Immunization Against Melanoma Differentiation Antigens

针对黑色素瘤分化抗原的免疫接种

• 批准号: 9884736
• 负责人: Jedd D. Wolchok
• 金额: $ 31.43万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 2022-09-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884736
• 关键词: Agonist; Animal Model; Antibodies; Antigen Receptors; Antigens; Area; BRAF gene; Biological Markers; Biological Models; Blocking Antibodies; CD8B1 gene; CTLA4 blockade; Cell Therapy; Cells; Cellular immunotherapy; Chemosensitization; Clinic; Clinical; Clinical Trials; Collaborations; Data; Development; Differentiation Antigens; Dose; Ensure; Family; Funding; Future; Genetic Engineering; Glean; Glucocorticoids; Goals; Human; Immune; Immune Targeting; Immune response; Immunity; Immunization; Immunomodulators; Immunotherapeutic agent; Immunotherapy; Innovative Therapy; Institution; Investigation; Leadership; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Monoclonal Antibodies; Normal Cell; OX40; Oncogenic; Outcome Measure; Pathway interactions; Patients; Peptides; Phase I Clinical Trials; Phenotype; Protein Family; Proteins; Public Health; Reagent; Receptor Cell; Refractory; Regulatory T-Lymphocyte; Research Personnel; Schedule; Surrogate Markers; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Transplantation; Tumor Immunity; Tumor Necrosis Factor Receptor; Tyrosinase related protein-1; base; cell type; cellular transduction; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; combinatorial; design; driver mutation; effector T cell; first-in-human; immune checkpoint blockade; immunoregulation; industry partner; innovation; melanocyte; melanoma; mouse model; neoplastic cell; next generation; novel; novel therapeutic intervention; patient subsets; phase I trial; pre-clinical; public health relevance; response; response biomarker; success; targeted treatment; therapeutic target; tumor; tumor necrosis factor receptor superfamily member 4

 DESCRIPTION (provided by applicant): Melanosomal differentiation antigens are a family of proteins uniquely expressed on melanocytes and melanoma cells. As such, they represent rational and convenient surrogate markers to measure immune responses to melanoma in both animal model systems and human patients on clinical trials of innovative immunotherapeutic strategies. They also are very attractive targets for immunotherapies given their restricted expression on normal cells. Given the progress made during the prior funding period, we have proposed three specific aims. The first is to continue our focus on GITR (glucocorticoid-induced TNF-receptor family related protein) as a novel target of agonist immunotherapeutic strategies. We defined a novel mechanism underlying GITR-induced immune modulation with regulatory T cells (Treg) losing lineage commitment and a favorable change in the Treg:T effector cell ratio. This will be applied to a first-in-human clinical trial of an agonist monoclonal antibody to GITR, which we are currently leading as well as a Phase I trial of the Merck anti-GITR antibody. We will further these biomarker investigations by exploring the expression of immune regulatory molecules on tumor cells. We also plan to further investigate the basis for sub-optimal response at later timepoints (refractory vs. responding tumors) using assessment of these biomarkers over time. In Aim 2, we will continue our efforts to identify the most impactful and relevant combinations of immune modulators by studying the effects of dual costimulation with agonist antibodies against the TNFR superfamily receptors OX40 and GITR in transplantable and spontaneous mouse models of melanoma, using immunity to melanosomal antigens as an outcome measure. This is directly applicable to clinical trials as we have ongoing collaborations with industry partners to make clinical grade reagents available for further trials. In Aim 3, we will have a unique opportunity to directly compare two cell-based immunotherapeutic strategies, chimeric antigen receptor T cells (CAR+) and T cells bearing a transgenic T cell receptor for the same antigen that the CAR+ cells recognize (TRP1, a melanosomal antigen). We will compare different host cells as well as antigen receptors to define an optimal cell therapy to combine with the antibody combination defined in prior Aims. Our overall goal is to use immunity to melanosomal antigens to identify the most potent immunotherapeutic strategies for melanoma that can be brought into clinical trials.

 描述（由适用提供）：黑色素分化抗原是在黑色素细胞和黑色素瘤细胞上唯一表达的蛋白质家族。因此，它们代表了在动物模型系统和人类患者中，在创新免疫疗法的临床试验中，在动物模型系统和人类患者中测量对黑色素瘤的免疫回报。鉴于它们在正常细胞上的表达受到限制，它们也是免疫疗法的非常有吸引力的靶标。鉴于以前的资金期间取得的进展，我们提出了三个具体目标。首先是继续我们的重点是GITR（糖皮质激素诱导的TNF受体家族蛋白），作为激动剂免疫治疗策略的新靶标。我们定义了GITR诱导的免疫调节的一种新型机制，其调节性T细胞（TREG）失去了谱系承诺和Treg：T效应细胞比率的有利变化。这将应用于与GITR的激动剂单克隆抗体的首次人类临床试验，我们目前正在领导该抗体以及默克抗GITR抗体的I期试验。我们将通过探索肿瘤细胞上免疫调节分子的表达来进一步进一步。我们还计划通过随着时间的推移评估这些生物标志物的评估，进一步研究在以后的时间点（难治性与反应肿瘤）下次优响应的基础。在AIM 2中，我们将继续努力，通过研究针对TNFR超级家族受体OX40和GITR的双重共刺激的影响，在可移植和赞助的黑色素瘤模型中使用免疫学对Melanosomal Antigensal Antomemal Memare的抗体模型，对TNFR超家族受体OX40和GITR的影响。这直接适用于临床试验，因为我们与行业合作伙伴进行了持续的合作，以使临床等级试剂可用于进一步试验。在AIM 3中，我们将有一个独特的机会直接比较两种基于细胞的免疫治疗策略，嵌合抗原受体T细胞（CAR+）和带有转基因T细胞受体的T细胞，用于CAR+细胞识别的相同抗原（TRP1，黑色素体抗原）。我们将比较不同的宿主细胞和抗原受体，以定义最佳细胞疗法以与 先前目标定义的抗体组合。我们的总体目标是将免疫学用于黑色素体抗原，以确定可将黑色素瘤的最潜在免疫治疗策略带入临床试验中。

项目成果

Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma.

• 发表时间: 2009
• 期刊: Cancer immunity
• 作者: Jianda Yuan;G. Ku;H. Gallardo;F. Orlandi;G. Manukian;T. Rasalan;Yinyan Xu;Hao-Kang Li;S. Vyas;Z. Mu;P. Chapman;S. Krown;K. Panageas;S. Terzulli;L. Old;A. Houghton;J. Wolchok

Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion.

• DOI: 10.1016/j.immuni.2015.12.018
• 发表时间: 2016-01-19
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Malandro N;Budhu S;Kuhn NF;Liu C;Murphy JT;Cortez C;Zhong H;Yang X;Rizzuto G;Altan-Bonnet G;Merghoub T;Wolchok JD
• 通讯作者: Wolchok JD

Development of effective vaccines for old mice in a tumor model.

• DOI: 10.1016/j.vaccine.2008.11.112
• 发表时间: 2009-02-11
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Posnett DN;Engelhorn ME;Lin Y;Merghoub T;Duan F;Wolchok JD;Houghton AN
• 通讯作者: Houghton AN

Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.

• DOI: 10.1126/scisignal.aak9702
• 发表时间: 2017-08-29
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Budhu S;Schaer DA;Li Y;Toledo-Crow R;Panageas K;Yang X;Zhong H;Houghton AN;Silverstein SC;Merghoub T;Wolchok JD
• 通讯作者: Wolchok JD

Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype.

• DOI: 10.1084/jem.20120532
• 发表时间: 2012-10-22
• 期刊: The Journal of experimental medicine
• 作者: Hirschhorn-Cymerman D;Budhu S;Kitano S;Liu C;Zhao F;Zhong H;Lesokhin AM;Avogadri-Connors F;Yuan J;Li Y;Houghton AN;Merghoub T;Wolchok JD
• 通讯作者: Wolchok JD