Abstract 641: PEGylated recombinant hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.641-641
• Main Authors: Clift, Renee, Lee, Jisook, Thompson, Curtis B., Huang, Yujun
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-641

Hyaluronan (HA) is an extracellular glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumors and is associated with rapid tumor progression and poor prognosis. In preclinical studies, enzymatic degradation of TME HA by intravenous PEGylated recombinant human hyaluronidase PH20 (PEGPH20) remodels the TME, reduces tumor interstitial fluid pressure, decompresses tumor blood vessels, and facilitates delivery of chemotherapeutics. We have previously shown that PEGPH20-mediated HA degradation enhances anti-PD-L1 and anti-PD1 efficacy in an HA accumulating murine pancreatic tumor model (Rosengren, AACR 2016 poster #4886). Accordingly, we aimed to extend these checkpoint blockade studies into orthotopic breast cancer models; while further elucidating the effect of PEGPH20-mediated HA degradation on modulating tumor infiltrating lymphocytes (TILs). The mammary fat pads of BALB/c mice were inoculated with either EMT-6 cells or 4T1/HAS3, a 4T1 cell line engineered to over-express hyaluronan synthase-3. During tumor progression, both EMT-6 and 4T1/HAS3 mammary carcinomas accumulate high levels of HA (average 730 ng/mg and 1408 ng/mg, respectively). When treated with PEGPH20 alone (0.0375mg/kg), EMT-6 tumor growth was inhibited by ≥30% (p=0.01). Additional EMT-6 studies were conducted to evaluate PEGPH20 in combination with anti-PD-L1. PEGPH20 increased anti-PD-L1 efficacy by 38% relative to anti-PD-L1 alone (86% vs 62.4% tumor growth inhibition (TGI), p=0.0024). Comparable tumor growth experiments were conducted in the 4T1/HAS3 model. TILs were evaluated by flow cytometry. PEGPH20-mediated HA removal enhanced both checkpoint efficacy and CD8+ T cell recruitment. Specifically, PEGPH20 alone (1mg/kg) increased anti-PD-L1 efficacy by 411% relative to anti-PD-L1 alone (93% vs 18.2% TGI, p