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Combined treatment with anti-HER2/neu and anti-4-1BB monoclonal antibodies induces a synergistic antitumor effect but requires dose optimization to maintain immune memory for protection from lethal rechallenge

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Human epidermal growth factor receptor type 2 (HER2)-positive breast cancer that is treated with anti-HER2/neu monoclonal antibody (mAb) is not free from late recurrences. Addition of anti-4-1BB mAb to anti-HER2/neu mAb has been demonstrated to strengthen the cytotoxic antitumor response. Our study expands on this by revealing the influence of anti-4-1BB mAb addition on the immune memory of anti-HER2/neu mAb. We designed murine breast cancer models by implanting TUBO and TUBO-P2J cell lines in mice, which were then treated with anti-HER2/neu and/or anti-4-1BB mAb. After complete surgical and/or chemical regression of the tumor, the mice were rechallenged with a second injection of cancer cells. Notably, anti-HER2/neu and anti-4-1BB mAb combination therapy had a synergistic antitumor effect at the initial treatment. However, the combination therapy did not evoke immune memory, allowing the tumors to thrive at rechallenge with reduced CD44+ expression in CD8+ T cells. Immune memory was also impaired when anti-4-1BB mAb was administered to naive CD8+ T cells but was sustained when this was administered to activated CD8+ T cells. In an attempt to resist the loss of immune memory, we controlled the dose of anti-4-1BB mAb to optimize the stimulation of activated CD8+ T cells. Immune memory was achieved with the dose regulation of anti-4-1BB mAb to 1 mg/kg in our model. Our study demonstrates the importance in understanding the adaptive immune mechanism of anti-HER2/neu and anti-4-1BB mAb combination therapy and suggests a dose optimization strategy is necessary to ensure development of successful immune memory.

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Funding

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) of Korea funded by the Korean Government (MSIT) Under Grant (No.2019M3A9H1103607); Under Grant (No.2017R1C1B5076247); Under Grant (No.2016R1D1A1B03935426); and the SAMJINPHARM.CO., LTD Under Grant (SJ-IIT-17-07).

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Author notes

  1. Hee Yeon Kim, Jae-Hyeog Choi, Anbok Lee and SaeGwang Park have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Busan Paik Hospital, College of Medicine, Inje University, Busan, 47392, Republic of Korea

    Hee Yeon Kim & Anbok Lee

  2. New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, Republic of Korea

    Jae-Hyeog Choi

  3. Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, 47392, Republic of Korea

    Md. Masudul Haque, Jin Hee Park & SaeGwang Park

  4. Department of Internal Medicine, Division of Oncology, Haeundae Paik Hospital, College of Medicine, Inje University, Busan, 48108, Republic of Korea

    Il-Hwan Kim

  5. Biomedicine Production Branch, National Cancer Center, Goyang, Republic of Korea

    Beom K. Choi

  6. Innovative Therapeutic Research Institute, College of Medicine, Inje University, Busan, 47397, Republic of Korea

    SaeGwang Park

Authors
  1. Hee Yeon Kim
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  2. Jae-Hyeog Choi
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Contributions

HYK, J-HC and SGP conceptualized the study and reviewed the writing of the manuscript. HYK, J-HC and MMH wrote the original draft of the manuscript and analyzed the data. JHP, I-HK and BKC investigated the immune cell population and activity. AL and SGP were involved in supervision, funding acquisition and project administration.

Corresponding authors

Correspondence to Anbok Lee or SaeGwang Park.

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The researcher claims no conflicts of interest.

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The experimental procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Inje University (2019-002).

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I would like to declare that the manuscript is approved by all authors for publication.

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Kim, H.Y., Choi, JH., Haque, M.M. et al. Combined treatment with anti-HER2/neu and anti-4-1BB monoclonal antibodies induces a synergistic antitumor effect but requires dose optimization to maintain immune memory for protection from lethal rechallenge. Cancer Immunol Immunother 71, 967–978 (2022). https://doi.org/10.1007/s00262-021-03120-1

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  • DOI: https://doi.org/10.1007/s00262-021-03120-1

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