Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
基本信息
- 批准号:10287834
- 负责人:
- 金额:$ 23.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-06 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:4T1AbraxaneAdjuvantAdvanced Malignant NeoplasmAgonistBreast Cancer ModelBreast Cancer TreatmentCD8-Positive T-LymphocytesClinicClinicalDataDevelopmentDiseaseERBB2 geneElementsEngineeringEnrollmentEstrogen ReceptorsExcisionExposure toFDA approvedFlagellinGoalsGrantHumanImmunityImmunosuppressionImmunotherapyKnowledgeLungMalignant NeoplasmsMalignant neoplasm of lungMediatingModalityModelingMusMyelogenousMyeloid-derived suppressor cellsNeoadjuvant TherapyOutcomePaclitaxelPatientsPharmaceutical PreparationsPharmacologyPhasePrimary NeoplasmProgesterone ReceptorsPublishingRegimenRodentRoleSafetySalmonellaSeptic ShockSignal PathwaySignal TransductionSyndromeT-LymphocyteTLR5 geneTestingTherapeuticToll-like receptorsTranslatingTreatment EfficacyTreatment-related toxicityTumor ImmunityUnresectableWorkanti-PD-L1anti-PD-L1 antibodiesbasebreast cancer diagnosiscancer typechemotherapyclinically relevantcombinatorialeffective therapyhuman diseaseimmune checkpoint blockadeimprovedin vivoinnovationmalignant breast neoplasmmelanomamouse modelneutrophilnonhuman primatenovelpre-clinicalprogrammed cell death ligand 1responsesurvival outcometargeted treatmenttriple-negative invasive breast carcinomatumortumor growthtumor microenvironment
项目摘要
Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses, is the most
aggressive form of the disease, and has the poorest clinical outcome. Chemotherapy is the mainstay treatment
for these patients despite significant treatment-related toxicities and short-term clinical responses. Therefore,
the need for more effective and better tolerated treatment modalities for TNBC is warranted. Immune checkpoint
blockade (ICB) is an immunotherapy-based approach that can reinvigorate durable immunity in advanced
cancers such as melanoma and lung. In the case of other cancer types, such as breast cancer, the FDA approved
the first immunotherapy for TNBC in March 2019. This regimen consists of α-PD-L1 antibody (Tecentriq) plus
Abraxane (Nab-paclitaxel) as a frontline therapy for patients with unresectable locally advanced or metastatic
PD-L1+ TNBC. Unfortunately, overall response rates remain relatively low and survival outcomes are extended
for only a few months due in large part to expansion of immunosuppressive polymorphonuclear myeloid-derived
suppressor cells (PMN-MDSCs) that potently suppress antitumor immunity. Thus, developing strategies to
reduce PMN-MDSC activity may improve response rates to α-PD-L1/Abraxane in TNBC. One approach to lessen
myeloid-based mechanisms of immune suppression is by modulating signaling pathways that govern immune
suppression to those that promote stimulation in a concept known as reprogramming. Toll-like receptor (TLR) 5
signaling can both mitigate MDSC activity and stimulate antitumor immunity against multiple pre-clinical tumor
models, including PD-L1+ TNBC. Thus, we posit that TLR5 agonists are a novel class of agents that can mediate
myeloid reprogramming with potential in vivo therapeutic efficacy in PD-L1+ TNBC. To this end, we engineered
and pharmacologically optimized entolimod, a derivative of the natural TLR5 agonist Salmonella flagellin.
Importantly, three Phase I safety trials cumulatively involving nearly 200 subjects showed that systemically
administered entolimod is safe. Our recent work showed that entolimod suppresses metastatic PD-L1+ TNBC by
stimulating durable CD8+ T cell immunity. Here, we show that entolimod-driven PMN-MDSC reprogramming
governs the anti-metastatic activity of entolimod in PD-L1+ TNBC. These findings provided the rationale for our
additional studies showing that combining entolimod with α-PD-L1/Paclitaxel triggers regression of early-stage
mouse PD-L1+ TNBC and induces durable immunity. However, whether entolimod enhances the antitumor
activity of α-PD-L1/Abraxane in locally advanced and the neoadjuvant and/or adjuvant setting of metastatic PD-
L1+ TNBC, for which this therapy is FDA approved, remains unknown, as well as whether entolimod alters the
PMN-MDSC response as part of its mechanism of action. To test our central hypothesis, we propose two aims:
(1) to determine the most effective TNBC treatment platform and disease setting by which entolimod bolsters
the efficacy of α-PD-L1/Abraxane; and (2) to elucidate the contribution of PMN-MDSCs to the mechanism by
which entolimod promotes the antitumor efficacy of α-PD-L1/Abraxane in TNBC.
三阴性乳腺癌(TNBC)占所有乳腺癌诊断的15-20%,是最常见的乳腺癌。
该疾病的侵袭性形式,并且具有最差的临床结果。化疗是主要的治疗方法
尽管存在显著的治疗相关毒性和短期临床反应,因此,我们认为,
需要更有效和更好耐受的TNBC治疗方式。免疫检查点
阻断(ICB)是一种基于免疫疗法的方法,可以在晚期患者中恢复持久的免疫力。
比如黑色素瘤和肺癌。对于其他癌症类型,如乳腺癌,FDA批准
2019年3月,TNBC的第一种免疫疗法。该方案包括α-PD-L1抗体(Tecentriq)加
Abraxane(蛋白结合型紫杉醇)作为不可切除的局部晚期或转移性患者的一线治疗
PD-L1+ TNBC。不幸的是,总体反应率仍然相对较低,生存期延长
在很大程度上是由于免疫抑制性多形性骨髓源性
抑制细胞(PMN-MDSC),其有效地抑制抗肿瘤免疫。因此,制定战略,
降低PMN-MDSC活性可提高TNBC对α-PD-L1/Abraxane的应答率。一种减少
基于骨髓的免疫抑制机制是通过调节控制免疫的信号通路来实现的。
抑制促进刺激的基因,这就是所谓的重编程。Toll样受体(TLR)5
信号转导既可以降低MDSC活性,又可以刺激针对多种临床前肿瘤的抗肿瘤免疫
包括PD-L1+ TNBC。因此,我们认为TLR 5激动剂是一类新的药物,可以介导,
骨髓重编程在PD-L1+ TNBC中具有潜在的体内治疗功效。为此,我们设计了
和优化的恩托莫德,一种天然TLR 5激动剂沙门氏菌鞭毛蛋白的衍生物。
重要的是,三项I期安全性试验累积涉及近200名受试者,表明系统性
使用恩托莫德是安全的。我们最近的研究表明,恩托莫德通过以下方式抑制转移性PD-L1+ TNBC:
刺激持久的CD 8 + T细胞免疫。在这里,我们表明,entolimod驱动的PMN-MDSC重编程
控制恩托莫德在PD-L1+ TNBC中的抗转移活性。这些发现为我们的研究提供了理论基础。
其他研究表明,联合使用恩托莫德与α-PD-L1/Paclitaxel可引发早期
小鼠PD-L1+ TNBC并诱导持久免疫。然而,恩托莫德是否能增强抗肿瘤作用,
α-PD-L1/Abraxane在局部晚期和转移性PD的新辅助和/或辅助治疗中的活性-
L1+ TNBC,这种疗法是FDA批准的,仍然是未知的,以及是否恩托莫德改变了TNBC。
PMN-MDSC反应作为其作用机制的一部分。为了检验我们的中心假设,我们提出了两个目标:
(1)确定最有效的TNBC治疗平台和疾病背景,
α-PD-L1/Abraxane的有效性;(2)阐明PMN-MDSC对该机制的贡献,
其中恩托莫德促进α-PD-L1/Abraxane在TNBC中的抗肿瘤功效。
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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Scott I. Abrams其他文献
Differences in Immune Cell Populations between Individuals with or without MGUS
- DOI:
10.1182/blood-2024-206171 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Sawyer Bawek;Janine M. Joseph;Alan Hutson;Sarah Parker;Joseph D. Tario Jr;Hamza Hassan;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Influence of interferon γ on modulation of Fas expression by human colon carcinoma cells and their subsequent sensitivity to antigen-specific CD8+ cytotoxic T lymphocyte attack
- DOI:
10.1007/s002620000105 - 发表时间:
2000-06-01 - 期刊:
- 影响因子:5.100
- 作者:
Elke S. Bergmann-Leitner;Scott I. Abrams - 通讯作者:
Scott I. Abrams
Immune response to a carcinoembryonic antigen polynucleotide vaccine.
对癌胚抗原多核苷酸疫苗的免疫反应。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
R. Conry;A. Lobuglio;Judy Kantor;Jeffrey Schlom;F. Loechel;S. Moore;L. Sumerel;D. L. Barlow;Scott I. Abrams;David T. Curici - 通讯作者:
David T. Curici
Immune Markers of Multiple Myeloma Patients Demonstrate Significant Change after Participation in Six-Month Physical Activity Intervention
- DOI:
10.1182/blood-2022-167655 - 发表时间:
2022-11-15 - 期刊:
- 影响因子:
- 作者:
Janine M. Joseph;Michaela Hillengass;Hillary Jacobson;Joseph D. Tario;Kristopher Attwood;Adrienne Groman;Rikki Cannioto;Bryan Wittmeyer;Kirsten Moysich;Scott I. Abrams;Jens Hillengass - 通讯作者:
Jens Hillengass
Induction of antitumor immunity by recombinant vaccinia viruses expressing B7-1 or B7-2 costimulatory molecules.
通过表达 B7-1 或 B7-2 共刺激分子的重组痘苗病毒诱导抗肿瘤免疫。
- DOI:
- 发表时间:
1994 - 期刊:
- 影响因子:11.2
- 作者:
J. Hodge;Scott I. Abrams;J. Schlom;Judy Kantor - 通讯作者:
Judy Kantor
Scott I. Abrams的其他文献
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{{ truncateString('Scott I. Abrams', 18)}}的其他基金
Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
- 批准号:
10322156 - 财政年份:2021
- 资助金额:
$ 23.59万 - 项目类别:
Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer
开发针对三阴性乳腺癌的新型免疫治疗平台
- 批准号:
10463811 - 财政年份:2021
- 资助金额:
$ 23.59万 - 项目类别:
Impact of Circulating Myeloid Cell Clusters on Anti-Tumor Immunity
循环骨髓细胞簇对抗肿瘤免疫的影响
- 批准号:
10543820 - 财政年份:2021
- 资助金额:
$ 23.59万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10653186 - 财政年份:2020
- 资助金额:
$ 23.59万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10171569 - 财政年份:2020
- 资助金额:
$ 23.59万 - 项目类别:
Tumor Immune Contexture and Breast Cancer Disparities: A Multi-Disciplinary Study in Women of African and European Ancestry
肿瘤免疫环境和乳腺癌差异:针对非洲和欧洲血统女性的多学科研究
- 批准号:
10404988 - 财政年份:2020
- 资助金额:
$ 23.59万 - 项目类别:
A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
- 批准号:
10320831 - 财政年份:2020
- 资助金额:
$ 23.59万 - 项目类别:
A Cobalt Porphyrin Nanoliposome Adjuvant for MHC-I-Restricted Cancer Peptide Vaccines
用于 MHC-I 限制性癌症肽疫苗的钴卟啉纳米脂质体佐剂
- 批准号:
10557071 - 财政年份:2020
- 资助金额:
$ 23.59万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10248383 - 财政年份:2019
- 资助金额:
$ 23.59万 - 项目类别:
Multidisciplinary Approaches to Tumor Immunology
肿瘤免疫学的多学科方法
- 批准号:
10472619 - 财政年份:2019
- 资助金额:
$ 23.59万 - 项目类别:
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