Biomarker Identification to Increase Adjunctive Cryoablation and Checkpoint-Inhibitor Immunotherapy Response

生物标志物鉴定可提高辅助冷冻消融和检查点抑制剂免疫治疗的反应

• 批准号: 10682580
• 负责人: Eric Wehrenberg-Klee
• 金额: $ 26.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682580
• 关键词: Ablation; Active Sites; Adaptive Immune System; Affect; Antigens; Applications Grants; Biological Markers; Biopsy Specimen; Blood; Blood specimen; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Carcinoma; Cell Death; Cell membrane; Cell physiology; Cells; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cryosurgery; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Eligibility Determination; Ensure; Environment; Flow Cytometry; Freezing; Future; Genomics; Granzyme; Image; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunologic Factors; Immunologic Techniques; Immunology; Immunooncology; Immunotherapy; Implant; In complete remission; Inflammation; Inflammatory; Innate Immune System; Interventional radiology; Mediating; Mentors; Modeling; Mus; Mutation; Necrosis; Neoplasm Metastasis; Patients; Positron-Emission Tomography; Protocols documentation; Reaction; Regimen; Research; Resistance; Route; Rupture; Site; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Transitional Cell Carcinoma; Tumor Antigens; Tumor Markers; Urothelium; Variant; Work; anti-tumor immune response; biomarker identification; career; checkpoint inhibition; checkpoint therapy; clinical development; cytokine; effector T cell; imaging agent; immunogenic; improved; improved outcome; inhibitor therapy; insight; invention; mouse model; neoplastic cell; non-genomic; pembrolizumab; pre-clinical; pre-clinical research; preclinical study; predicting response; predictive marker; programmed cell death protein 1; prospective; research clinical testing; resistance mechanism; responders and non-responders; response; response biomarker; single-cell RNA sequencing; skills; success; tool; tumor; tumor-immune system interactions

1 Checkpoint inhibitors (CPI) have significantly improved outcomes in many tumor types, but there is still 2 immense room for improvement. A tremendous amount of preclinical and clinical research thus is aimed at 3 evaluating combination therapeutic regimens that may increase CPI response rate as well as identifying 4 biomarkers that indicate whether a patient will benefit from or be resistant to immunotherapy. 5 Cryoablation is a promising adjunctive strategy that may be able to significantly increase the CPI response 6 rate. Cryoablation of a single metastatic focus causes necrotic cell death, rupturing cell membranes through 7 alternating freeze and thaw cycles. Tumoral antigens are released along with inflammatory intracellular 8 contents. This markedly inflammatory reaction activates dendritic cells to take up the released tumor antigen 9 which, in turn, activates the adaptive immune system to attack tumor sites elsewhere in the body. 10 I have developed a dual-implanted tumor model to investigate the systemic benefit of adjunctive cryoablation 11 and have found that when added to CPI therapy cryoablation significantly increases the complete response 12 rate of the non-ablated tumor relative to CPI alone. As adding cryoablation to CPI is minimally studied, there 13 remains significant work to identify biomarkers to determine which tumors will benefit most by cryoablation 14 addition. To identify response biomarkers I am helped by a unique investigative tool that I co-invented, 15 granzyme B PET imaging. Localizing to the site of active immune-mediated tumor killing, granzyme B PET 16 allows us to distinguish CPI responders from non-responders prior to changes in tumor size. We can then 17 interrogate the immune-response while it is still active, facilitating unique insights. 18 In this proposal, in a murine tumor model I will develop an optimized preclinical cryoablation and CPI regimen 19 across multiple tumor lines reflective of the range of CPI responsiveness. In these models I will then use 20 granzyme B PET imaging to help identify genomic and non-genomic biomarkers of response and identify 21 mechanisms of resistance to the combination of cryoablation and CPI. I will also simultaneously be leading a 22 clinical trial evaluating the ability of cryoablation to increase pembrolizumab response in metastatic urothelial 23 carcinoma. From patient blood and biopsy specimens obtained at the time of cryoablation I propose to analyze 24 the tumoral and systemic immune microenvironment for response biomarkers in these patients. These data will 25 be essential to guide the development of future optimized clinical protocols evaluating the ability of cryoablation 26 to increase systemic immunity across multiple tumor types. I will conduct this research in the excellent 27 research environment of MGH, guided by mentors expert in the fields of immunology, immuno-oncology, and 28 interventional radiology. Their guidance will help ensure the success of this project and my successful 29 transition to an independent research career.

1个检查点抑制剂（CPI）在许多肿瘤类型中的结局显着改善，但仍有 2巨大的改进空间。因此，大量的临床前研究和临床研究针对 3评估可能提高CPI反应率并识别的组合治疗方案 4个生物标志物，表明患者是否会从免疫疗法中受益或抗性。 5冷冻设施是一种有希望的辅助策略，可能能够显着增加CPI响应 6率。单个转移焦点的冷冻化导致坏死细胞死亡，通过 7交替的冻结和解冻周期。肿瘤抗原与细胞内释放 8个内容。这种明显的炎症反应激活了树突状细胞以吸收释放的肿瘤抗原 9反过来，它激活了自适应免疫系统以攻击体内其他地方的肿瘤部位。 10我已经开发了一个双植入肿瘤模型，以研究辅助冷冻的系统性益处 11并发现，当添加到CPI治疗中，冷冻化会显着增加完整的响应 仅相对于CPI的非灭绝肿瘤的12速率。由于对CPI的添加冷冻化是最少的，因此 13仍然是识别生物标志物以确定哪些肿瘤将通过冷冻化受益最大的重要工作 14添加。为了确定响应生物标志物，我通过我共同发明的独特调查工具帮助了我 15颗粒状B宠物成像。定位于主动免疫介导的肿瘤杀死的部位，颗粒B PET 16使我们能够在肿瘤大小变化之前将CPI响应者与非反应者区分开。然后我们可以 17在仍然活跃的同时审问免疫反应，从而促进了独特的见解。 18在此提案中，在鼠类肿瘤模型中，我将开发出优化的临床前冷冻和CPI方案 19跨多个肿瘤线反映了CPI响应范围。在这些模型中，我将使用 20颗粒酶B PET成像，有助于鉴定反应的基因组和非基因组生物标志物并识别 21耐候冷冻和CPI组合的机制。我也会同时领导 22临床试验评估冷冻化增加转移性尿路上皮中pembrolizumab反应的能力 23癌。从冷冻化时获得的患者血液和活检标本，我建议分析 24这些患者的肿瘤和全身免疫微环境，用于反应生物标志物。这些数据将 25对于指导未来优化的临床方案的制定至关重要，以评估冷冻化的能力 26增加多种肿瘤类型的全身免疫力。我将以优秀的方式进行这项研究 27 MGH的研究环境，由免疫学，免疫肿瘤学领域的导师专家指导 28介入放射学。他们的指导将有助于确保该项目的成功和我的成功 29过渡到独立研究职业。

项目成果

The double-balloon technique: a safe and effective adjunctive technique in patients undergoing arterial therapy for hepatic malignancies with vascular supply not amenable to selective administration.

• DOI: 10.1186/s42155-023-00349-y
• 发表时间: 2023-02-07
• 期刊: CVIR ENDOVASCULAR
• 影响因子: 1.2
• 作者: Tanaka, Mari;Uppot, Raul;Daye, Dania;Liu, Raymond;Wehrenberg-Klee, Eric
• 通讯作者: Wehrenberg-Klee, Eric

Image-guided intratumoral immunotherapy: Developing a clinically practical technology.

• DOI: 10.1016/j.addr.2022.114505
• 发表时间: 2022-10
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1

Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer.

经皮瘤内免疫辅助凝胶可增加冷冻消融对检查点抑制剂耐药癌症的远隔效应。

• DOI: 10.1002/adhm.202301848
• 发表时间: 2024
• 期刊: Advanced healthcare materials
• 影响因子: 10
• 作者: Som,Avik;Rosenboom,Jan-Georg;Wehrenberg-Klee,Eric;Chandler,Alana;Ndakwah,Gabrielle;Chen,Eric;Suggs,Jack;Morimoto,Joshua;Kim,Jonathan;Mustafa,AbdulRehman;Marcos-Vidal,Asier;Fintelmann,FlorianJ;Basu,Arijit;Langer,Robert;Travers
• 通讯作者: Travers

Immune Checkpoint Inhibitor-Mediated Cancer Theranostics with Radiolabeled Anti-Granzyme B Peptide.

• DOI: 10.3390/pharmaceutics14071460
• 发表时间: 2022-07-13
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Ferreira, Carolina de Aguiar;Heidari, Pedram;Ataeinia, Bahar;Sinevici, Nicoleta;Granito, Alyssa;Kumar, Hritik Mahajan;Wehrenberg-Klee, Eric;Mahmood, Umar
• 通讯作者: Mahmood, Umar