Abstract 1743: Rationale for evaluating PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20) in patients with hyaluronan (HA)-accumulating colorectal cancer
Authors: Clift Renee , Thompson Benjamin J. , Taverna Darin , Blouw Barbara , Lee Jisook , Thompson Curtis B. , Maneval Daniel C. 
Published: August 2018

Abstract
Colorectal cancer is the third most common cancer, and the third most common cause of cancer-related death, among both men and women in the United States. To address this unmet clinical need, ongoing efforts have focused on classifying different subtypes of colorectal cancer, with the goal of identifying therapies with the highest likelihood of success for a given tumor subtype. One marker that has been associated with poor clinical outcome in multiple solid tumor types, including colorectal cancer, is the accumulation of the glycosaminoglycan hyaluronan (HA), which, in preclinical tumor models, increases interstitial fluid pressure, compresses tumor vasculature, and restricts the access of therapeutics. PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20), which enzymatically degrades HA, is currently being evaluated in combination with existing therapies in clinical trials for HA-accumulating pancreatic, gastric, non-small cell lung, and bile duct cancers. Here, we review the available data for PEGPH20 as published by the authors to evaluate the potential utility of PEGPH20 in treating colorectal cancer. We first studied PEGPH20 in two HA-accumulating murine colon tumor models: CT26 transduced with hyaluronan synthase-3 (HAS3) and MC38 (Charles River Laboratories). In CT26-HAS3 tumors, PEGPH20 monotherapy induced 43% tumor growth inhibition and was associated with tumor blood vessel decompression. In combination with anti-CTLA4 treatment, PEGPH20 further enhanced tumor growth inhibition (79%, p≤0.002 vs anti-CTLA4 alone and PEGPH20 alone). In MC38 tumors, combination of PEGPH20 with anti-PD-L1 treatment significantly increased infiltration of CD8+ T cells (2.8-fold, p&lt;0.05) and NK cells (3-fold, p&lt;0.0001) compared with anti-PD-L1 alone. We then investigated the prevalence of HA accumulation in human colorectal cancer. To do this, we histologically analyzed 138 patient tumor specimens for stromal content and presence of HA. In 38 samples (28%), ≥50% of the tumor stromal area stained positive for HA. Additionally, Phase 1 studies with single agent PEGPH20 included several subjects with colorectal cancer. Pharmacodynamic measurements before and after treatment demonstrated increased tumor perfusion as measured by median volume transfer constant (Ktrans), decreased tumor metabolic activity as measured by 18F-FDG-PET/CT in one patient, and decreased tumor HA following PEGPH20 administration. Collectively, these data warrant further investigation of the potential for PEGPH20 to benefit patients with HA-high colorectal cancer.
Citation Format: Renee Clift, Benjamin J. Thompson, Darin Taverna, Barbara Blouw, Jisook Lee, Curtis B. Thompson, Daniel C. Maneval. Rationale for evaluating PEGylated recombinant human hyaluronidase PH20 (pegvorhyaluronidase alfa; PEGPH20) in patients with hyaluronan (HA)-accumulating colorectal cancer [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 1743.