. Disclosure Information I. Skandorff Pedersen: A. Employment (full or part-time); Significant; InProTher Aps. K. Orfin: A. Employment (full or part-time); Significant; InProTher Aps. K.N. Nielsen: A. Employment (full or part-time); Significant; InProTher Aps. P.J. Holst: A. Employment (full or part-time); Significant; InProTher Aps. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; InProTher Aps.
  • Publisher: London: BMJ Publishing Group LTD
  • Language: English
  • Identifier: EISSN: 2051-1426
    DOI: 10.1136/jitc-2020-ITOC7.40
  • Source: ROAD
    PubMed Central
    ProQuest Central
    DOAJ Directory of Open Access Journals
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