Abstract 959: Extracellular matrix-binding immunotherapies show enhanced antitumor efficacy and reduced adverse events
Authors: Ishihara Jun , Ishihara Ako , Fukunaga Kazuto , Potin Lambert , Hosseinchi Peyman , Swartz Melody A. , Hubbell Jeffrey A. 
Published: August 2018

Abstract
Immune checkpoint inhibitors (CPI) and co-stimulatory agonist antibody therapies have exhibited considerable antitumor effects, but instances of severe side effects have been previously reported. We hypothesized that conjugation of an extracellular matrix (ECM)-binding peptide derived from placenta growth factor-2 (PlGF-2123-144) to CPI (combination of anti-CTLA4 antibody (αCTLA4) and αPD-L1) or agonistic αCD40 would accomplish local cancer immunotherapy, minimizing the antibodies' systemic exposure. Here, we show that enhanced tissue retention and lower antibody concentrations in blood plasma resulted from PlGF-2123-144 conjugation when the antibodies were administered peri-tumorally compared to unmodified antibodies administered by the same route at the same dose. This resulted in decreases in systemic cytokine release in the blood serum, and in liver tissue damage, as was assessed both biochemically and histologically, indicating lower systemic side effects after CPI and αCD40 therapies. Particularly, we show that PlGF-2123-144 conjugation reduces the risks of αPD-L1-induced autoimmune diabetes in the male nonobese diabetic mouse. Because PD-1/PD-L1-inhibition induced diabetes has been reported in the clinic, this supports the idea that PlGF-2123-144 conjugation to antibodies may reduce adverse events. This observation with localized PlGF-2123-144-antibodies could be an important breakthrough in treating patients who have discontinued immunotherapy due to the associated side effects. Regarding efficacy, we show that either PlGF-2123-144-CPI treatment or PlGF-2123-144-αCD40 treatment showed significantly higher antitumor activity compared to unmodified forms in multiple cancer models: B16F10 and Tyr:Cre-ER+/LSL-BrafV600E/Ptenfl/fl melanoma, CT26 colon carcinoma, and MMTV-PyMT breast cancer. Local injections of PlGF-2123-144-CPI increased the number of activated CD8+ and CD4+ T cells within the tumor, compared to normal CPI. PlGF-2123-144-αCD40 treatment increased the frequency of activated dendritic cells in the tumor-draining lymph node, activated CD8+ T cells within the tumor, and secretion of endogenous antibodies against tumor cells. This immune cell activation resulted in growth suppression of a distant tumor. These data suggest the feasibility of treating patients with oligometastatic tumors by administration of PlGF-2123-144- PlGF-2123-144-CPI or PlGF-2123-144-αCD40 into one accessible metastasis. Our data suggest that local injection of either PlGF-2123-144-CPI or PlGF-2123-144-αCD40 efficiently activates tumor antigen-specific T cells while maintaining systemic immune homeostasis by avoiding influencing nontumor antigen-specific T cells. This simple approach of engineered ECM-binding immunotherapy antibodies may be clinically useful.
Citation Format: Jun Ishihara, Ako Ishihara, Kazuto Fukunaga, Lambert Potin, Peyman Hosseinchi, Melody A. Swartz, Jeffrey A. Hubbell. Extracellular matrix-binding immunotherapies show enhanced antitumor efficacy and reduced adverse events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 959.