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Immunology. 2018 May 23. doi: 10.1111/imm.12954. [Epub ahead of print]

ImmTAC/Anti-PD-1 antibody combination to enhance killing of cancer cells by reversing regulatory T-cell-mediated immunosuppression.

Author information

1
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
2
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China.
3
XiangXue Life Sciences Research Centre, XiangXue Pharmaceutical Co. Ltd, Guangzhou, Guangdong, China.
4
State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institutes of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
5
Department of Melanoma Medical Oncology and Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA.

Abstract

Recently, bi-functional molecules that can redirect immune effectors to tumour cells have emerged as potentially robust mediators of tumour regression in clinical trials. Two modalities in particular, bi-specific antibodies for T-cell redirection and activation (BiTe) and immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC), are being evaluated in efficacy studies as 'off-the-shelf' reagents. Optimal therapy will require an understanding and means to address regulatory mechanisms of limiting efficacy. In light of this, we evaluated the impact of induced regulatory T (iTreg) cells on the efficacy of tumour cell killing redirected by ImmTAC and demonstrated down-regulation of T-cell proliferation and expression of CD25, CD107a, Granzyme B and Perforin by ImmTAC-redirected T cells. Significant recovery of ImmTAC potency, however, could be achieved when combined with an anti-programmed cell death protein 1 monoclonal antibody. Furthermore, we found that among lung cancer patients failing to respond to ImmTAC therapy, there was a significantly higher fraction of Treg cells in the peripheral blood mononuclear cells of lung cancer patients than in healthy donors. These results provide in vitro evidence for an iTreg cell-mediated immunosuppression of ImmTAC-redirected T-cell responses. Whilst immune checkpoint blockade can reverse the Treg cell suppression, it forms a rational basis for a combination of the blockade with ImmTAC in clinical trials.

KEYWORDS:

ImmTAC; anti-PD-1 monoclonal antibody; cancer; immunotherapy; regulatory T cells

PMID:
29791021
DOI:
10.1111/imm.12954

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