Preclinical GEM and GDA Models of Primary and Metastatic Melanoma

原发性和转移性黑色素瘤的临床前 GEM 和 GDA 模型

基本信息

批准号：
10702646
负责人：
SHYAM SHARAN
金额：
$ 138.49万
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/10702646
关键词：
Adjuvant Allografting Anatomy Antibodies Apoptosis Biotechnology Blood CD8B1 gene Clinical Clinical Management Collaborations Combination immunotherapy Complex Cooperative Research and Development Agreement Cutaneous Melanoma Data Disease model Early treatment Engineering Evaluation Exhibits Fc Receptor Frequencies Gene Expression Profiling Generations HGF gene IgG1 Image Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunologics Immunomodulators Immunooncology Immunotherapeutic agent Infiltration Intervention Laboratories Lesion Malignant Neoplasms Metastatic Melanoma Modality Modeling Molecular Monitor Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis Outcome Pathway interactions Patients Pattern Privatization Procedures Publishing Recurrence Relapse Research Resected Resistance T-Lymphocyte Therapeutic Tumor-infiltrating immune cells anti-CTLA4 antibodies anti-PD-L1 anti-PD-L1 antibodies anti-PD-L1 therapy cohort drug development efficacy evaluation genetic signature imaging probe immune checkpoint blockade melanoma melanomagenesis mouse model multidisciplinary mutant neoantigens neoplastic cell novel patient subsets pre-clinical predictive signature prevent programs recruit response targeted treatment treatment response tumor

项目摘要

As an essential part of the collaborative program with Dr. Glenn Merlino's laboratory at the NCI, we have previously developed several immunocompetent allograft models for metastatic melanoma that appeared sensitive to immune checkpoint blockade (ICB) with an anti-CTLA-4 antibody. This collaboration included an NCI CRADA to evaluate sensitivity to AstraZeneca's proprietary mouse anti-PD-L1 antibody in the Hgftg;Cdk4R24C/R24C GEM-derived allograft model. This antibody (designated clone 80) is the mouse isotype IgG1 engineered to correspond to durvalumab, carrying the D265A mutation to minimize Fc receptor interaction and tumor cell apoptosis. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice, mirroring the comparable subset of patients with melanoma that respond to the same immunotherapeutic intervention. We have pursued additional internal research into early treatment assessment. We analyzed gene expression profiles, T-cell infiltration, and TCR signatures in regressing tumors compared with tumors exhibiting no response to anti-PD-L1 treatment. Successful anti-PD-L1 antibody treatment response in melanoma required infiltration of CD8-positive T cells, a gene signature of immune activity, and recruitment of a diverse pool of TCR rearrangements with selective increase in productive frequency. TCR blood and tumor sequence data indicated that a positive anti-PD-L1 response in melanoma results in expansion of the TCR CDR3 repertoire to generate a rich TCR set of diverse clonotypes, but analysis of TCRs in blood only does not reflect the true diversity of clones present in responder tumors. The diversified TCR clonotype repertoire we identified in tumors, published in Molecular Cancer Res., proved to be essential for targeting the multitude of neoantigens that are expressed on tumor cells. Moreover, we found that Hgftg;Cdk4R24C/R24C tumors exhibited a recurrent non-uniform response to anti-PD-L1 that will be useful for evaluation of potential combination immunotherapies to increase the number of mice with durable response and prevent relapse.

作为与Glenn Merlino博士在NCI的合作计划的重要组成部分，我们以前已经开发了几种用于转移性黑色素瘤的免疫能力同种异体移植模型，这些模型似乎对具有抗CTLA-4抗体的免疫检查点阻断（ICB）敏感。这种合作包括NCI CRADA，以评估HGFTG中对Astrazeneca专有小鼠抗PD-L1抗体的敏感性； CDK4R24C/R24C GEM衍生的同种异体移植模型。该抗体（指定的克隆80）是与Durvalumab相对应的小鼠同种型IgG1，携带D265A突变，以最大程度地减少FC受体相互作用和肿瘤细胞细胞凋亡。与黑色素瘤中ICB的临床观察结果一致，抗PD-L1治疗在含黑色素瘤小鼠的一部分中引起了完整和耐用的反应，这反映了黑色素瘤患者可比的子集对相同的免疫治疗干预的反应。我们对早期治疗评估进行了其他内部研究。与对抗PD-L1治疗无反应的肿瘤相比，我们分析了回归肿瘤的基因表达谱，T细胞浸润和TCR特征。黑色素瘤中成功的抗PD-L1抗体治疗反应需要CD8阳性T细胞，一种免疫活性的基因特征，并募集了多种TCR重排的多样性，并选择性地增加了生产频率。 TCR血液和肿瘤序列数据表明，黑色素瘤中阳性的抗PD-L1反应会导致TCR CDR3曲目的扩展，以产生丰富的TCR多种多样的Clonotypes，但仅反映血液中TCR的分析并不反映呼吸器肿瘤中克隆的真实多样性。我们在肿瘤中鉴定出的多样化的TCR克隆型曲目，该曲目发表在分子癌中，被证明对于靶向靶向在肿瘤细胞上表达的多种新抗原至关重要。此外，我们发现HGFTG; CDK4R24C/R24C肿瘤表现出对抗PD-L1反复发生的非均匀反应，这将有助于评估潜在的联合免疫疗法以增加具有持久反应的小鼠数量，并防止复发。