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

• Published in: Immunology Vol. 155; no. 2; pp. 238 - 250
• Main Authors: Zhang, Huanling, Li, Yanyan, Liu, Xiaoping, Liang, Zhaoduan, Yan, Mengyong, Liu, Qiang, Chen, Anan, Bao, Yifeng, Zhou, Chengzhi, Li, Shiyue, Yee, Cassian, Li, Yi
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2018; John Wiley and Sons Inc
• Subjects: anti‐PD‐1 monoclonal antibody; Apoptosis; cancer; CD25 antigen; Cell activation; Cell death; Cell proliferation; Clinical trials; Granzyme B; ImmTAC; Immune checkpoint; Immunosuppression; immunotherapy; Leukocytes (mononuclear); Lung cancer; Lymphocytes; Lymphocytes T; Monoclonal antibodies; Original; Perforin; Peripheral blood mononuclear cells; Reagents; Receptors; Regulatory mechanisms (biology); regulatory T cells; Robustness (mathematics); Therapy; Tumors; regulatory T cells; ImmTAC; cancer; anti-PD-1 monoclonal antibody; immunotherapy
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12954

Summary 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. Our study demonstrated the significant suppressive effects of induced regulatory T (iTreg) cells, which could diminish the T‐cell activating function of the ImmTAC, and presented in combination with an anti‐programmed cell death protein‐1 antibody, which is an immune check‐point blockade reagent, ImmTAC molecule may eventually overcome the suppression of iTreg cells.