CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

• Published in: Oncoimmunology Vol. 9; no. 1; p. 1747688
• Main Authors: Lv, Zhuangwei, Zhang, Ping, Li, Dandan, Qin, Mengting, Nie, Longzhu, Wang, Xiaoqian, Ai, Li, Feng, Zhaozu, Odhiambo, Woodvine Otieno, Ma, Yunfeng, Ji, Yanhong
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2020; Taylor & Francis Group
• Subjects: anti-PD1; B cell vaccine; breast cancer; CD19; combination therapy; immunotherapy; Original Research; breast cancer; combination therapy; anti-PD1; B cell vaccine; CD19; immunotherapy
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2020.1747688

In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2 D4 ) was found to enhance IFN-γ-producing-CD8 + T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2 D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2 D4 and anti-tumor immunity, as evidenced by the reversal of tumor-infiltrating CD8 + T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.