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Curtis B Thompson - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2740: PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models
Immunology, 2018Co-Authors: Renee Clift, Curtis B Thompson, Barbara Blouw, Yujun HuangAbstract:Hyaluronan (HA) is an extracellular glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumors. 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. PEGPH20-mediated HA degradation increases anti-PD-L1 efficacy in HA-rich EMT-6 tumors and enhances CD8+ T-cell infiltration in tumors. Cancer patients can be resistant to anti-PD-L1; strategies to increase T cell infiltration may lead to anti-PD-L1 effectiveness in nonresponders. We hypothesized that PEGPH20 may convert HA-rich tumors with low T cell infiltration from resistant to sensitive to anti-PD-L1 immunotherapy. 4T1 breast cancer cells transduced with HAS3 to generate HA-rich 4T1/HAS3 cells averaged ~2.9×104 CD8+ T cell/g tumor on day 18 post-tumor inoculation and were resistant to anti-PD-L1 monotherapy. PEGPH20 treatment of 4T1/HAS3 tumors significantly increased CD8+ T cell infiltration to ~7.2×104/g tumor (p=0.0007) and 4T1/HAS3 tumors became sensitive to anti-PD-L1 treatment. PEGPH20 + anti-PD-L1 led to 64.0% tumor growth inhibition (TGI; p Citation Format: Renee Clift, Xiaoming Li, Barbara Blouw, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models [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 2740.
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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
Cancer Research, 2017Co-Authors: Renee Clift, Curtis B Thompson, Jisook Lee, Yujun HuangAbstract: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 Citation Format: Renee Clift, Jisook Lee, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models [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 641. doi:10.1158/1538-7445.AM2017-641
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abstract 1240 evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate pegylated Recombinant Hyaluronidase ph20 pegph20 mediated musculoskeletal adverse events
Cancer Research, 2017Co-Authors: Marc R Azar, Curtis B Thompson, Daniel C Maneval, Michael Shepard, Ya Huang, Piet Vervaet, Rudy PaladiniAbstract:Some cancers accumulate high levels of the glycosaminoglycan hyaluronan (HA) within the tumor microenvironment (TME), and this HA accumulation is associated with rapid tumor progression and poor clinical outcomes. As preclinical data have demonstrated that enzymatic degradation of HA, via intravenous (IV) administration of PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20), increases therapeutic efficacy in HA-accumulating tumors, several clinical trials evaluating PEGPH20 in combination with anti-cancer therapies are ongoing. The most advanced clinical trial (Phase 3) is evaluating PEGPH20 plus Abraxane® (nab-paclitaxel)/gemcitabine (AG) in patients with stage IV untreated pancreatic ductal adenocarcinoma (PDA)(NCT02715804). The safety profile of PEGPH20/Abraxane/gemcitabine (PAG) was generally similar to AG alone in an interim analysis of the Phase 2 data, with the exception of a potential imbalance of thromboembolic events (TEs), and an increased incidence of musculoskeletal events (MSEs) in the PAG arm, with the predominant MSE being muscle spasms (55.4% PAG vs. 1.6% AG, all grades)(Bullock, ASCO 2016). In an effort to find pharmacological agent(s) that might decrease MSEs in PAG-treated patients, a rat locomotor activity assay was developed. In brief, locomotor activity of male Sprague Dawley rats was measured with an automated infrared photobeam monitoring apparatus (Hamilton/Kinder®, San Diego) during the 12h dark cycle when rats are normally active. Any PEGPH20-mediated decrease in rat locomotor activity was interpreted as MSE-like effects. In response to PEGPH20 (1 mg/kg) the locomotor activity of male rats was reduced by ~75% for the first 2 dark cycles post-treatment (48h), and then gradually returned to vehicle baseline levels by days 4-5. FDA approved drugs used clinically to alleviate pain were subsequently tested for their ability to ameliorate the effects of PEGPH20 on locomotor activity. Agents included anti-inflammatories, anti-spasmodics, neuropathic pain medications, neuroleptics, diuretics, anti-hypertensives, anti-fibromyalgics and opioids. The steroid dexamethasone, currently being used in the Phase 2 and Phase 3 PDA clinical trials to manage MSEs, was the positive control. As a class, nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac, ketoprofen, diclofenac, and piroxicam, increased rat ambulation by ~40% on the first night following PEGPH20 treatment compared to PEGPH20 alone. Mobility in rats treated with NSAIDs/PEGPH20 increased ~60% on the second night compared to PEGPH20 alone. No other drug classes increased rodent ambulation. These data suggest that NSAIDs may be useful in partially alleviating the MSEs experienced by patients receiving PEGPH20. Citation Format: Li Ma, Marc R. Azar, Michael Shepard, Ya Huang, Piet A. Vervaet, Daniel C. Maneval, Curtis B. Thompson, Rudy Paladini. Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated Recombinant Hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events [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 1240. doi:10.1158/1538-7445.AM2017-1240
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abstract lb 198 combination of pegylated Recombinant Hyaluronidase ph20 pegph20 with live attenuated double deleted ladd listeria enhances tumor infiltrating cd8 t cell response and antitumor efficacy in mice
Cancer Research, 2017Co-Authors: Jisook Lee, Sanna Rosengren, Benjamin J. Thompson, Barbara Blouw, Yujun Huang, Meredith L Leong, Dirk G Brockstedt, Curtis B ThompsonAbstract:Successful immunotherapy is highly dependent on inducing an efficient CD8+ T cell-mediated antitumor immune response. The trafficking and activation of these effector CD8+ T cells are often inhibited by various immunosuppressive mechanisms in the tumor microenvironment (TME). Hyaluronan (HA), a glycosaminoglycan that accumulates in the TME of many solid tumors, is associated with rapid tumor progression, poor prognosis and increased immunosuppression. We have previously demonstrated in nonclinical models that enzymatic degradation of TME HA by intravenous PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) facilitates delivery of chemotherapeutics to tumors and enhances checkpoint inhibitor efficacy. Based on these observations we hypothesized that PEGPH20 may improve current cancer immunotherapies by increasing immune cell infiltration into tumors. To test this hypothesis we used CT26/HAS3 tumors, CT26 murine colon carcinoma cells engineered to over-express hyaluronan synthase-3, and treated them with PEGPH20 in combination with Recombinant live-attenuated double-deleted strains of Listeria monocytogenes expressing AH1 (gp70423-431, SPSYVYHQF), the immunodominant CD8+ T cell epitope of CT26 (LADD-AH1). PEGPH20 (1mpk), which results in nearly complete removal of HA at 24hrs, was administered 24hrs prior to LADD-AH1. In this model, LADD-AH1 alone inhibited tumor growth which correlated with an increase in IFNγ+ (p=0.0019) and granzyme B+ CD8+ tumor infiltrating lymphocytes (TILs) (p=0.0006). Tumor-associated macrophages (TAMs) from LADD-AH1 treated tumors were more immunostimulatory with a decrease in MHCIIlow (p=0.0205) and CD206+ TAMs (p=0.0003). Moreover, the combination of PEGPH20 and LADD-AH1 resulted in enhanced anti-tumor activity compared to either PEGPH20 (p=0.0047) or LADD-AH1 alone (p=0.0002). Significant TME changes were observed in the combination treatment with an increase in CD8+ TILs (p=0.0200, of which 88% were granzyme B+), NK cells (p=0.0205) and an increase in CD8:Treg ratio (p=0.0007).These findings were corroborated by immunohistochemical analysis demonstrating an increase in CD3+ T cells with PEGPH20 treatment. Taken together, these data suggest that HA accumulation in tumors may act as a barrier to immune cell access and that reduction of HA by PEGPH20 facilitates increased accumulation of tumor antigen-specific CD8+ effector T cells induced by LADD immunotherapy. Our findings reveal a benefit of PEGPH20 in enhancing tumor infiltration of cytotoxic CD8+ T cells induced by LADD that translate into a significant improvement in efficacy in a murine model of HA-high tumors. Citation Format: Jisook Lee, Meredith Leong, Yujun Huang, Benjamin J. Thompson, Sanna Rosengren, Barbara Blouw, Dirk G. Brockstedt, Curtis B. Thompson. Combination of PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) with live-attenuated, double-deleted (LADD) Listeria enhances tumor infiltrating CD8+ T cell response and antitumor efficacy in mice [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 LB-198. doi:10.1158/1538-7445.AM2017-LB-198
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abstract 283 pegylated Recombinant Hyaluronidase ph20 pegph20 enhances pemetrexed antitumor efficacy in a human nonsquamous nsclc xenograft model
Cancer Research, 2016Co-Authors: Renee Clift, Susan Zimmerman, Ping Jiang, Daniel C Maneval, Jessica Cowell, Mathieu Marella, Arnold B Gelb, Michael J Labarre, Curtis B ThompsonAbstract:Introduction: Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that has been shown to accumulate at high levels in several cancers, including non-small cell lung cancer (NSCLC). The accumulation of HA in NSCLC is associated with a more aggressive phenotype and shortened overall survival. In a prevalence analysis using tissue microarrays of archival human specimens (N = 194) stained by affinity histochemistry, we demonstrated that 55% of adenocarcinomas, 74% of squamous cell carcinomas and 83% of large cell carcinomas accumulated HA. The engineered enzyme PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) removes HA from the tumor microenvironment. PEGPH20-based therapies are being evaluated in clinical studies of several solid tumors, including NSCLC (NCT02346370, NCT02563548). Herein, we evaluated the hypothesis that PEGPH20 combination therapy could enhance the efficacy of pemetrexed (PEM), a folate antimetabolite approved by FDA as a first-line treatment in combination with cisplatin, against locally advanced and metastatic NSCLC in patients with non-squamous histology. Methods: We evaluated PEGPH20 plus PEM in a NSCLC xenograft model. First, the human NSCLC adenocarinoma cell line A549 was transduced with hyaluronan synthase-3 (HAS3) to generate the A549/HAS3 cell line. Next, A549/HAS3 cells were inoculated adjacent to the tibial periosteum of nude mice and tumor growth was monitored via ultrasonography. When tumors size reached ∼250 mm3, mice were staged into six groups: (1) vehicle; (2) PEGPH20, (3) PEM daily, (4) PEM weekly, (5) PEGPH20+PEM daily or (6) PEGPH20+PEM weekly. Vascular volume, hypoxia and tumor growth inhibition (TGI) were assessed using conventional methods. Affinity histochemical staining for HA was performed on formalin-fixed paraffin-embedded tissue sections after harvest. Results: A549/HAS3 tumors grew faster than parental A549 tumors in vivo. PEGPH20 monotherapy significantly reduced tumoral HA, increased vascular volume and reduced hypoxia in tumors. Further, TGI with PEGPH20+PEM, weekly or daily, was 29.7 or 31.1%, respectively, whereas in either PEGPH20 alone or PEM alone, both were Conclusion: These data suggest that addition of PEGPH20 to pemetrexed increases the efficacy of PEM and support further investigation of PEGPH20 plus PEM treatment in NSCLC tumors of non-squamous histology that accumulate HA. Citation Format: Renee Clift, Jessica A. Cowell, Susan J. Zimmerman, Mathieu Marella, Ping Jiang, Arnold B. Gelb, Michael J. LaBarre, Daniel C. Maneval, Curtis B. Thompson, Xiaoming Li. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances pemetrexed antitumor efficacy in a human nonsquamous NSCLC xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 283.
Ping Jiang - One of the best experts on this subject based on the ideXlab platform.
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abstract 283 pegylated Recombinant Hyaluronidase ph20 pegph20 enhances pemetrexed antitumor efficacy in a human nonsquamous nsclc xenograft model
Cancer Research, 2016Co-Authors: Renee Clift, Susan Zimmerman, Ping Jiang, Daniel C Maneval, Jessica Cowell, Mathieu Marella, Arnold B Gelb, Michael J Labarre, Curtis B ThompsonAbstract:Introduction: Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that has been shown to accumulate at high levels in several cancers, including non-small cell lung cancer (NSCLC). The accumulation of HA in NSCLC is associated with a more aggressive phenotype and shortened overall survival. In a prevalence analysis using tissue microarrays of archival human specimens (N = 194) stained by affinity histochemistry, we demonstrated that 55% of adenocarcinomas, 74% of squamous cell carcinomas and 83% of large cell carcinomas accumulated HA. The engineered enzyme PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) removes HA from the tumor microenvironment. PEGPH20-based therapies are being evaluated in clinical studies of several solid tumors, including NSCLC (NCT02346370, NCT02563548). Herein, we evaluated the hypothesis that PEGPH20 combination therapy could enhance the efficacy of pemetrexed (PEM), a folate antimetabolite approved by FDA as a first-line treatment in combination with cisplatin, against locally advanced and metastatic NSCLC in patients with non-squamous histology. Methods: We evaluated PEGPH20 plus PEM in a NSCLC xenograft model. First, the human NSCLC adenocarinoma cell line A549 was transduced with hyaluronan synthase-3 (HAS3) to generate the A549/HAS3 cell line. Next, A549/HAS3 cells were inoculated adjacent to the tibial periosteum of nude mice and tumor growth was monitored via ultrasonography. When tumors size reached ∼250 mm3, mice were staged into six groups: (1) vehicle; (2) PEGPH20, (3) PEM daily, (4) PEM weekly, (5) PEGPH20+PEM daily or (6) PEGPH20+PEM weekly. Vascular volume, hypoxia and tumor growth inhibition (TGI) were assessed using conventional methods. Affinity histochemical staining for HA was performed on formalin-fixed paraffin-embedded tissue sections after harvest. Results: A549/HAS3 tumors grew faster than parental A549 tumors in vivo. PEGPH20 monotherapy significantly reduced tumoral HA, increased vascular volume and reduced hypoxia in tumors. Further, TGI with PEGPH20+PEM, weekly or daily, was 29.7 or 31.1%, respectively, whereas in either PEGPH20 alone or PEM alone, both were Conclusion: These data suggest that addition of PEGPH20 to pemetrexed increases the efficacy of PEM and support further investigation of PEGPH20 plus PEM treatment in NSCLC tumors of non-squamous histology that accumulate HA. Citation Format: Renee Clift, Jessica A. Cowell, Susan J. Zimmerman, Mathieu Marella, Ping Jiang, Arnold B. Gelb, Michael J. LaBarre, Daniel C. Maneval, Curtis B. Thompson, Xiaoming Li. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances pemetrexed antitumor efficacy in a human nonsquamous NSCLC xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 283.
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Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment
BioMed research international, 2014Co-Authors: Anne Kultti, Ryan Osgood, Curtis B Thompson, Chunmei Zhao, Susan Zimmerman, Rebecca Symons, Ping Jiang, Netai C. Singha, Jeffrey R. InfanteAbstract:Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human Recombinant Hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.
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a phase ib study of gemcitabine plus pegph20 pegylated Recombinant human Hyaluronidase in patients with stage iv previously untreated pancreatic cancer
Journal of Clinical Oncology, 2013Co-Authors: Sunil R Hingorani, William P Harris, Thaddeus J Beck, Boris A Berdov, Stephanie Ann Wagner, Eduard M Pshevlotsky, Sergei Tjulandin, Oleg Gladkov, Randall F Holcombe, Ping JiangAbstract:4010 Background: PEGPH20 is a PEGylated version of human Recombinant Hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetical...
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abstract 3796 pegylated human Recombinant Hyaluronidase ph20 reduces solid tumor hypoxia
Cancer Research, 2012Co-Authors: Ping Jiang, Ryan Osgood, Rebecca Symons, Michael H Shepard, Daniel C Maneval, Curtis B ThompsonAbstract:Tumor hypoxia, the pathophysiological result of the structural and functional disruption of the tumor microcirculation and the deterioration of normal diffusion geometry, is strongly associated with tumor proliferation and resistance to therapy, both chemotherapy and radiotherapy. Indeed, hypoxia-associated resistance to photon radiotherapy is a severe clinical problem, as the radiation doses required to achieve the same treatment effect in hypoxic tumors can be three times the doses required in normoxic tumors. The extracellular matrix (ECM) glycosaminoglycan hyaluronan (HA) accumulates to high levels in ∼30% of solid tumors. Since HA is highly hydrophilic, ECM HA accumulation is believed to contribute to the elevated interstitial fluid pressure (IFP) and subsequent tumor vessel constriction observed in solid tumors. This vascular constriction contributes to the pathologic hypoxia present in these tumors. PEGPH20, a pegylated human Recombinant Hyaluronidase PH20, when delivered intravenously in preclinical models has been shown to enzymatically remove tumor HA and decrease both tumor IFP and water, leading to increased tumor vascular perfusion and enhanced chemotherapeutic delivery (Thompson 2010). Here we aimed to extend these observations and determine whether PEGPH20 would both increase tumor blood flow and reduce tumor hypoxia following PEGPH20-mediated HA removal. Nude mice were inoculated with human BxPC-3 pancreatic cancer cells adjacent to the right tibial periosteum. When tumors reached 15-20 mm in diameter (nα8/group), mice were staged into two treatment groups: (1) vehicle control and (2) PEGPH20 monotherapy. Vehicle or PEGPH20 (4.5 mg/kg) was administered to animals intravenously twice weekly for one week. The hypoxyprobe pimonidazole (60 mg/kg, ip) was administered to animals two hours prior to sacrifice, and fluorescent carbocyanine (75 μL, iv) 5 minutes prior to sacrifice. At sacrifice, whole tumors were removed, bisected, embedded in OCT medium, and processed for immunohistochemistry (hypoxyprobe and CD31) or simply imaged microscopically (carbocyanine). Hypoxia, blood vessel position, and tumor perfusion were assessed using pimonidazole, CD31 and carbocyanine, respectively. Compound images were created and the spatial relationship between hypoxia and vasculature perfusion evaluated. Consistent with prior studies, tumor HA was depleted in the PEGPH20-treated tumors. Further, tumor vascular perfusion (carbocyanine) increased 86% (p=0.0007) and tumor hypoxia decreased by 66% (p=0.03) in PEGPH20-treated animals, relative to the vehicle controls. These findings suggest that PEGPH20-mediated reduction in tumor HA increases tumor perfusion, while concomitantly reducing tumor hypoxia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3796. doi:1538-7445.AM2012-3796
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abstract 2501 pegylated human Recombinant Hyaluronidase pegph20 enhances radiotherapy in hyaluronan rich solid tumors
Cancer Research, 2011Co-Authors: Jesse Bahn, Ryan Osgood, Rebecca Symons, Ping Jiang, James Skipper, Arnie Garcia, Gregory I Frost, Harold Michael Shepard, Curtis B ThompsonAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The accumulation of the glycosaminoglycan hyaluronan (HA) in the extracellular matrix (ECM) of solid tumors contributes to increased tumor interstitial fluid pressure IFP), localized edema and reduced intratumoral blood flow. We recently reported that sustained enzymatic depletion of tumor HA with a pegylated Recombinant human Hyaluronidase PH20 (PEGPH20) decreases tumor IFP and water content, while significantly increasing vascular perfusion within HA-rich prostate PC3 tumors (Thompson et al, 2010). As localized tissue hypoxia reduces the effectiveness of radiation therapy (Baumgartner et al, 1998), we hypothesized that PEGPH20 treatment would reduce tumor hypoxia, thereby radio-sensitizing tumor cells. To evaluate whether PEGPH20 sensitizes HA-rich tumors, radiotherapy resistant human prostate PC3 cells (2×106) were inoculated into the right tibia periosteum of nude mice (NCR nu/nu) and tumor growth monitored with a high resolution 3D ultrasound. When the tumors reached ∼800 mm3 (n ≥ 8/group), mice were staged into 4 treatment groups: (1) vehicle control; (2) mono-radiotherapy at 2.5 Gy, q3d; (3) PEGPH20 monotherapy, 4.5 mg/kg, i.v. q3d; or (4) PEGPH20 plus radiotherapy. To increase intra-tumoral blood flow, PEGPH20 was administrated 3 hours prior to radiation therapy. Histological evaluation of a subset of mice confirmed that HA was completely degraded 3 hours post- PEGPH20 treatment. At study Day 15, tumor growth inhibition (TGI) with radiation alone or PEGPH20 alone was 99.2% (p=0.009) and 71.4% (p=0.08), respectively, relative to vehicle treated animals. PEGPH20 plus radiotherapy inhibited tumor growth by 140.6% (p=0.0002), relative to vehicle treated animals. The mean tumor size of the PEGPH20 plus radiotherapy group was reduced to ∼550 mm3, with 3-out-of-8 partial regressors (i.e. tumor size decrease to 50% or less of tumor staging size). These findings suggest that PEGPH20-mediated HA removal, and subsequent increase in tumoral blood flow, may increase the efficacy of radiation therapy in hyaluronan-rich tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2501. doi:10.1158/1538-7445.AM2011-2501
Yujun Huang - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2740: PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models
Immunology, 2018Co-Authors: Renee Clift, Curtis B Thompson, Barbara Blouw, Yujun HuangAbstract:Hyaluronan (HA) is an extracellular glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumors. 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. PEGPH20-mediated HA degradation increases anti-PD-L1 efficacy in HA-rich EMT-6 tumors and enhances CD8+ T-cell infiltration in tumors. Cancer patients can be resistant to anti-PD-L1; strategies to increase T cell infiltration may lead to anti-PD-L1 effectiveness in nonresponders. We hypothesized that PEGPH20 may convert HA-rich tumors with low T cell infiltration from resistant to sensitive to anti-PD-L1 immunotherapy. 4T1 breast cancer cells transduced with HAS3 to generate HA-rich 4T1/HAS3 cells averaged ~2.9×104 CD8+ T cell/g tumor on day 18 post-tumor inoculation and were resistant to anti-PD-L1 monotherapy. PEGPH20 treatment of 4T1/HAS3 tumors significantly increased CD8+ T cell infiltration to ~7.2×104/g tumor (p=0.0007) and 4T1/HAS3 tumors became sensitive to anti-PD-L1 treatment. PEGPH20 + anti-PD-L1 led to 64.0% tumor growth inhibition (TGI; p Citation Format: Renee Clift, Xiaoming Li, Barbara Blouw, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models [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 2740.
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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
Cancer Research, 2017Co-Authors: Renee Clift, Curtis B Thompson, Jisook Lee, Yujun HuangAbstract: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 Citation Format: Renee Clift, Jisook Lee, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models [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 641. doi:10.1158/1538-7445.AM2017-641
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abstract lb 198 combination of pegylated Recombinant Hyaluronidase ph20 pegph20 with live attenuated double deleted ladd listeria enhances tumor infiltrating cd8 t cell response and antitumor efficacy in mice
Cancer Research, 2017Co-Authors: Jisook Lee, Sanna Rosengren, Benjamin J. Thompson, Barbara Blouw, Yujun Huang, Meredith L Leong, Dirk G Brockstedt, Curtis B ThompsonAbstract:Successful immunotherapy is highly dependent on inducing an efficient CD8+ T cell-mediated antitumor immune response. The trafficking and activation of these effector CD8+ T cells are often inhibited by various immunosuppressive mechanisms in the tumor microenvironment (TME). Hyaluronan (HA), a glycosaminoglycan that accumulates in the TME of many solid tumors, is associated with rapid tumor progression, poor prognosis and increased immunosuppression. We have previously demonstrated in nonclinical models that enzymatic degradation of TME HA by intravenous PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) facilitates delivery of chemotherapeutics to tumors and enhances checkpoint inhibitor efficacy. Based on these observations we hypothesized that PEGPH20 may improve current cancer immunotherapies by increasing immune cell infiltration into tumors. To test this hypothesis we used CT26/HAS3 tumors, CT26 murine colon carcinoma cells engineered to over-express hyaluronan synthase-3, and treated them with PEGPH20 in combination with Recombinant live-attenuated double-deleted strains of Listeria monocytogenes expressing AH1 (gp70423-431, SPSYVYHQF), the immunodominant CD8+ T cell epitope of CT26 (LADD-AH1). PEGPH20 (1mpk), which results in nearly complete removal of HA at 24hrs, was administered 24hrs prior to LADD-AH1. In this model, LADD-AH1 alone inhibited tumor growth which correlated with an increase in IFNγ+ (p=0.0019) and granzyme B+ CD8+ tumor infiltrating lymphocytes (TILs) (p=0.0006). Tumor-associated macrophages (TAMs) from LADD-AH1 treated tumors were more immunostimulatory with a decrease in MHCIIlow (p=0.0205) and CD206+ TAMs (p=0.0003). Moreover, the combination of PEGPH20 and LADD-AH1 resulted in enhanced anti-tumor activity compared to either PEGPH20 (p=0.0047) or LADD-AH1 alone (p=0.0002). Significant TME changes were observed in the combination treatment with an increase in CD8+ TILs (p=0.0200, of which 88% were granzyme B+), NK cells (p=0.0205) and an increase in CD8:Treg ratio (p=0.0007).These findings were corroborated by immunohistochemical analysis demonstrating an increase in CD3+ T cells with PEGPH20 treatment. Taken together, these data suggest that HA accumulation in tumors may act as a barrier to immune cell access and that reduction of HA by PEGPH20 facilitates increased accumulation of tumor antigen-specific CD8+ effector T cells induced by LADD immunotherapy. Our findings reveal a benefit of PEGPH20 in enhancing tumor infiltration of cytotoxic CD8+ T cells induced by LADD that translate into a significant improvement in efficacy in a murine model of HA-high tumors. Citation Format: Jisook Lee, Meredith Leong, Yujun Huang, Benjamin J. Thompson, Sanna Rosengren, Barbara Blouw, Dirk G. Brockstedt, Curtis B. Thompson. Combination of PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) with live-attenuated, double-deleted (LADD) Listeria enhances tumor infiltrating CD8+ T cell response and antitumor efficacy in mice [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 LB-198. doi:10.1158/1538-7445.AM2017-LB-198
Renee Clift - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2740: PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models
Immunology, 2018Co-Authors: Renee Clift, Curtis B Thompson, Barbara Blouw, Yujun HuangAbstract:Hyaluronan (HA) is an extracellular glycosaminoglycan that accumulates in the tumor microenvironment (TME) of many solid tumors. 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. PEGPH20-mediated HA degradation increases anti-PD-L1 efficacy in HA-rich EMT-6 tumors and enhances CD8+ T-cell infiltration in tumors. Cancer patients can be resistant to anti-PD-L1; strategies to increase T cell infiltration may lead to anti-PD-L1 effectiveness in nonresponders. We hypothesized that PEGPH20 may convert HA-rich tumors with low T cell infiltration from resistant to sensitive to anti-PD-L1 immunotherapy. 4T1 breast cancer cells transduced with HAS3 to generate HA-rich 4T1/HAS3 cells averaged ~2.9×104 CD8+ T cell/g tumor on day 18 post-tumor inoculation and were resistant to anti-PD-L1 monotherapy. PEGPH20 treatment of 4T1/HAS3 tumors significantly increased CD8+ T cell infiltration to ~7.2×104/g tumor (p=0.0007) and 4T1/HAS3 tumors became sensitive to anti-PD-L1 treatment. PEGPH20 + anti-PD-L1 led to 64.0% tumor growth inhibition (TGI; p Citation Format: Renee Clift, Xiaoming Li, Barbara Blouw, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (pegvorHyaluronidase alfa PEGPH20) converts HA-rich tumors from resistant to sensitive to anti-PD-L1 immunotherapy in murine syngeneic breast cancer models [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 2740.
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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
Cancer Research, 2017Co-Authors: Renee Clift, Curtis B Thompson, Jisook Lee, Yujun HuangAbstract: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 Citation Format: Renee Clift, Jisook Lee, Curtis B. Thompson, Yujun Huang. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances tumor infiltrating CD8+ T cell accumulation and improves checkpoint inhibitor efficacy in murine syngeneic breast cancer models [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 641. doi:10.1158/1538-7445.AM2017-641
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Abstract 4886: PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances checkpoint inhibitor efficacy in syngeneic mouse models of cancer
Immunology, 2016Co-Authors: Sanna Rosengren, Susan Zimmerman, Renee Clift, Jennifer Souratha, Benjamin J. Thompson, Barbara Blouw, Qiping Zhao, Michael Shepard, Dan C. ManevalAbstract:Hyaluronan (HA), a major extracellular matrix component in many solid tumors, has been proposed to contribute to tumor progression, and to play a complex role in T lymphocyte biology. Its depletion by intravenous PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) remodels the tumor stroma, reduces intratumoral pressure, decompresses tumor blood vessels, and facilitates tumor drug delivery. However, the impact of HA removal on intra-tumoral immune responses and the efficacy of immune checkpoint inhibitors is unknown. To evaluate checkpoint blockade efficacy with PEGPH20, two mouse tumor cell lines, CT26 (colon) and MH194 (pancreatic, derived from spontaneous tumors in KrasLSL-G12D/+Trp53LSL-R172H/+Cre mice) were transduced with hyaluronan synthase-3 (HAS3) to generate syngeneic HA-high tumor models. For anti-CTLA4 studies, parental CT26 and CT26/HAS3 cells were implanted peritibially in Balb/C mice. While treatment with anti-mouse-CTLA4 alone (clone 9D9) inhibited tumor growth in CT26 tumors (37%), PEGPH20 alone did not significantly inhibit tumor growth or increase anti-CTLA4 efficacy. In contrast, tumor growth of CT26/HAS3 tumors was inhibited to a greater extent by the combination of PEGPH20 and anti-CTLA4 (79%) (PEGPH20 treatment 24h prior to anti-CTLA4 treatment), compared to anti-CTLA4 alone (60%, p = 0.002) or PEGPH20 alone (43%, p = 0.0001). Furthermore, gene expression of markers associated with immune suppression, such as IL10 and FoxP3, was higher in CT26/HAS3 than in CT26 tumors; suggesting an association between HA content and immune suppression. To evaluate the effect of PEGPH20 on tumor growth inhibition by PD-1 blockade, MH194/HAS3 cells were implanted peritibially in C57BL/6 mice along with immortalized pancreatic stellate cells. Growth of MH194/HAS3 tumors was significantly inhibited (33%, p = 0.049) by anti-mouse-PD-L1 antibody (clone 10F.9G2), and the addition of PEGPH20 (24h prior to anti-PD-L1) to anti-PD-L1 further enhanced tumor growth inhibition (79%, p Citation Format: Sanna Rosengren, Renee Clift, Susan J. Zimmerman, Jennifer Souratha, Benjamin J. Thompson, Barbara Blouw, Xiaoming Li, Qiping Zhao, Michael Shepard, Dan C. Maneval, Christopher D. Thanos, Curtis B. Thompson. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances checkpoint inhibitor efficacy in syngeneic mouse models of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4886.
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abstract 283 pegylated Recombinant Hyaluronidase ph20 pegph20 enhances pemetrexed antitumor efficacy in a human nonsquamous nsclc xenograft model
Cancer Research, 2016Co-Authors: Renee Clift, Susan Zimmerman, Ping Jiang, Daniel C Maneval, Jessica Cowell, Mathieu Marella, Arnold B Gelb, Michael J Labarre, Curtis B ThompsonAbstract:Introduction: Hyaluronan (HA) is an extracellular matrix glycosaminoglycan that has been shown to accumulate at high levels in several cancers, including non-small cell lung cancer (NSCLC). The accumulation of HA in NSCLC is associated with a more aggressive phenotype and shortened overall survival. In a prevalence analysis using tissue microarrays of archival human specimens (N = 194) stained by affinity histochemistry, we demonstrated that 55% of adenocarcinomas, 74% of squamous cell carcinomas and 83% of large cell carcinomas accumulated HA. The engineered enzyme PEGylated Recombinant human Hyaluronidase PH20 (PEGPH20) removes HA from the tumor microenvironment. PEGPH20-based therapies are being evaluated in clinical studies of several solid tumors, including NSCLC (NCT02346370, NCT02563548). Herein, we evaluated the hypothesis that PEGPH20 combination therapy could enhance the efficacy of pemetrexed (PEM), a folate antimetabolite approved by FDA as a first-line treatment in combination with cisplatin, against locally advanced and metastatic NSCLC in patients with non-squamous histology. Methods: We evaluated PEGPH20 plus PEM in a NSCLC xenograft model. First, the human NSCLC adenocarinoma cell line A549 was transduced with hyaluronan synthase-3 (HAS3) to generate the A549/HAS3 cell line. Next, A549/HAS3 cells were inoculated adjacent to the tibial periosteum of nude mice and tumor growth was monitored via ultrasonography. When tumors size reached ∼250 mm3, mice were staged into six groups: (1) vehicle; (2) PEGPH20, (3) PEM daily, (4) PEM weekly, (5) PEGPH20+PEM daily or (6) PEGPH20+PEM weekly. Vascular volume, hypoxia and tumor growth inhibition (TGI) were assessed using conventional methods. Affinity histochemical staining for HA was performed on formalin-fixed paraffin-embedded tissue sections after harvest. Results: A549/HAS3 tumors grew faster than parental A549 tumors in vivo. PEGPH20 monotherapy significantly reduced tumoral HA, increased vascular volume and reduced hypoxia in tumors. Further, TGI with PEGPH20+PEM, weekly or daily, was 29.7 or 31.1%, respectively, whereas in either PEGPH20 alone or PEM alone, both were Conclusion: These data suggest that addition of PEGPH20 to pemetrexed increases the efficacy of PEM and support further investigation of PEGPH20 plus PEM treatment in NSCLC tumors of non-squamous histology that accumulate HA. Citation Format: Renee Clift, Jessica A. Cowell, Susan J. Zimmerman, Mathieu Marella, Ping Jiang, Arnold B. Gelb, Michael J. LaBarre, Daniel C. Maneval, Curtis B. Thompson, Xiaoming Li. PEGylated Recombinant Hyaluronidase PH20 (PEGPH20) enhances pemetrexed antitumor efficacy in a human nonsquamous NSCLC xenograft model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 283.
Sunil R Hingorani - One of the best experts on this subject based on the ideXlab platform.
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phase ib study of pegylated Recombinant human Hyaluronidase and gemcitabine in patients with advanced pancreatic cancer
Clinical Cancer Research, 2016Co-Authors: Sunil R Hingorani, William P Harris, Thaddeus J Beck, Boris A Berdov, Stephanie Ann Wagner, Eduard M Pshevlotsky, Sergei Tjulandin, Oleg Gladkov, Randall F HolcombeAbstract:Purpose: This Phase 1b study evaluated the safety and tolerability of PEGylated human Recombinant Hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a Phase 2 dose for patients with untreated Stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated. Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In Cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated. Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n=4), 1.6 (n=4), or 3.0 µg/kg (n=20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pre-treatment tissue hyaluronan (HA) levels, median PFS and OS were 7.2 and 13.0 months for "high"-HA patients (n=6), and 3.5 and 5.7 months for "low"-HA patients (n=11), respectively. Conclusion: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high-HA tumors.
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a phase ib study of gemcitabine plus pegph20 pegylated Recombinant human Hyaluronidase in patients with stage iv previously untreated pancreatic cancer
Journal of Clinical Oncology, 2013Co-Authors: Sunil R Hingorani, William P Harris, Thaddeus J Beck, Boris A Berdov, Stephanie Ann Wagner, Eduard M Pshevlotsky, Sergei Tjulandin, Oleg Gladkov, Randall F Holcombe, Ping JiangAbstract:4010 Background: PEGPH20 is a PEGylated version of human Recombinant Hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetical...