Evaluation of Immune-based Combinations in Prostate Cancer

前列腺癌免疫组合的评估

基本信息

批准号：
10926386
负责人：
Ravi Madan
金额：
$ 48.57万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10926386
关键词：
Cancer Vaccines Cell Line Cells Chemotherapy and/or radiation Clinical Collaborations Combination immunotherapy Combined Modality Therapy DNA Development Dose Evaluation Goals Histones Immune Immune checkpoint inhibitor Immune response Immunotherapy Interleukin-12 Malignant neoplasm of prostate Metastatic/Recurrent Mutation Necrosis Induction Newly Diagnosed Patients Phase Phenotype Population Pre-Clinical Model Progression-Free Survivals Prostate Cancer therapy Protocols documentation Radiation Radiation Oncology Recurrence Renal carcinoma Research T cell infiltration Toxic effect castration resistant prostate cancer chemotherapy clinical efficacy cytokine docetaxel melanoma necrotic tissue programs standard of care synergism systemic toxicity therapeutic evaluation tumor tumor microenvironment tumor-immune system interactions

项目摘要

Current studies are exploring a combination of standard of care chemotherapy with an immunocytokine combination treatment. Unlike checkpoint inhibitors which may require T-cell infiltration or high tumor mutational burden to be effective, cytokines provide an opportunity to impact multiple immune cell lines within the prostate cancer microenvironment and convert them broadly from immune suppressive to a more anti-tumor phenotype. Indeed, cytokines have been a key part of immune treatments for kidney cancer and melanoma before the development of checkpoint inhibitors, but the potential systemic toxicity of high doses of cytokines often limited treatment delivery and thus efficacy. Immunocytokines are able to deliver smaller doses of cytokines in a targeted fashion to the tumor microenvironment, thereby limiting systemic toxicity and perhaps enhancing clinical efficacy. NHS-IL12 (M9241) has been developed clinically within the GMB Immunotherapy Section and specifically targets histones of exposed DNA in necrotic tissue. This capability forms the basis of a key strategy within my research program. By using standard therapies for prostate cancer such as radiation and chemotherapy to induce necrosis, the goal is to use NHS-IL12 to alter the pleiotropic immune microenvironment, including multiple immune cell populations, shifting it to a more anti-tumor phenotype. We have completed the phase 1 portion of 21-c-0001, which has established a safe dose of docetaxel with M9241. We will now explore immune responses in this study as we move into the phase 2 portion of the study that will focus on metastatic castration resistant prostate cancer. We also recently opened a new study combining NHS-IL12 and radiation in patients with newly diagnosed and localized prostate cancer in a collaboration with the Radiation Oncology Branch (protocol 000114). This is based on the potential synergy of radiation and M9241 established in preclinical models. Immunotherapy combinaton studies are also being done in recurrent prostate cancer (18-c-0005)

目前的研究正在探索标准护理化疗与免疫细胞因子联合治疗的组合。与可能需要 T 细胞浸润或高肿瘤突变负荷才能有效的检查点抑制剂不同，细胞因子提供了影响前列腺癌微环境内的多种免疫细胞系并将其从免疫抑制广泛转化为更具抗肿瘤表型的机会。事实上，在检查点抑制剂开发之前，细胞因子一直是肾癌和黑色素瘤免疫治疗的关键部分，但高剂量细胞因子的潜在全身毒性往往限制了治疗的实施，从而限制了疗效。免疫细胞因子能够以靶向方式将较小剂量的细胞因子递送至肿瘤微环境，从而限制全身毒性并可能增强临床疗效。 NHS-IL12 (M9241) 已在 GMB 免疫治疗科内进行临床开发，专门针对坏死组织中暴露 DNA 的组蛋白。这种能力构成了我的研究计划中关键策略的基础。通过使用前列腺癌的标准疗法（例如放疗和化疗来诱导坏死），目标是使用 NHS-IL12 来改变多效性免疫微环境，包括多种免疫细胞群，将其转变为更具抗肿瘤的表型。我们已经完成了 21-c-0001 的第一阶段部分，确定了多西紫杉醇与 M9241 的安全剂量。现在，随着我们进入研究的第二阶段部分，我们将探讨本研究中的免疫反应，该研究将重点关注转移性去势抵抗性前列腺癌。我们最近还与放射肿瘤科合作开展了一项新研究，将 NHS-IL12 与放射治疗相结合，用于治疗新诊断的局限性前列腺癌患者（方案 000114）。这是基于临床前模型中建立的辐射和 M9241 的潜在协同作用。免疫治疗组合研究也在复发性前列腺癌中进行 (18-c-0005)

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Life under the CABOSUN: Cabozantinib improves quality-adjusted survival in comparison with sunitinib.

CABOSUN 治疗下的生活：与舒尼替尼相比，卡博替尼可改善质量调整生存期。

DOI：
10.1002/cncr.33168
发表时间：
2020
期刊：
Cancer
影响因子：
6.2
作者：
Aragon-Ching,JeannyB;Madan,RaviA
通讯作者：
Madan,RaviA

Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer.

DOI：
10.1136/jitc-2021-003238
发表时间：
2021-09
期刊：
Journal for immunotherapy of cancer
影响因子：
10.9
作者：
DeMaria PJ;Lee-Wisdom K;Donahue RN;Madan RA;Karzai F;Schwab A;Palena C;Jochems C;Floudas C;Strauss J;Marté JL;Redman JM;Dombi E;Widemann B;Korchin B;Adams T;Pico-Navarro C;Heery C;Schlom J;Gulley JL;Bilusic M
通讯作者：
Bilusic M

First-line pembrolizumab plus androgen deprivation therapy for locally advanced microsatellite instability-high prostate cancer in a patient with Muir-Torre syndrome: A case report.

DOI：
10.3389/fonc.2023.1126476
发表时间：
2023
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
通讯作者：

Assessment of Aortoiliac Atherosclerotic Plaque on CT in Prostate Cancer Patients Undergoing Treatment.

DOI：
10.3390/tomography8020050
发表时间：
2022-03-01
期刊：
Tomography (Ann Arbor, Mich.)
影响因子：
0
作者：
Lee S;Elton DC;Gulley JL;Pickhardt PJ;Dahut WL;Madan RA;Pinto PA;Citrin DE;Summers RM
通讯作者：
Summers RM

The Winds of Change: Emerging Therapeutics in Prostate Cancer.

变革之风：前列腺癌的新兴治疗方法。