Project 2: Androgen deprivation as an immune modulating therapy in combination with targeted immunotherapy of prostate cancer

项目2：雄激素剥夺作为免疫调节疗法与前列腺癌靶向免疫疗法相结合

• 批准号: 10555401
• 负责人: DOUGLAS G. MCNEEL
• 金额: $ 34.67万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555401
• 关键词: Affect; Androgen Receptor; Androgens; Antigen Targeting; Antigens; Antitumor Response; CD8-Positive T-Lymphocytes; Cancer Vaccines; Castration; Cell Line; Cells; Clinical; Clinical Trials; Combined Modality Therapy; DNA Vaccines; Development; Disease; Disease Resistance; Epitope spreading; Epitopes; Evaluation; Goals; HLA-A2 Antigen; Health; Human; Immune; Immune response; Immunization; Immunologic Memory; Immunologics; Immunotherapy; Infiltration; Interferon Type II; Laboratories; Ligand Binding Domain; Malignant Neoplasms; Malignant neoplasm of prostate; Memory; Metastatic Prostate Cancer; Methods; Mission; Modification; Mus; Myeloid Cells; National Cancer Institute; Neoadjuvant Therapy; Newly Diagnosed; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Population; Pre-Clinical Model; Production; Prostate; Prostate Cancer therapy; Prostatectomy; Prostatic Neoplasms; Proteins; Recurrence; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; T cell infiltration; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Effect; Thymus Gland; Time; Tissues; Transgenic Mice; Universities; Vaccination; Vaccines; Wisconsin; advanced prostate cancer; androgen deprivation therapy; anti-tumor immune response; antitumor effect; arm; biomarker driven; cancer infiltrating T cells; cancer therapy; checkpoint receptors; clinical development; deprivation; design; high risk; immune cell checkpoints; immune checkpoint; immune checkpoint blockade; immune function; immunomodulatory therapies; improved; inhibitor; men; mouse model; neoplastic cell; novel; overexpression; phase I trial; preclinical study; programmed cell death ligand 1; programmed cell death protein 1; prostate cancer cell; prostate cancer model; prostate cancer risk; receptor; receptor vaccine; recruit; resistance mechanism; response; therapy development; tumor; tumor DNA; tumor eradication; vaccination outcome

PROJECT SUMMARY Prostate cancer is a significant worldwide health problem for which new treatments are needed. The goal of our laboratory for the past twenty years has been to develop immunotherapy treatments for prostate cancer. We have evaluated multiple cancer-associated proteins as anti-tumor vaccine targets and have focused recent efforts on the ligand-binding domain of the androgen receptor (AR LBD) as a target. We demonstrated that a DNA vaccine encoding the AR LBD (pTVG-AR) can elicit epitope-specific cytolytic CD8+ T cells in HLA-A2 transgenic mice, and immunization of prostate tumor-bearing mice elicited anti-tumor responses and significantly prolonged their overall survival. Based on these results, we recently completed a multi-center phase I clinical trial using the pTVG-AR vaccine for patients with metastatic prostate cancer and demonstrated that vaccination is safe and immunologically active. Consistent with our preclinical studies, the development of T-cell immune response to the AR LBD was associated with a prolonged time to castration resistance. In preclinical studies, we have found that androgen deprivation (AD) leads to overexpression of the AR protein in prostate cancer cells, and this in turn makes them more recognized by CD8+ T cells activated by AR- targeted vaccination. We have subsequently demonstrated that AD can thus be used strategically with immunization. In other preclinical studies, we have further found that CD8+ T cells activated by vaccination express multiple immune checkpoint receptors (ICR), and that blockade of certain ICR with vaccination leads to greater anti-tumor effects. Together, these findings have led to the hypothesis to be tested in this proposal that combined AD, with AR-targeted vaccination and T-cell checkpoint blockade, will lead to increased tumor-specific CD8+ T cell infiltration, tumor eradication, and persistent immune memory. We will use relevant murine models of prostate cancer to conduct a mechanistic evaluation of the effects of AD with vaccination and ICR blockade on the development of T cell memory and antigen spread. This approach will also be evaluated in an investigator- initiated clinical trial in patients with high-risk prostate cancer prior to prostatectomy, with a design amenable to modification of study arms depending on the outcomes from the preclinical studies. This proposal, consequently, capitalizes on development of a novel anti-tumor vaccine that has now completed phase I clinical trial evaluation, and explores methods to increase its therapeutic effect in preclinical models and in a biomarker-driven clinical trial. Results from this proposal will identify optimal strategies and clinical scenarios for further clinical development of this treatment approach.

项目摘要 前列腺癌是需要新治疗的全球健康问题。目标 在过去的二十年中，我们的实验室是为了开发针对前列腺癌的免疫疗法。 我们已经评估了多种与癌症相关的蛋白作为抗肿瘤疫苗靶标的，并重点是 雄激素受体（AR LBD）作为目标的配体结合结构域的努力。我们证明了 编码AR LBD（PTVG-AR）的DNA疫苗可以引起HLA-A2中表位特异性细胞溶解CD8+ T细胞 转基因小鼠和前列腺肿瘤小鼠的免疫引起抗肿瘤反应，并显着 延长了整体生存。基于这些结果，我们最近完成了多中心I期临床 使用PTVG-AR疫苗对转移性前列腺癌患者进行试验，并证明了疫苗接种 是安全且免疫学上的活跃。与我们的临床前研究一致，T细胞免疫的发展 对AR LBD的反应与延长的cast割耐药性有关。 在临床前研究中，我们发现雄激素剥夺（AD）导致AR过表达 前列腺癌细胞中的蛋白质，这反过 目标疫苗接种。随后，我们证明了AD可以在战略上与 免疫。在其他临床前研究中，我们进一步发现CD8+ T细胞通过疫苗接种激活 表达多个免疫检查点受体（ICR），并以疫苗接种的某些ICR阻断导致 更大的抗肿瘤作用。 这些发现总之导致了该假设在此提案中进行了检验，该提议将AD与 靶向AR的疫苗接种和T细胞检查点封锁将导致肿瘤特异性CD8+ T细胞增加 浸润，消除肿瘤和持续的免疫记忆。我们将使用相关的前列腺模型 癌症以对AD的疫苗接种和ICR阻断对AD的影响进行机械评估对 T细胞记忆和抗原扩散的发展。该方法还将在研究人员中进行评估 - 在前列腺切除术前进行高危前列腺癌患者的临床试验，设计可正常 根据临床前研究的结果，修改研究臂。因此，该提议 利用开发一种新型的抗肿瘤疫苗，该疫苗现已完成I期临床试验评估， 并探讨在临床前模型和生物标志物临床中增加其治疗作用的方法 审判。该提案的结果将确定最佳策略和临床方案，以进一步临床 这种治疗方法的发展。