Liposomal Irinotecan Shows a Larger Therapeutic Index than Non-liposomal Irinotecan in Patient-Derived Xenograft Models of Pancreatic Cancer.

IF 3.2 Q2 ONCOLOGY

Oncology and Therapy Pub Date : 2023-03-01 Epub Date: 2023-01-16 DOI:10.1007/s40487-022-00215-2

Sandrine Barbier, Benjamin Beaufils, Ricardo de Miguel, Melissa Reyre, Yannick Le Meitour, Andreanne Lortie, Marc Hillairet de Boisferon, Sophie Chaumeron, Anne Espirito, Lina Fossati, Pauline Lagarde, Stephan Klinz, Arunthathi Thiagalingam, Stéphane Lezmi, Florence Meyer-Losic

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Abstract

Introduction: Liposomal irinotecan promotes controlled sustained release of irinotecan (CPT-11), therefore, we hypothesize that the therapeutic index (quantitative measurement of the relative efficacy/safety ratio of a drug) will be higher for liposomal than non-liposomal irinotecan.

Methods: We compared the therapeutic indexes of liposomal and non-liposomal irinotecan in mice bearing subcutaneous patient-derived xenograft (PDX) pancreatic tumors under dosing regimens approximating the clinical setting. Following preliminary drug sensitivity/antitumor activity analyses on three PDX tumor models, one model was selected for analyses of efficacy, biomarker, toxicology, pharmacokinetics in mice receiving liposomal irinotecan (2.5, 10, 50 mg/kg/week) or non-liposomal irinotecan (10, 25, 50 mg/kg/week). The maximum tolerated dose (MTD) for each treatment was 50 mg/kg/week.

Results: Using the selected IM-PAN-001 model at the MTD (both treatments, 50 mg/kg/week), antitumor activity, phospho-histone gamma-H2AX protein staining in cancer cell nuclei, histological tumor regression, and plasma levels of CPT-11 and its active metabolite SN-38 after 24 h were greater with liposomal than non-liposomal irinotecan, but tumor SN-38 levels were similar. At the lowest doses assessed, antitumor activity, histological tumor regression, and jejunum and bone marrow toxicity were similar. Based on these findings, liposomal and non-liposomal irinotecan had therapeutic indexes of 20 and 5, respectively.

Conclusion: This non-clinical study showed a fourfold broader therapeutic index with liposomal than non-liposomal irinotecan in mice bearing IM-PAN-001 PDX pancreatic tumors, even at optimal dosing for the two drugs. These findings support the clinical benefit observed with liposomal irinotecan in patients with pancreatic cancer.

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在胰腺癌患者来源的异种移植模型中，脂质体伊立替康显示出比非脂质体伊立替康更大的治疗指数。

简介:伊立替康脂质体促进伊立替康控释(CPT-11)，因此，我们假设脂质体的治疗指数(药物相对有效性/安全性的定量测量)将高于非脂质体的伊立替康。方法:比较伊立替康脂质体和非脂质体在接近临床的剂量方案下对小鼠皮下患者源异种移植胰腺肿瘤的治疗指标。在对三种PDX肿瘤模型进行初步的药物敏感性/抗肿瘤活性分析后，选择一种模型进行伊立替康脂质体(2.5、10、50 mg/kg/周)或非伊立替康脂质体(10、25、50 mg/kg/周)小鼠的疗效、生物标志物、毒理学和药代动力学分析。每次治疗的最大耐受剂量(MTD)为50 mg/kg/周。结果:采用所选IM-PAN-001模型(两种治疗均为50 mg/kg/周)，伊立替康脂质体的抗肿瘤活性、肿瘤细胞核磷酸化组蛋白γ - h2ax蛋白染色、肿瘤组织学消退、24 h后血浆CPT-11及其活性代谢物SN-38水平均高于非脂质体，但肿瘤SN-38水平相似。在评估的最低剂量下，抗肿瘤活性、组织学肿瘤消退、空肠和骨髓毒性相似。基于这些结果，伊立替康脂质体和非脂质体的治疗指数分别为20和5。结论:这项非临床研究显示，即使在两种药物的最佳剂量下，脂质体伊立替康对IM-PAN-001 PDX胰腺肿瘤小鼠的治疗指数也比非脂质体伊立替康宽4倍。这些发现支持伊立替康脂质体治疗胰腺癌患者的临床获益。

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来源期刊

Oncology and Therapy ONCOLOGY-

CiteScore

3.40

自引率

0.00%

发文量

审稿时长

6 weeks

期刊介绍： Now indexed in PubMed Aims and Scope Oncology and Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality pre-clinical, clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all therapeutic areas. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Oncology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research. Rapid Publication The journal’s rapid publication timelines aim for a peer review decision within 2 weeks of submission. If an article is accepted it will be published online 3-4 weeks from acceptance. These rapid timelines are achieved through the combination of a dedicated in-house editorial team, who closely manage article workflow, and an extensive Editorial and Advisory Board who assist with rapid peer review. This allows the journal to support the rapid dissemination of research, whilst still providing robust peer review. Combined with the journal’s open access model this allows for the rapid and efficient communication of the latest research and reviews, allowing the advancement of clinical therapies. Personal Service The journal’s dedicated in-house editorial team offer a personal “concierge service” meaning that authors will always have a personal point of contact able to update them on the status of their manuscript. The editorial team check all manuscripts to ensure that articles conform to the most recent COPE, GPP and ICMJE publishing guidelines. This supports the publication of ethically sound and transparent research. We also encourage pre-submission enquiries and are always happy to provide a confidential assessment of manuscripts. Digital features and plain language summaries Oncology and Therapy offers a range of additional features designed to increase the visibility, readership and educational value of the journal’s content. Each article is accompanied by key summary points, giving a time-efficient overview of the content to a wide readership. Articles may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand the scientific content and overall implications of the article. The journal also provides the option to include various types of digital features including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations. All additional features are peer reviewed to the same high standard as the article itself. If you consider that your paper would benefit from the inclusion of a digital feature, please let us know. Our editorial team are able to create high-quality slide decks and infographics in-house, and video abstracts through our partner Research Square, and would be happy to assist in any way we can. For further information about digital features, please contact the journal editor (see ‘Contact the Journal’ for email address), and see the ‘Guidelines for digital features and plain language summaries’ document under ‘Submission guidelines’. Preprints We encourage posting of preprints of primary research manuscripts on preprint servers, authors'' or institutional websites, and open communications between researchers whether on community preprint servers or preprint commenting platforms. Posting of preprints is not considered prior publication and will not jeopardize consideration in our journals. Please see here for further information on preprint sharing: https://www.springer.com/gp/authors-editors/journal-author/journal-author-helpdesk/submission/1302#c16721550 Peer Review Process Upon submission, manuscripts are assessed by the editorial team to ensure they fit within the aims and scope of the journal and are also checked for plagiarism. All suitable submissions are then subject to a comprehensive single-blind peer review. Reviewers are selected based on their relevant expertise and publication history in the subject area. The journal has an extensive pool of editorial and advisory board members who have been selected to assist with peer review based on the afore-mentioned criteria. At least two extensive reviews are required to make the editorial decision, with the exception of some article types such as Commentaries, Editorials and Letters which are generally reviewed by one member of the Editorial Board. Where reviewer recommendations are conflicted, the editorial board will be contacted for further advice and a presiding decision. Manuscripts are then either accepted, rejected or authors are required to make major or minor revisions (both reviewer comments and editorial comments may need to be addressed). Once a revised manuscript is re-submitted, it is assessed along with the responses to reviewer comments and if it has been adequately revised it will be accepted for publication. Accepted manuscripts are then copyedited and typeset by the production team before online publication. Appeals against decisions following peer review are considered on a case by case basis and should be sent to the journal editor. Copyright Oncology and Therapy''s content is published open access under the Creative Commons Attribution-Noncommercial License, which allows users to read, copy, distribute, and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited. The author assigns the exclusive right to any commercial use of the article to Springer. For more information about the Creative Commons Attribution-Noncommercial License, click here: http://creativecommons.org/licenses/by-nc/4.0 Publication Fees Upon acceptance of an article, authors will be required to pay the mandatory Rapid Service Fee of £3650/€4500/$5100. The journal will consider fee discounts for developing countries and this is decided on a case by case basis. Open Access All articles published by Oncology and Therapy are published open access Contact For more information about the journal, including pre-submission enquiries, please contact managing editor Lydia Alborn at lydia.alborn@springer.com.