PO-262 Remodelling of the tumour microenvironment by pegvorhyalurondiase alfa (PEGPH20): a novel, first-in-class biologic that enzymatically degrades tumour hyaluronan (HA) to improve anti-tumour efficacy

Abstract

IntroductionHyaluronan (HA) is a naturally occurring glycosaminoglycan that can accumulate in the tumour microenvironment (TME). In pancreatic and other cancers, high levels of HA are associated with poor clinical outcome. In mouse models, high levels of HA in the TME can increase interstitial fluid pressure and compress tumour vasculature, thereby impairing delivery of anti-cancer therapeutics. Here, a novel, first-in-class biologic that enzymatically degrades HA, PEGPH20, increased tumour vascular volume (VV) and improved anti-tumour efficacy when combined with chemotherapy or checkpoint inhibitor antibodies in multiple HA-accumulating tumour models.Material and methodsVarious human and mouse cancer cell lines were transduced with hyaluronan synthase 3 (HAS3) to increase HA production, and implanted in the mammary fat pat (4 T1/HAS3) or adjacent to the tibial periosteum (all other cell lines). Tumour VV was measured by high resolution ultrasound coupled with micro-bubbles (A549/HAS3 and WT-CLS1/HAS3), or IHC (CT26/HAS3), following PEGPH20 treatment (0.0375 mg/kg or 1 mg/kg, IV, 2qw). For BxPC3/HAS3 studies, mice were dosed with vehicle or PEGPH20 (4.5 mg/kg, IV, 2qw)±nab paclitaxel (NAB, 10 mg/kg, IV, 2qw)±gemcitabine (GEM, 180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For AsPC1/HAS3 studies, mice were dosed with vehicle or PEGPH20 (0.0375 mg/kg, IV, 2qw)±NAB (10 mg/kg, IV, qw)±GEM (180 mg/kg, IP; 24 hour after PEGPH20 ±NAB, qw). For checkpoint inhibitor studies (CT26/HAS3, 4 T1/HAS3, Pan02/HAS3), mice were dosed with PEGPH20 (0.0375 mg/kg, IV) 24 hour prior to anti-CTLA4 (clone 9D9, 4 mg/kg, IP) or anti-PD-L1 (clone 10F.9G2, 5 mg/kg, IP).Results and discussionsPEGPH20 administration resulted in degradation of HA in all tumour models tested, and resulted in increased VV in the 3 models tested. PEGPH20 +GEM + NAB led to enhanced tumour growth inhibition (TGI) compared to GEM+NAB in the BxPC3/HAS3 (104% v 70%, respectively, p<0.0001) and AsPC1/HAS3 (78% v 53%, respectively, p=0.0021) models. In CT26/HAS3, PEGPH20 +anti-CTLA4 resulted in enhanced TGI compared to anti-CTLA4 alone (p=0.002). PEGPH20 +anti-PD-L1 resulted in enhanced TGI compared to anti-PD-L1 alone 4 T1/HAS3 (93% v 18%, respectively, p<0.0001) and Pan02/HAS3 (50% v 5%, respectively, p<0.01).ConclusionThese studies demonstrate that the use of PEGPH20 to enzymatically remodel the TME in HA-high tumours may represent a novel approach for enhancing the efficacy of cancer therapeutics. A Phase 3 study of GEM and NAB ±PEGPH20 in patients with prospectively selected HA-high PDA is ongoing (NCT02715804).