Abstract 594: Dual targeting of TGFb and PD-L1 promotes potent anti-tumor efficacy in multiple murine models of solid carcinomas
Authors: Knudson Karin M. , Gameiro Sofia R. , Lo Kin-Ming , Schlom Jeffrey 
Published: July 2017

Abstract
Tumors evade host immune surveillance through multiple mechanisms, including promoting a tumor microenvironment able to effectively suppress immune effector functions. Secretion of cytokines such as TGFb and upregulation of immune checkpoint molecules are two main contributors to immune evasion and tumor progression. TGFb is an important immunosuppressive cytokine with pleiotropic actions in cancer, including promotion of epithelial to mesenchymal transition and metastasis. It promotes tumor immune evasion by impairing T and NK cell maturation, recruitment, and function. Tumors also inhibit antitumor immune responses through tumor cell-immune cell interaction, in which the negative regulatory checkpoint PD-L1/PD-1 interaction plays a major role. Therapies that independently target TGFb signaling or PD-L1/PD-1 interaction demonstrate limited clinical efficacy.
Anti-PD-L1/TGFbTRAP (M7824) is a novel immunotherapeutic agent designed to simultaneously block the PD-L1 and TGFb immunosuppressive pathways. It is comprised of the extracellular domain of human TGFbRII (TGFbTRAP) linked to the C-terminus of human anti-PD-L1 heavy chain (anti-PD-L1). M7824 has shown potent anti-tumor activities in preclinical models1 and some evidence of clinical efficacy in a phase 1 study2. Here, we demonstrate that anti-PD-L1/ TGFbTRAP neutralizes murine TGFb-induced signaling and binds to murine PD-L1 in multiple murine breast and colon carcinoma models.
In non-tumor bearing mice, anti-PD-L1/TGFbTRAP increases the number of CD8+ T cells in the lymph nodes, and elicits splenic CD8+ T and NK cells with a more active phenotype. Initial examination of peripheral immune subsets in tumor-bearing mice indicates that anti-PD-L1/TGFbTRAP induces CD8+ T cells and NK cells with a more active, less exhausted phenotype. Furthermore, dual targeting of PD-L1 and TGFb increases tumor expression of MHC-I, MHC-II, and PD-L1, suggesting additional immune effects in the tumor microenvironment.
Importantly, anti-PD-L1/TGFbTRAP displays potent anti-tumor efficacy against various murine models of breast and colorectal carcinomas. This response is durable, preventing relapses up to 7 months. Anti-PD-L1/TGFbTRAP also decreases spontaneous metastasis in a murine model of triple-negative breast cancer.
Taken together, these findings support the preclinical proof of concept for dual targeting of TGFb and PD-L1/PD-1 pathways with anti-PD-L1/ TGFbTRAP, its mode of action, and its potential clinical use as a monotherapy or in combination with other immunotherapies or standards of care.
1 Lan Y et al, Preclinical evaluation of M7824 (MSB0011359C), a novel bifunctional fusion protein targeting the PD-L1 and TGFb pathways. Keystone Symposium, Jan 2017.
2 Strauss J et al, Phase I trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGFb, in advanced solid tumors. Keystone Symposium, Jan 2017.
Citation Format: Karin M. Knudson, Sofia R. Gameiro, Kin-Ming Lo, Jeffrey Schlom. Dual targeting of TGFb and PD-L1 promotes potent anti-tumor efficacy in multiple murine models of solid carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2017-594