Development of a tumor-retentive immunostimulant as adjunct therapy for solid tumor cancers
开发肿瘤保留免疫刺激剂作为实体瘤癌症的辅助治疗
基本信息
- 批准号:10602219
- 负责人:
- 金额:$ 39.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-07 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Abscopal effectBreast MelanomaCD8B1 geneCT26CXCL1 geneCaliberCancer PatientCationsCellsChargeClinicalClinical TrialsComplexDataDevelopmentDiagnosisDiffusionDoseEventExhibitsExtracellular MatrixFormulationFutureGoalsHead and Neck NeoplasmsHead and neck structureHourITGAM geneImageImmuneImmune checkpoint inhibitorImmune responseImmune systemImmunologic AdjuvantsImmunologicsImmunotherapyInfiltrationInjectableInjectionsInterferon Type IIInterleukin-2Interleukin-6Legal patentMalignant NeoplasmsMaximum Tolerated DoseMetastatic Neoplasm to the LungModelingMolecularMultiple SclerosisMusNecrosisOutcomePalpablePatientsPeptidesPharmacologic SubstancePhasePhase I Clinical TrialsPositioning AttributePreparationPropertyPublishingRefractoryResistanceSafetySamplingSerumSignal TransductionSiteSmall Business Technology Transfer ResearchSolid NeoplasmStructureSuspensionsTNF geneTestingToxic effectTumor BurdenTumor TissueTumor-infiltrating immune cellsUnresectableabsorptionanti-PD-1cancer cellcancer immunotherapycheckpoint therapycopolymer 1cytokinecytokine release syndromedesigndraining lymph nodeimmune activationimmune-related adverse eventsimprovedimproved outcomeinnovationmolecular sizemouse modelnanoparticlenovelparticlerecruitself assemblyside effectstandard caresubcutaneoussuccesssynergismtumortumor growthtumor microenvironmentuptakewater solubilityzeta potential
项目摘要
PROJECT SUMMARY/ABSTRACT
Cancer immunotherapy activates the host immune system to seek and destroy cancer cells. Checkpoint
inhibitors block immunosuppressive signals, thereby ‘releasing the brakes’ of the immune system. Solid tumors,
however, typically do not respond well to checkpoint inhibitors. They are only effective in the 20-30% patients
with an already immunologically ‘hot’ tumor. Thus, novel immunostimulant therapies aim to recruit immune cells
to tumor tissue, turning cold tumors hot and working synergistically with checkpoint inhibitors.
Immunostimulants that induce local immune-cell infiltration may induce an Abscopal effect and may increase
responsiveness in patients that are resistant to checkpoint inhibitors. Unfortunately, immunostimulants often
induce systemic immune-related adverse events (e.g., cytokine release syndrome), even when administered
locally to tumor tissue. Most immunostimulants exhibit molecular properties promoting diffusion and systemic
absorption (e.g., small molecular size, negative charge, high water solubility), This presents a major limitation
as it leads to limited immune activation in the target tumor tissue after administration and immune-related
adverse events. In this project, we will advance KIN-001 – a tumor-retentive formulation of the immunostimulant
CpG designed to persist in tumor tissue thereby mitigating systemic immune-related adverse events and
potentiating immune activity in the tumor microenvironment and draining lymph nodes. KIN-001 is a small
volume nanosuspension for intratumoral injection comprised of commercially available glatiramer acetate (GA)
(Copaxone®, approved for multiple sclerosis) complexed with CpG (immunostimulant). Through preliminary
studies of KIN-001, our group has demonstrated its efficacy in recruiting immune cells to the tumor without
inducing significant systemic cytokines, and we have identified the optimal mass ratio of GA to CpG. This Phase
I STTR study has three Specific Aims: In Specific Aim 1, we will complete an in-use stability study of different
formulations of KIN-001 to demonstrate that KIN-001 is a stable composition and quality is maintained between
preparation and injection into the tumor under anticipated conditions of use. Specific Aim 2 will focus on
identifying the maximum tolerated dose of KIN-001 compared to CpG in a predominant immunotherapy mouse
model. In Specific Aim 3, we will establish proof of mechanism by elucidating KIN-001’s tumor retention and
synergy potential when combined with anti-PD1, a checkpoint inhibitor. The long-term goal of this project is to
commercialize KIN-001 as the first and only tumor-retentive immunostimulant with low toxicity for cancer
patients that have palpable (i.e., injectable) solid tumors and are refractory to checkpoint inhibitors. KIN-001
will improve efficacy of standard treatment (e.g., checkpoint inhibitors) with minimal side effects, leading to
improved outcomes and survival.
项目总结/摘要
癌症免疫疗法激活宿主免疫系统以寻找和摧毁癌细胞。检查点
抑制剂阻断免疫抑制信号,从而“释放免疫系统的刹车”。实体瘤,
然而,它们通常对检查点抑制剂反应不佳。它们仅对20-30%的患者有效
一个已经免疫“热”的肿瘤因此,新的免疫刺激疗法旨在募集免疫细胞
肿瘤组织,使冷肿瘤变热,并与检查点抑制剂协同作用。
诱导局部免疫细胞浸润的免疫刺激剂可能会诱导Abscopal效应,并可能增加
对检查点抑制剂耐药的患者的反应性。不幸的是,免疫刺激剂通常
诱导全身免疫相关的不良事件(例如,细胞因子释放综合征),即使当给予
局部转移到肿瘤组织。大多数免疫刺激剂表现出促进扩散和全身免疫的分子特性。
吸收(例如,分子尺寸小、带负电荷、水溶性高),这带来了一个主要限制
因为它在给药后导致靶肿瘤组织中有限的免疫激活,
不良事件。在这个项目中,我们将推进KIN-001 -免疫刺激剂的肿瘤滞留制剂
CpG被设计为在肿瘤组织中持续存在,从而减轻全身免疫相关的不良事件,
增强肿瘤微环境和引流淋巴结中的免疫活性。KIN-001是一款小型
用于肿瘤内注射的体积纳米混悬液,其包含市售醋酸格拉替雷(GA)
(Copaxone®,批准用于多发性硬化症)与CpG(免疫刺激剂)复合。通过初步
KIN-001的研究,我们的小组已经证明了它在招募免疫细胞到肿瘤中的功效,
诱导显著的全身性细胞因子,并且我们已经确定了GA与CpG的最佳质量比。这个阶段
I STTR研究有三个具体目标:在具体目标1中,我们将完成不同的使用中稳定性研究
KIN-001的制剂,以证明KIN-001是稳定的组合物,并且在以下范围内保持质量:
在预期的使用条件下制备并注射到肿瘤中。具体目标2将侧重于
确定在主要免疫治疗小鼠中与CpG相比KIN-001的最大耐受剂量
模型在具体目标3中,我们将通过阐明KIN-001的肿瘤保留来建立机制证据,
当与抗PD 1(一种检查点抑制剂)组合时,具有协同潜力。该项目的长期目标是
将KIN-001商业化,作为第一个也是唯一一个对癌症具有低毒性的肿瘤滞留免疫刺激剂
可触知的患者(即,可注射的)实体瘤并且对检查点抑制剂是难治的。KIN-001
将提高标准治疗的功效(例如,检查点抑制剂),副作用极小,
改善结果和生存率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Marcus Laird Forrest其他文献
Intralesional injection of CpG ODNs complexed with glatiramer acetate mitigates systemic cytokine toxicities and synergistically advances checkpoint blockade efficacy
- DOI:
10.1007/s13346-025-01798-9 - 发表时间:
2025-01-29 - 期刊:
- 影响因子:5.500
- 作者:
Huan Gong;J. Daniel Griffin;Chad E. Groer;Xiaoqing Wu;Mengyue Li;Moustafa M. Abdelaziz;Liang Xu;Marcus Laird Forrest;Cory J. Berkland - 通讯作者:
Cory J. Berkland
Marcus Laird Forrest的其他文献
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{{ truncateString('Marcus Laird Forrest', 18)}}的其他基金
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
- 批准号:
10363259 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
- 批准号:
10523358 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Mitochondria targeting for Alzheimer's Disease
线粒体靶向治疗阿尔茨海默病
- 批准号:
10335201 - 财政年份:2021
- 资助金额:
$ 39.56万 - 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
- 批准号:
8882897 - 财政年份:2014
- 资助金额:
$ 39.56万 - 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
- 批准号:
9124601 - 财政年份:2014
- 资助金额:
$ 39.56万 - 项目类别:
Development of an Integrated Mathematical Model for Comparative Characterization of Complex Molecule
复杂分子比较表征综合数学模型的开发
- 批准号:
8925802 - 财政年份:2014
- 资助金额:
$ 39.56万 - 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
- 批准号:
8422252 - 财政年份:2013
- 资助金额:
$ 39.56万 - 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
- 批准号:
8821486 - 财政年份:2013
- 资助金额:
$ 39.56万 - 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
- 批准号:
9022438 - 财政年份:2013
- 资助金额:
$ 39.56万 - 项目类别:
Biomaterials for treatment of head and neck cancer
用于治疗头颈癌的生物材料
- 批准号:
8628816 - 财政年份:2013
- 资助金额:
$ 39.56万 - 项目类别:
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