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Scott Eliasof - One of the best experts on this subject based on the ideXlab platform.
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Lata Jayaraman, Edward Graeme Garmey, Joel E Tepper, Scott EliasofAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.
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efficacy of the nanoparticle drug conjugate Crlx101 in combination with bevacizumab in metastatic renal cell carcinoma results of an investigator initiated phase i iia clinical trial
Annals of Oncology, 2016Co-Authors: Stephen M Keefe, Scott Eliasof, Edward Graeme Garmey, Roger B Cohen, Ronac Mamtani, Jean H Hoffmancensits, Daniel F Heitjan, Andrew B Nixon, B Turnbull, Orvar GunnarssonAbstract:ABSTRACT Background Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. Crlx101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of Crlx101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to Crlx101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions Crlx101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.
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abstract 1345 tumor selective localization of Crlx101 an investigational nanoparticle drug conjugate of camptothecin
Cancer Research, 2016Co-Authors: Christian G Peters, Scott Eliasof, Douglas Lazarus, Adam Stockmann, Donna Brown, Roy I Case, Ellen Rohde, Ningning Zhang, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. In preclinical models, Crlx101 is believed to release camptothecin in the tumor in a slow and prolonged manner due to its long circulation half-life. Crlx101 has been shown preclinically to be a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α. It has demonstrated striking anti-tumor activity in several different tumor models. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way. We hypothesized that Crlx101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of Crlx101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we detected camptothecin fluorescence in Crlx101-treated tumor cells in culture as well as in tumor tissue from mice treated with Crlx101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. More recently, we have shown that camptothecin and anti-PEG co-localize specifically in tumors of patients treated with Crlx101 but not in adjoining normal tissue. We can also demonstrate that macropinocytosis and activation of actin polymerization play a role in the process by which tumor cells take up Crlx101. Using an anti-CD31 antibody, we can visualize the distance traversed by Crlx101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and Crlx101-conjugated camptothecin over time in Crlx101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with Crlx101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of Crlx101 into tumor tissue. Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Adam P. Stockmann, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Tumor selective localization of Crlx101, an investigational nanoparticle-drug conjugate of camptothecin. [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 1345.
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abstract ct090 phase ii trial of the ndc Crlx101 in combination with bevacizumab in patients with platinum resistant ovarian cancer proc
Cancer Research, 2016Co-Authors: C N Krasner, Scott Eliasof, Lata Jayaraman, Christian Peters, Michael J Birrer, Andres Tellez, William Downing, Adrian M SenderowiczAbstract:Background: Crlx101 is an investigational nanoparticle-drug conjugate (NDC) with a camptothecin payload. Crlx101 is a dual inhibitor of topoisomerase 1 and hypoxia inducible factors 1α and 2α (HIF1-α and HIF-2α). Crlx101 is being explored clinically in several tumor types including renal cell carcinoma (RCC) in combination with Avastin®, (Keefe, ASCO 2015, 4543) and platinum-resistant ovarian cancer (PROC) (Krasner ASCO 2014, 5581). The PROC study has a Crlx101 monotherapy arm (Group A) and a combination arm with Avastin (Group B). Group A patients (pts) received Crlx101 at 15mg/m2 every other week and Group B patients received Crlx101 15 mg/m2 with Avastin 10 mg/kg every other week until progression or unacceptable toxicity. The primary endpoint for both groups was rate of progression free survival at 6 months (PFS6) using RECIST 1.1 criteria. Secondary endpoints were objective response rate (ORR), PFS, ?50% reduction of CA125 over baseline, and safety. Adverse events (AEs) were assessed by CTCAE v4.0. Pre- and post-treatment tumor biopsies were collected from a cohort of patients in Group A to evaluate relevant PD endpoints, suggesting that Crlx101 is active in PROC. Results: A total of 18 PROC patients were evaluated in Group B. Demographics: Median age of the patient was 59years (range: 46-68). Median number of previous regimens was 2 (range: 1-3), ECOG PS 0 (13 pts) or 1 (5 pts). The PFS6 was demonstrated in 56% pts (10 out of 18). The PR and stable disease (SD) rates were 17% (3 out of 18 pts) and 78% (14 out of 18 pts), respectively. Median progression-free survival is 6.2 months to date. A ? 50% decline in CA125 was demonstrated in 44% pts (8 out of 18). AEs most commonly observed with the combination were nausea (10 pts, 56%), anemia (10 pts, 56%); proteinuria (8 pts, 44%) and fatigue (6 pts, 33%). The majority of AEs were Grade 1. There were only two drug-related AEs Grade ? 3: one patient developed uncomplicated and reversible elevated ALT (grade 3) and another patient had a short-lived decrease in ANC (grade 4). A retrospective analysis for both cohorts, Group A vs. Group B, demonstrated that the combination showed increased antitumor activity: PFS6: 27 vs 56%, mPFS 4.2 vs 6.2 months and CA125: 23 vs 44%. Conclusions: Crlx101 15 mg/m2 in combination with Avastin 10 mg/kg given every other week demonstrated antitumor activity and was generally well-tolerated in advanced PROC pts. An additional 25 pts will be enrolled in Group B. This combination is currently being explored in an ongoing randomized controlled Phase 2 trial in 3rd and 4th line RCC, and is also being tested in combination with weekly paclitaxel in an ongoing Phase 1b trial in PROC. Clinical trial information: NCT01652079 Citation Format: Carolyn Krasner, Michael Birrer, Christian Peters, Lata Jayaraman, Scott Eliasof, Andres Tellez, William Downing, Adrian Senderowicz. Phase II trial of the NDC Crlx101 in combination with bevacizumab in patients with platinum-resistant ovarian cancer (PROC). [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 CT090.
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abstract 3209 Crlx101 an investigational nanoparticle drug conjugate of camptothecin demonstrates synergy with immunotherapy agents in preclinical models
Cancer Research, 2016Co-Authors: Douglas Lazarus, Scott Eliasof, Christian Peters, Adam Stockmann, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. Crlx101 has been shown preclinically to be active in many different tumor types as a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α (HIF-1α). It has a long circulation half-life and has been shown pre-clinically to release camptothecin in a slow and prolonged manner in tumors. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way. Recent publications have suggested that tumor expression of the immune-suppressive molecule PD-L1 is controlled by HIF-1α. Since Crlx101 is a potent inhibitor of HIF-1α, it is possible that Crlx101 behaves as an inhibitor of the PD-1/PD-L1 axis in vivo. We therefore hypothesized that a combination of Crlx101 with agents that are being investigated in combination with the anti PD-1 antibody would lead to increased efficacy. Indole diamine oxygenase (IDO) inhibitors are a new class of drugs that decrease tumor-induced immune suppression and are currently being evaluated in the clinic with anti-PD-1 antibodies. Using syngeneic tumor models, we tested the combination of Crlx101 with three different IDO inhibitors. Treatment of the B16.F10 melanoma model with IDO inhibitors NLG919, INCB024360 or indoximod had no effect on tumor growth while Crlx101 as monotherapy showed moderate anti-tumor activity. When Crlx101 was combined with any of the three IDO inhibitors, the anti-tumor activity was greatly improved compared to monotherapy. Similar results were noted in other syngeneic tumor models. This improved combination response was not observed in IDO inhibitor combinations with the clinically approved topoisomerase inhibitor irinotecan, suggesting that Crlx101 provides a unique advantage in this context. Interestingly, Crlx101/IDO inhibitor combination was also superior to the combination of anti-PD-1 antibody and IDO inhibitor. These data suggest that Crlx101 in combination with IDO inhibitors can successfully block host-mediated immune-suppression to enhance anti-tumor immunity, and this combination may therefore show improved therapeutic activity in the clinic. We therefore plan to explore the immune-specific effects of Crlx101 as well as the mechanistic basis for the observed combination response, and use that information to guide Crlx101 clinical strategy in the setting of chemo-immunotherapy regimens. Citation Format: Douglas Lazarus, Christian Peters, Adam Stockmann, Scott Eliasof, Lata Jayaraman. Crlx101, an investigational nanoparticle-drug conjugate of camptothecin, demonstrates synergy with immunotherapy agents in preclinical models. [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 3209.
Edward Graeme Garmey - One of the best experts on this subject based on the ideXlab platform.
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pilot trial of Crlx101 in patients with advanced chemotherapy refractory gastroesophageal cancer
Journal of gastrointestinal oncology, 2017Co-Authors: Joseph Chao, Devin T. Wiley, Andrew J. Clark, Edward Graeme Garmey, James Lin, Paul Frankel, Marwan Fakih, Dean Lim, Vincent Chung, Eloise LuevanosAbstract:Background: Camptothecin (CPT) derivatives such as irinotecan have activity in 2nd-line therapy in advanced GEC with reported response rates of 0-15%. Crlx101 is an investigational nanoparticle-drug conjugate (NDC) with a CPT payload. Preclinical evidence indicates preferential uptake in tumors, and animal GEC xenograft models demonstrate superiority of Crlx101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) to assess preferential uptake of Crlx101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in patients with chemotherapy-refractory GEC. Data demonstrating preferential tumor uptake of Crlx101 has been presented separately and here we report on the clinical outcomes of patients enrolled. Methods: All pts initiated Crlx101 dosed intravenously at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle until disease progression or intolerant toxicity. While detection of preferential Crlx101 tumor uptake was the primary endpoint, with 10 pts enrolled a secondary analysis could be performed with the study having 90% power to detect ≥ 1 responder if the true response rate is ≥ 21%. Responses were assessed using RECIST 1.1. Results: Between Dec. 2012 and Dec. 2014, 10 patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) GEC and adenocarcinoma histology were enrolled and evaluable for response and toxicity. The median time-to-progression was 1.9 mo (range 0.6-8.7 mo). Best response was seen in 1 pt with stable disease (SD) for 8 cycles. Only ≥ grade 3 toxicities related to Crlx101 occurred in a single patient with grade 3 anemia and chest pain who was able to resume therapy without any further toxicity after Crlx101 was reduced to 12 mg/m2. Conclusions: Crlx101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with Crlx101 in advanced GEC should focus on combination strategies. Its favorable toxicity profile and evidence of preferential tumor uptake support further clinical research of combining Crlx101 with other targeted therapies such as anti-angiogenesis (ramucirumab) and/or immune checkpoint inhibitors. Clinical trial information: NCT01612546 Clinical trial information: NCT01612546.
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Pauline Wu, Lata Jayaraman, Edward Graeme Garmey, Joel E TepperAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle–drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 [NCT02010567][1]). Cancer Res; 77(1); 112–22. ©2016 AACR . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02010567&atom=%2Fcanres%2F77%2F1%2F112.atom
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Lata Jayaraman, Edward Graeme Garmey, Joel E Tepper, Scott EliasofAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.
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efficacy of the nanoparticle drug conjugate Crlx101 in combination with bevacizumab in metastatic renal cell carcinoma results of an investigator initiated phase i iia clinical trial
Annals of Oncology, 2016Co-Authors: Stephen M Keefe, Scott Eliasof, Edward Graeme Garmey, Roger B Cohen, Ronac Mamtani, Jean H Hoffmancensits, Daniel F Heitjan, Andrew B Nixon, B Turnbull, Orvar GunnarssonAbstract:ABSTRACT Background Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. Crlx101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of Crlx101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to Crlx101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions Crlx101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.
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chapter 8 polymeric nanoparticles and cancer lessons learnt from Crlx101
2016Co-Authors: Ismael Gritli, Scott Eliasof, Mark E. Davis, Edward Graeme Garmey, Andres Tellez, Yen YunAbstract:Crlx101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. Crlx101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of Crlx101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1α (HIF-1α) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with Crlx101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1α and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1α inhibition with antiangiogenics. Finally, we return to Crlx101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.
Christian G Peters - One of the best experts on this subject based on the ideXlab platform.
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abstract pr10 significant improvements in therapeutic index for conjugated payloads using a nanoparticle drug conjugate ndc platform to provide sustained drug release and potentially improved anticancer effects
Cancer Research, 2017Co-Authors: Chester A Metcalf, Christian G Peters, Derek Van Der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Donna Brown, Roy I Case, Ellen RohdeAbstract:Cerulean Pharma Inc.9s Dynamic Tumor Targeting™ Platform creates nanoparticle-drug conjugates (NDCs) designed to significantly mitigate a payload9s limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. By conjugating drug payloads to our novel β-cyclodextrin-PEG copolymer through linker strategies that allow modulation of release and pharmacokinetics (PK), we provide advantages over entrapped nanoparticle strategies, e.g., polymeric nanoparticles and liposomes. Cerulean has two NDCs in the clinic, Crlx101 and CRLX301, evidencing the translatability of our technology. Crlx101 has been dosed in over 350 patients and CRLX301 is in an ongoing Phase 1/2a trial. Our Dynamic Tumor Targeting Platform is applicable to a diverse range of drug payload possibilities, including small molecules with a host of physiochemical properties, i.e., hydrophobic and hydrophilic payloads, and functional groups with chemical handles for conjugation. To illustrate the capabilities of our platform we will present the biological impact of a series of cabazitaxel-containing NDCs with linkers encompassing a diversity of in vitro release rates. In vivo PK studies showed high and sustained levels of released drug in tumor tissues (>168 hrs), and in vivo mouse tumor model studies demonstrated vastly improved efficacy, i.e., tumor regression and significant tumor growth delay, and survival over separately dosed cabazitaxel including efficacy in a taxane-resistant tumor model. Cerulean continues to expand its platform through the development of new and emerging capabilities to treat patients living with cancer. In this regard, we also will address the future evolution of NDCs, including the conjugation of multiple payloads to a single NDC and the development of antibody-conjugated NDCs. This abstract is also being presented as Poster B43. Citation Format: Chester Metcalf, III, Derek van der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Christian Peters, Donna Brown, Roy Case, Ellen Rohde, Lata Jayaraman, Hongwei Wang, Tiffany Crowell, Adrian Senderowicz, Scott Eliasof. Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR10.
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Pauline Wu, Lata Jayaraman, Edward Graeme Garmey, Joel E TepperAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle–drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 [NCT02010567][1]). Cancer Res; 77(1); 112–22. ©2016 AACR . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02010567&atom=%2Fcanres%2F77%2F1%2F112.atom
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Lata Jayaraman, Edward Graeme Garmey, Joel E Tepper, Scott EliasofAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.
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preclinical efficacy of bevacizumab with Crlx101 an investigational nanoparticle drug conjugate in treatment of metastatic triple negative breast cancer
Cancer Research, 2016Co-Authors: Elizabeth Pham, Christian G Peters, Lata Jayaraman, Donna Brown, Ellen Rohde, Christina R Lee, Shan Man, Ping Xu, Melissa Yin, Annabelle ChowAbstract:VEGF-pathway targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops and one major mechanism is elevated tumor hypoxia and upregulated HIF-1α caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF-1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here we evaluated bevacizumab and Crlx101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of Crlx101 and bevacizumab to treat post-surgical, advanced metastatic breast cancer in mice. Crlx101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, Crlx101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. Crlx101 durably suppressed HIF-1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer.
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preclinical efficacy of bevacizumab with Crlx101 an investigational nanoparticle drug conjugate in treatment of metastatic triple negative breast cancer
Cancer Research, 2016Co-Authors: Elizabeth Pham, Christian G Peters, Lata Jayaraman, Donna Brown, Ellen Rohde, Christina R Lee, Shan Man, Melissa Yin, Annabelle Chow, Douglas LazarusAbstract:VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and Crlx101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of Crlx101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. Crlx101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, Crlx101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. Crlx101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.
Lata Jayaraman - One of the best experts on this subject based on the ideXlab platform.
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Pauline Wu, Lata Jayaraman, Edward Graeme Garmey, Joel E TepperAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle–drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 [NCT02010567][1]). Cancer Res; 77(1); 112–22. ©2016 AACR . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02010567&atom=%2Fcanres%2F77%2F1%2F112.atom
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Crlx101 a nanoparticle drug conjugate containing camptothecin improves rectal cancer chemoradiotherapy by inhibiting dna repair and hif1α
Cancer Research, 2017Co-Authors: Xi Tian, Minh Nguyen, Henry P Foote, Joseph M Caster, Kyle C Roche, Christian G Peters, Lata Jayaraman, Edward Graeme Garmey, Joel E Tepper, Scott EliasofAbstract:Novel agents are needed to improve chemoradiotherapy for locally advanced rectal cancer. In this study, we assessed the ability of Crlx101, an investigational nanoparticle-drug conjugate containing the payload camptothecin (CPT), to improve therapeutic responses as compared with standard chemotherapy. Crlx101 was evaluated as a radiosensitizer in colorectal cancer cell lines and murine xenograft models. Crlx101 was as potent as CPT in vitro in its ability to radiosensitize cancer cells. Evaluations in vivo demonstrated that the addition of Crlx101 to standard chemoradiotherapy significantly increased therapeutic efficacy by inhibiting DNA repair and HIF1α pathway activation in tumor cells. Notably, Crlx101 was more effective than oxaliplatin at enhancing the efficacy of chemoradiotherapy, with Crlx101 and 5-fluorouracil producing the highest therapeutic efficacy. Gastrointestinal toxicity was also significantly lower for Crlx101 compared with CPT when combined with radiotherapy. Our results offer a preclinical proof of concept for Crlx101 as a modality to improve the outcome of neoadjuvant chemoradiotherapy for rectal cancer treatment, in support of ongoing clinical evaluation of this agent (LCC1315 NCT02010567). Cancer Res; 77(1); 112-22. ©2016 AACR.
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preclinical efficacy of bevacizumab with Crlx101 an investigational nanoparticle drug conjugate in treatment of metastatic triple negative breast cancer
Cancer Research, 2016Co-Authors: Elizabeth Pham, Christian G Peters, Lata Jayaraman, Donna Brown, Ellen Rohde, Christina R Lee, Shan Man, Ping Xu, Melissa Yin, Annabelle ChowAbstract:VEGF-pathway targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops and one major mechanism is elevated tumor hypoxia and upregulated HIF-1α caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF-1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here we evaluated bevacizumab and Crlx101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of Crlx101 and bevacizumab to treat post-surgical, advanced metastatic breast cancer in mice. Crlx101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, Crlx101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. Crlx101 durably suppressed HIF-1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer.
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preclinical efficacy of bevacizumab with Crlx101 an investigational nanoparticle drug conjugate in treatment of metastatic triple negative breast cancer
Cancer Research, 2016Co-Authors: Elizabeth Pham, Christian G Peters, Lata Jayaraman, Donna Brown, Ellen Rohde, Christina R Lee, Shan Man, Melissa Yin, Annabelle Chow, Douglas LazarusAbstract:VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and Crlx101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of Crlx101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. Crlx101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, Crlx101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. Crlx101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.
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abstract 1345 tumor selective localization of Crlx101 an investigational nanoparticle drug conjugate of camptothecin
Cancer Research, 2016Co-Authors: Christian G Peters, Scott Eliasof, Douglas Lazarus, Adam Stockmann, Donna Brown, Roy I Case, Ellen Rohde, Ningning Zhang, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. In preclinical models, Crlx101 is believed to release camptothecin in the tumor in a slow and prolonged manner due to its long circulation half-life. Crlx101 has been shown preclinically to be a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α. It has demonstrated striking anti-tumor activity in several different tumor models. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way. We hypothesized that Crlx101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of Crlx101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we detected camptothecin fluorescence in Crlx101-treated tumor cells in culture as well as in tumor tissue from mice treated with Crlx101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. More recently, we have shown that camptothecin and anti-PEG co-localize specifically in tumors of patients treated with Crlx101 but not in adjoining normal tissue. We can also demonstrate that macropinocytosis and activation of actin polymerization play a role in the process by which tumor cells take up Crlx101. Using an anti-CD31 antibody, we can visualize the distance traversed by Crlx101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and Crlx101-conjugated camptothecin over time in Crlx101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with Crlx101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of Crlx101 into tumor tissue. Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Adam P. Stockmann, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Tumor selective localization of Crlx101, an investigational nanoparticle-drug conjugate of camptothecin. [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 1345.
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preclinical efficacy of bevacizumab with Crlx101 an investigational nanoparticle drug conjugate in treatment of metastatic triple negative breast cancer
Cancer Research, 2016Co-Authors: Elizabeth Pham, Christian G Peters, Lata Jayaraman, Donna Brown, Ellen Rohde, Christina R Lee, Shan Man, Melissa Yin, Annabelle Chow, Douglas LazarusAbstract:VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and Crlx101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of Crlx101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. Crlx101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, Crlx101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. Crlx101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.
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abstract 3209 Crlx101 an investigational nanoparticle drug conjugate of camptothecin demonstrates synergy with immunotherapy agents in preclinical models
Cancer Research, 2016Co-Authors: Douglas Lazarus, Scott Eliasof, Christian Peters, Adam Stockmann, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. Crlx101 has been shown preclinically to be active in many different tumor types as a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α (HIF-1α). It has a long circulation half-life and has been shown pre-clinically to release camptothecin in a slow and prolonged manner in tumors. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way. Recent publications have suggested that tumor expression of the immune-suppressive molecule PD-L1 is controlled by HIF-1α. Since Crlx101 is a potent inhibitor of HIF-1α, it is possible that Crlx101 behaves as an inhibitor of the PD-1/PD-L1 axis in vivo. We therefore hypothesized that a combination of Crlx101 with agents that are being investigated in combination with the anti PD-1 antibody would lead to increased efficacy. Indole diamine oxygenase (IDO) inhibitors are a new class of drugs that decrease tumor-induced immune suppression and are currently being evaluated in the clinic with anti-PD-1 antibodies. Using syngeneic tumor models, we tested the combination of Crlx101 with three different IDO inhibitors. Treatment of the B16.F10 melanoma model with IDO inhibitors NLG919, INCB024360 or indoximod had no effect on tumor growth while Crlx101 as monotherapy showed moderate anti-tumor activity. When Crlx101 was combined with any of the three IDO inhibitors, the anti-tumor activity was greatly improved compared to monotherapy. Similar results were noted in other syngeneic tumor models. This improved combination response was not observed in IDO inhibitor combinations with the clinically approved topoisomerase inhibitor irinotecan, suggesting that Crlx101 provides a unique advantage in this context. Interestingly, Crlx101/IDO inhibitor combination was also superior to the combination of anti-PD-1 antibody and IDO inhibitor. These data suggest that Crlx101 in combination with IDO inhibitors can successfully block host-mediated immune-suppression to enhance anti-tumor immunity, and this combination may therefore show improved therapeutic activity in the clinic. We therefore plan to explore the immune-specific effects of Crlx101 as well as the mechanistic basis for the observed combination response, and use that information to guide Crlx101 clinical strategy in the setting of chemo-immunotherapy regimens. Citation Format: Douglas Lazarus, Christian Peters, Adam Stockmann, Scott Eliasof, Lata Jayaraman. Crlx101, an investigational nanoparticle-drug conjugate of camptothecin, demonstrates synergy with immunotherapy agents in preclinical models. [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 3209.
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abstract 1345 tumor selective localization of Crlx101 an investigational nanoparticle drug conjugate of camptothecin
Cancer Research, 2016Co-Authors: Christian G Peters, Scott Eliasof, Douglas Lazarus, Adam Stockmann, Donna Brown, Roy I Case, Ellen Rohde, Ningning Zhang, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin, is currently being clinically evaluated in multiple treatment-refractory solid tumors. In preclinical models, Crlx101 is believed to release camptothecin in the tumor in a slow and prolonged manner due to its long circulation half-life. Crlx101 has been shown preclinically to be a dual inhibitor of topoisomerase 1 and hypoxia-inducible factor 1α. It has demonstrated striking anti-tumor activity in several different tumor models. Camptothecin itself was identified as an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not shown significant toxicity in over 300 patients to date, offers a unique opportunity to improve cancer treatment in a meaningful way. We hypothesized that Crlx101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of Crlx101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we detected camptothecin fluorescence in Crlx101-treated tumor cells in culture as well as in tumor tissue from mice treated with Crlx101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. More recently, we have shown that camptothecin and anti-PEG co-localize specifically in tumors of patients treated with Crlx101 but not in adjoining normal tissue. We can also demonstrate that macropinocytosis and activation of actin polymerization play a role in the process by which tumor cells take up Crlx101. Using an anti-CD31 antibody, we can visualize the distance traversed by Crlx101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and Crlx101-conjugated camptothecin over time in Crlx101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with Crlx101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of Crlx101 into tumor tissue. Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Adam P. Stockmann, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Tumor selective localization of Crlx101, an investigational nanoparticle-drug conjugate of camptothecin. [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 1345.
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abstract b37 selective tumor localization of Crlx101 a novel nanoparticle drug conjugate
Molecular Cancer Therapeutics, 2015Co-Authors: Christian G Peters, Scott Eliasof, Douglas Lazarus, Donna Brown, Roy I Case, Ellen Rohde, Ningning Zhang, Lata JayaramanAbstract:Crlx101, an investigational nanoparticle-drug conjugate (NDC) containing the payload camptothecin conjugated to a biocompatible copolymer of cyclodextrin and polyethylene glycol (PEG), is currently being evaluated clinically in multiple treatment-refractory solid tumors. Crlx101 is a dual inhibitor of topoisomerase 1 (TOPO 1) and hypoxia-inducible factor 1α (HIF-1α) and has been shown pre-clinically to be active in many different tumor types. It has a long circulation half-life and is believed to release camptothecin in a slow and prolonged fashion in the tumor. Camptothecin is an active anti-tumor agent preclinically but was not developed clinically due to its poor tolerability in patients. The development of Crlx101, which has not demonstrated significant toxicity in over 250 patients dosed to date, offers a unique opportunity to improve cancer treatment in a meaningful way. We have previously published that in gastric cancer patients treated with Crlx101, camptothecin fluorescence can be visualized in tumor tissue but not adjoining normal tissue. Based on these data we hypothesized that Crlx101 utilizes the enhanced permeability and retention (EPR) effect to accumulate selectively in tumors. In this study, we sought to mechanistically dissect the process of Crlx101 entry and accumulation into tumor cells using multiple methods, both in vitro and in xenograft tumors in vivo. Using confocal microscopy, we can detect camptothecin fluorescence in Crlx101- treated tumor cells in culture as well as in tumor tissue from mice treated with Crlx101. We can co-localize this camptothecin with intact nanoparticles using an anti-PEG antibody that specifically detects the PEG loops in the NDCs. We can also demonstrate that macropinocytosis plays a role in the manner by which tumor cells take up Crlx101. Using an anti-CD31 antibody, we can visualize the distance traversed by Crlx101 from the tumor vasculature over time. We have developed novel analytical methods to precisely quantify both released and Crlx101-conjugated camptothecin over time in Crlx101 treated tumor cells in vitro, as well as in tumor tissue from mice treated with Crlx101 in vivo. Using cell viability assays, we can correlate the kinetics of camptothecin released inside tumor cells to the degree of tumor cell kill. We believe that these data are an important step forward in understanding the precise mechanism(s) underlying selective delivery of Crlx101 into tumor tissue. Citation Format: Christian G. Peters, Douglas Lazarus, Donna Brown, Ningning Zhang, Roy Case, Ellen Rohde, Scott Eliasof, Lata Jayaraman. Selective tumor localization of Crlx101, a novel nanoparticle-drug conjugate. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B37.
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abstract 4124 potent anti tumor and metastatic breast cancer efficacy of bevacizumab with Crlx101 an investigational chemotherapy nanoparticle drug conjugate that secondarily suppresses hif 1α
Cancer Research, 2015Co-Authors: Elizabeth Pham, Scott Eliasof, Christian G Peters, Douglas Lazarus, Christina R Lee, Shan Man, Melissa Yin, Stuart F Foster, Robert S KerbelAbstract:Despite the approval of seven different VEGF-pathway targeting agents, such as bevacizumab, for ten different cancer types, VEGF inhibition has shown only modest survival benefits - especially in breast cancer. One hypothesis for this is the adaptive resistance that emerges, such as increased tumor hypoxia and elevated hypoxia-inducible factor 1α (HIF-1α), which up-regulates genes causing tumor angiogenesis, resistance and metastasis. Here we evaluated bevacizumab paired with a potent cytotoxic investigational drug called Crlx101, a nanoparticle-drug conjugate containing the payload camptothecin that secondarily suppresses HIF-1α. In a preclinical mouse model of primary human breast tumor xenografts grown in the mammary fat pad after cell-line implantation, Crlx101 monotherapy was highly efficacious. More importantly, Crlx101 with bevacizumab resulted in dramatic primary tumor shrinkages and greatly improved mice survival, despite bevacizumab alone having no activity in this model. This potent anti-tumor efficacy was further confirmed in a patient-derived xenograft (PDX) model, where again Crlx101 and bevacizumab led to obvious shrinkage of established primary tumors. HIF-1α suppression was confirmed by immunohistochemistry while changes in tumor hypoxia and perfusion were evaluated using photoacoustic imaging and contrast-enhanced ultrasound, respectively. To better reflect the clinical treatment setting, the combination was next evaluated in our preclinical model of post-surgical, overt metastatic disease. Both Crlx101 monotherapy and Crlx101 in combination with bevacizumab showed shrinkage of existing metastatic masses and prevented the emergence of new metastases. In conclusion, we showed that pairing an anti-angiogenic agent with a potent chemotherapy backbone that is able to suppress HIF-1α up-regulation induced by anti-angiogenic therapy greatly improve efficacy in both primary and metastatic breast cancer models. The data from these preclinical experiments demonstrate that further research of the combination of bevacizumab and other anti-angiogenic drugs with Crlx101 is warranted in solid tumors. Citation Format: Elizabeth Pham, Christina R. Lee, Ping Xu, Shan Man, Melissa Yin, F. Stuart Foster, Christian G. Peters, Douglas Lazarus, Scott Eliasof, Robert S. Kerbel. Potent anti-tumor and metastatic breast cancer efficacy of bevacizumab with Crlx101, an investigational chemotherapy nanoparticle-drug conjugate that secondarily suppresses HIF-1α. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4124. doi:10.1158/1538-7445.AM2015-4124