Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma
项目 2:使用 CMP-001 瘤内注射和纳武单抗治疗黑色素瘤的免疫疗法
基本信息
- 批准号:10683757
- 负责人:
- 金额:$ 36.97万
- 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:2021-08-15 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAdverse eventAgonistAntibodiesAntigen PresentationB-LymphocytesBindingBiologicalCD8-Positive T-LymphocytesCD8B1 geneCTLA4 blockadeCancer VaccinesCell DeathCell MaturationCellsCellular Indexing of Transcriptomes and Epitopes by SequencingClinicalCombination immunotherapyCytosineDefectDendritic CellsDendritic cell activationEpitope spreadingEpitopesEvaluable DiseaseExperimental ModelsFlow CytometryFrequenciesGuanosineHumanImmune responseImmunotherapyInterferon Type IInterferon alphaInterferonsMediatingMelanoma CellMetastatic MelanomaMethylationMonoclonal AntibodiesMusNecrosisNeoadjuvant TherapyNivolumabPD-1 blockadePathologicPatientsPeptide VaccinesPhase II/III Clinical TrialPositron-Emission TomographyProductionProgression-Free SurvivalsPropertyRIPK3 geneRandomizedRefractoryResectableResistanceSerious Adverse EventSignal TransductionSkin CancerSolid NeoplasmSurvival RateT cell receptor repertoire sequencingT cell responseT-LymphocyteTLR9 geneTherapeuticToxic effectTumor AntigensTumor ExpansionTumor ImmunityTumor PromotionVaccinesanti-CTLA4anti-PD-1anti-PD1 antibodiesantigen-specific T cellsbeta-2 Microglobulincancer infiltrating T cellsclinical efficacycombinatorialdigitalexhaustfirst-in-humanhigh riskimmune checkpoint blockadeimmunogenicityimprovedin vivomelanomamelanoma-associated antigenneoantigensnovelprogrammed cell death protein 1programsrecruitresistance mechanismresponsespectrographtranscriptomicstumortumor microenvironment
项目摘要
PROJECT SUMMARY ABSTRACT: Project 2
Immunotherapy with anti-PD1 monoclonal antibodies (mAbs) is associated with improved response and
survival rates in multiple solid tumors, including melanoma1. Anti-PD1 mAbs (anti-PD1) produces durable
clinical responses in 33-40% of melanoma patients with minimal toxicity. While dual anti-PD1/anti-CTLA4
blockade produces higher response rates (58%) and 5-year PFS (36%), this is associated with 55% grade 3/4
adverse events. Therefore, there is a critical need for novel combinatorial immunotherapy to improve the
efficacy of anti-PD1 while mitigating the rate of serious adverse events in advanced melanoma. One major
barrier limiting the efficacy of anti-PD1 is the lack of spontaneous tumor-infiltrating T cells (TILs) and defective
IFNa production in tumor microenvironment (TME) in so-called “cold” or non-inflamed tumors. One promising
therapeutic approach to overcome this hurdle is via toll-like receptor 9 (TLR9) agonists. TLR9 is predominantly
expressed by plasmacytoid dendritic cells (pDCs) and B cells and binds to agonists including unmethylated
cytosine guanosine oligodinucleotides (CpG). We have recently performed the first-in-human trial of
neoadjuvant intratumoral CMP, a novel type A CpG, and Nivolumab in PD1-naïve high-risk resectable
melanoma (NCT03618641). In 30 evaluable melanoma patients, we have observed 60% major pathologic
responses with increased CD8+ TILs and peritumoral CD303+ pDCs in injected tumors, and higher frequency
circulating PD1+Ki67+CD8+ T cells in responders. Therapy with intratumoral CMP and Nivolumab
(CMP/Nivolumab) has also shown clinical efficacy in PD1 refractory melanoma with responses in non-injected
tumors, supporting the occurrence of systemic antitumor immunity beyond the injected tumors. To further our
understanding of the mechanisms of responses or resistance to CMP/Nivolumab in injected and non-injected
tumors, we will take advantage of a substudy of 60 melanoma patients included in the randomized phase II/III
clinical trial evaluating CMP/nivolumab vs. nivolumab in PD1 naïve metastatic melanoma with accessible
tumors for intratumoral CMP. Based on our preliminary findings, we will investigate whether CMP/Nivolumab
:1) increases pDC activation and recruitment into injected tumors to promote CD8+TIL expansion and functions
in injected and non-injected tumors; 2) induces melanoma cell death, primes potent neoepitope-specific CD8+T
cells in injected tumors, and epitope spreading to melanoma-associated antigens; and 3) fails to induce potent
T cell responses because of melanoma cell-extrinsic or melanoma cell-intrinsic mechanisms. Collectively, the
findings in this application will improve our understanding of the mechanisms of response and resistance to
CMP/Nivolumab in melanoma. They will further support novel combinatorial immunotherapies to further
enhance the immunogenicity and clinical activity of CMP/Nivolumab in injected and non-injected tumors of
advanced melanoma.
项目摘要:项目二
项目成果
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{{ truncateString('HASSANE M ZAROUR', 18)}}的其他基金
Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma
项目 2:使用 CMP-001 瘤内注射和纳武单抗治疗黑色素瘤的免疫疗法
- 批准号:
10469636 - 财政年份:2021
- 资助金额:
$ 36.97万 - 项目类别:
Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma
项目 2:使用 CMP-001 瘤内注射和纳武单抗治疗黑色素瘤的免疫疗法
- 批准号:
10270232 - 财政年份:2021
- 资助金额:
$ 36.97万 - 项目类别:
Fecal Microbiota Transplant and PD-1 blockade in Melanoma
黑色素瘤中的粪便微生物群移植和 PD-1 阻断
- 批准号:
10441408 - 财政年份:2018
- 资助金额:
$ 36.97万 - 项目类别:
Fecal Microbiota Transplant and PD-1 blockade in Melanoma
黑色素瘤中的粪便微生物群移植和 PD-1 阻断
- 批准号:
10018469 - 财政年份:2018
- 资助金额:
$ 36.97万 - 项目类别:
Fecal Microbiota Transplant and PD-1 blockade in Melanoma
黑色素瘤中的粪便微生物群移植和 PD-1 阻断
- 批准号:
10196995 - 财政年份:2018
- 资助金额:
$ 36.97万 - 项目类别:
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