Tumor lysate particle only vaccine (TLPO) vs. Tumor lysate particle-loaded, dendritic cell vaccine (TLPLDC) to prevent recurrence in resected stage III/IV melanoma patients: Results of a phase I/IIa trial

Article

作者: Yu, Xianzhong ; Carpenter, Elizabeth L. ; Berger, Adam C ; Cindass, Jessica L. ; Adams, Alexandra M. ; Peoples, George E ; Wagner, Thomas ; Faries, Mark B. ; O'Shea, Anne E. ; Sussman, Jeffrey J ; Van Decar, Spencer G ; Hyngstrom, John ; Jakub, James W ; Cindass, Jessica L ; Chick, Robert C ; Sussman, Jeffrey J. ; Carpenter, Elizabeth L ; McCarthy, Patrick M ; Clifton, Guy T. ; Vreeland, Timothy J ; Tiwari, Ankur ; Hickerson, Annelies T ; Stojadinovic, Alex ; Hale, Diane F ; Vreeland, Timothy J. ; Hale, Diane F. ; McCarthy, Patrick M. ; O'Shea, Anne E ; Van Decar, Spencer G. ; Berger, Adam C. ; Jakub, James W. ; Valdera, Franklin A. ; Bohan, Phillip M Kemp ; Shaheen, Montaser ; Adams, Alexandra M ; Valdera, Franklin A ; Clifton, Guy T ; Chick, Robert C. ; Hickerson, Annelies T. ; Faries, Mark B ; Peoples, George E.

BACKGROUND:

The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is produced from dendritic cells (DC) loaded ex vivo with autologous tumor lysate (TL). TLPLDC has been shown to decrease recurrence in resected Stage III/IV melanoma patients in a Phase IIb trial. The TL particle only (TLPO) vaccine is produced by loading of yeast cell wall particles with autologous TL and direct injection allowing for in vivo DC loading. We have compared the TLPO and TLPLDC vaccines in an embedded Phase I/IIa trial of a larger Phase IIb trial of the TLPLDC vaccine.

METHODS:

Patients rendered clinically disease-free after surgery were randomized 2:1 to receive the TLPO or TLPLDC vaccine and followed for recurrence and death. Patients had scheduled intradermal inoculations at 0, 1, 2, 6, 12, and 18 months after enrollment. Kaplan-Meier and log-rank analysis were used to compare disease-free survival (DFS) and overall survival (OS) in an intention-to-treat (ITT) analysis.

RESULTS:

Sixty-three patients were randomized, 43 TLPO and 20 TLPLDC. Patients randomized to the TLPO arm were more likely to be female (37.2% vs. 10.0 %, p = 0.026), but otherwise no significant clinicopathological differences were identified. No differences in related adverse events (AE) were found between treatment arms. At a median follow-up of 20.5 months, the DFS (60.8% vs. 58.7 %, p = 0.714) and OS (94.6% vs. 93.8 %, p = 0.966) were equivalent between the TLPO and TLPLDC groups, respectively. No statistical differences were found in subgroup analyses between vaccine types, which accounted for receipt of immunotherapy and the use of G-CSF pre-blood draw.

CONCLUSIONS:

In a randomized, double-blind Phase I/IIa trial, there were no differences in DFS or OS in resected Stage III/IV melanoma patients receiving adjuvant TLPO versus TLPLDC vaccines. Given manufacturing advantages, further efficacy testing of TLPO is warranted in a Phase III trial.

2023-08-01·Journal for immunotherapy of cancer

Prospective, randomized, double-blind phase 2B trial of the TLPO and TLPLDC vaccines to prevent recurrence of resected stage III/IV melanoma: a prespecified 36-month analysis

Article

作者: Berger, Adam C ; Clifton, Guy Travis ; Peoples, George E ; Carpenter, Elizabeth Lee ; Yu, Xianzhong ; Hale, Diane ; Kemp Bohan, Phillip ; O'Shea, Anne E ; Smolinsky, Todd ; Thomas, Katryna ; Hyngstrom, John ; Vreeland, Timothy ; Cindass, Jessica ; Tiwari, Ankur ; Van Decar, Spencer ; Wagner, Thomas E ; Jakub, James ; Shaheen, Montaser F ; Hickerson, Annelies ; Valdera, Franklin A ; McCarthy, Patrick ; Faries, Mark ; Adams, Alexandra M ; Sussman, Jeffrey J ; Chick, Robert Connor

Background:

The tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine is made by ex vivo priming matured autologous dendritic cells (DCs) with yeast cell wall particles (YCWPs) loaded with autologous tumor lysate (TL). The tumor lysate, particle only (TLPO) vaccine uses autologous TL-loaded YCWPs coated with silicate for in vivo DC loading. Here we report the 36-month prespecified analyses of this prospective, randomized, double-blind trial investigating the ability of the TLPO and TLPLDC (±granulocyte-colony stimulating factor (G-CSF)) vaccines to prevent melanoma recurrence in high-risk patients.

Methods:

Patients with clinically disease-free stage III/IV melanoma were randomized 2:1 initially to TLPLDC versus placebo (n=124) and subsequently TLPO versus TLPLDC (n=63). All patients were randomized and blinded; however, the placebo control arm was replaced in the second randomization scheme with another novel vaccine; some analyses in this paper therefore reflect a combination of the two randomization schemes. Patients receiving the TLPLDC vaccine were further divided by their method of DC harvest (with or without G-CSF pretreatment); this was not randomized. The use of standard of care checkpoint inhibitors was not stratified between groups. Safety was assessed and Kaplan-Meier and log-rank analyses compared disease-free (DFS) and overall survival (OS).

Results:

After combining the two randomization processes, a total of 187 patients were allocated between treatment arms: placebo (n=41), TLPLDC (n=103), or TLPO (n=43). The allocation among arms created by the addition of patients from the two separate randomization schemes does not reflect concurrent randomization among all treatment arms. TLPLDC was further divided by use of G-CSF in DC harvest: no G-CSF (TLPLDC) (n=47) and with G-CSF (TLPLDC+G) (n=56). Median follow-up was 35.8 months. Only two patients experienced a related adverse event ≥grade 3, one each in the TLPLDC+G and placebo arms. DFS was 27.2% (placebo), 55.4% (TLPLDC), 22.9% (TLPLDC+G), and 60.9% (TLPO) (p<0.001). OS was 62.5% (placebo), 93.6% (TLPLDC), 57.7% (TLPLDC+G), and 94.6% (TLPO) (p=0.002).

Conclusions:

The TLPO and TLPLDC (without G-CSF) vaccines were associated with improved DFS and OS in this clinical trial. Given production and manufacturing advantages, the efficacy of the TLPO vaccine will be confirmed in a phase 3 trial.

Trial registration number:

NCT02301611.

2023-03-01·Cancer immunology, immunotherapy : CII

Divergent clinical outcomes in a phase 2B trial of the TLPLDC vaccine in preventing melanoma recurrence and the impact of dendritic cell collection methodology: a randomized clinical trial

Article

作者: Shaheen, Montaser F ; Peoples, George E ; Tiwari, Ankur ; Hale, Diane F ; McCarthy, Patrick M ; Chick, Robert C ; Vreeland, Timothy J ; Hyngstrom, John R ; O'Shea, Anne E ; Sussman, Jeffrey J ; Jakub, James W ; Adams, Alexandra M ; Kemp Bohan, Phillip M ; Yu, Xianzhong ; Wagner, Thomas E ; Valdera, Franklin A ; Clifton, Guy T ; Faries, Mark B ; Carpenter, Elizabeth L ; Berger, Adam C ; Hickerson, Annelies T

BACKGROUND:

A randomized, double-blind, placebo-controlled phase 2b trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was conducted in patients with resected stage III/IV melanoma. Dendritic cells (DCs) were harvested with and without granulocyte-colony stimulating factor (G-CSF). This analysis investigates differences in clinical outcomes and RNA gene expression between DC harvest methods.

METHODS:

The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles (YCWPs) and exposing them to phagocytosis by DCs. For DC harvest, patients had a direct blood draw or were pretreated with G-CSF before blood draw. Patients were randomized 2:1 to receive TLPLDC or placebo. Differences in disease-free survival (DFS) and overall survival (OS) were evaluated. RNA-seq analysis was performed on the total RNA of TLPLDC + G and TLPLDC vaccines to compare gene expression between groups.

RESULTS:

144 patients were randomized: 103 TLPLDC (47 TLPLDC/56 TLPLDC + G) and 41 placebo (19 placebo/22 placebo + G). Median follow-up was 27.0 months. Both 36-month DFS (55.8% vs. 24.4% vs. 30.0%, p = 0.010) and OS (94.2% vs. 69.8% vs. 70.9%, p = 0.024) were improved in TLPLDC compared to TLPLDC + G or placebo, respectively. When compared to TLPLDC + G vaccine, RNA-seq from TLPLDC vaccine showed upregulation of genes associated with DC maturation and downregulation of genes associated with DC suppression or immaturity.

CONCLUSIONS:

Patients receiving TLPLDC vaccine without G-CSF had improved OS and DFS. Outcomes remained similar between patients receiving TLPLDC + G and placebo. Direct DC harvest without G-CSF had higher expression of genes linked to DC maturation, likely improving clinical efficacy.

项与 Orbis Health Solutions LLC 相关的新闻（医药）

2024-03-08

·生物谷

晚讯｜全球首款基于眼动的创新医疗器械获批、687亿市值药企发布高比例分红，10年分红超百亿元

1. 全球首款基于眼动的创新医疗器械获批，脑功能客观诊断有望迎来全新“度量衡”我国自主研发的“大脑生理与认知功能辅助评估系统”获批，可对轻度认知功能障碍进行客观早期辅助诊断，有效支撑医生临床诊断。该系统通过高精度眼动追踪技术实现快速、精准评估，有望为阿尔茨海默病等认知障碍疾病的早期发现和治疗提供重要帮助。2. 687亿市值药企发布高比例分红，10年分红超百亿元上海医药发布高比例分红预案，计划向全体股东派发现金分红总额占当年净利润的40%，持续稳定回馈投资者。同时，公司在创新药领域和医药商业板块积极拓展，与赛诺菲达成战略合作，助力中国医疗健康生态发展。3. 复星医药年内已有5款药获批临床，包括多款创新药复星医药年内已有5款药获批临床，包括自主研发的多款创新药，涉及细胞治疗、小分子抑制剂等领域，用于治疗多种血液瘤、实体瘤等疾病。其中部分新药为全球首创，拟开展I期或II期临床试验。4. 远大医药：15年来首个获批激素类纳米制剂在美获批上市远大医药宣布其合作伙伴的眼科纳米制剂GPN00833获美国FDA批准上市，用于眼科术后抗炎镇痛，同时其另一款眼科药物GPN00884也获中国药监局批准进行临床试验。GPN00833是15年来首个获批的激素类纳米制剂，具有显著疗效和良好安全性，而GPN00884则是一款用于延缓儿童近视进展的创新药。5. 诺和控股领投，Orbis Medicine获2800万美元融资用于开发下一代口服大环肽药物丹麦生物技术公司Orbis Medicines获得2800万美元种子轮融资，由诺和控股和欧洲生命科学风险投资公司Forbion领投，资金将用于开发下一代口服大环肽药物。诺和控股是生命科学领域的领先投资者，此次投资是其对生命科学公司的持续支持之一。6. Tava Health在B轮融资中筹集2000万美元位于盐湖城的心理健康平台Tava Health在Catalyst投资者的带领下获得了2000万美元的B系列资金，现有投资者和新投资者都参与了该项目。该公司计划将资金用于产品开发和网络扩展。Tava Health提供优质心理保健服务，优先考虑治疗师，并提供一整套综合服务。最近，它与安泰和UHC等国家运营商签署了协议，并扩大了与45家地区医疗运营商的当地合作关系。本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

上市批准

2024-02-29

·BioSpace

Novo Holdings, Forbion Lead Financing for Orbis Medicine’s $28M Seed Round

Pictured: Wall sign of the Novo Nordisk Foundation and Novo Holdings in Denmark/iStock, CR Danish biotech Orbis Medicines announced its emergence on the drug development scene Thursday with €26 million ($28.1 million) in seed financing backed by Novo Holdings and life sciences venture capital firm Forbion. According to Orbis, the funds will support its expansion. The company is focused on macrocycle drugs, described as a family of compounds with “highly desirable therapeutic properties” that have a cyclic structure. While Orbis did not provide the exact targets for its pipeline, the company will initially “focus on high-value oral alternatives to blockbuster biologic drugs and opening new targets to therapeutic intervention.” Orbis is also working on a pipeline of macrocycle drugs for “intra-and extra-cellular targets” but did not provide specifics. “After decades of challenging de novo synthesis, the universe of potential macrocycle targets is now available for exploration. Not only can Orbis reach a wealth of new targets, both inside and outside cells, but we can do this while preserving an oral format to pioneer a new therapeutic class of oral macrocycles. It’s a milestone for drug development,” Morten Døssing, chair of the Orbis board and partner at Novo Holdings said in a statement. Orbis was founded in 2021 by the Seeds Investment team of Novo Holdings, with the scientific foundation of the company being developed by Chrisitan Heinis and Sevan Habeshian, at the Swiss Federal Institute of Technology in Lausanne. Habeshian is also co-founder and CTO at Orbis. “We can generate hundreds of thousands of diverse compounds in record time and immediately apply a range of functional assays in a high-throughput fashion to each compound to home in on winners. Establishing this robust, reliable engine for candidate design was crucial for us as we look to bring macrocycle drugs to major patient populations,” Døssing said. Novo Holdings made a big splash earlier this month with its purchase of contract manufacturer Catalent for over $16 billion, providing a massive shot in the arm for Novo Nordisk to expand its production capacity for its hot-selling GLP-1 drugs. In September 2023, Forbion co-led a Series B for Mariana Oncology and invested in Calluna Pharma in January 2024. Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

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