Fc-enhanced CD40 agonist antibodies for immune modulation of the tumor microenvironment

Fc 增强的 CD40 激动剂抗体用于肿瘤微环境的免疫调节

• 批准号: 10249062
• 负责人: David A. Knorr
• 金额: $ 21.2万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249062
• 关键词: Address; Advisory Committees; Affect; Agonist; Anti-CD40; Antibodies; Antibody Therapy; Antigen Presentation; Antigen-Presenting Cells; BCG Live; Bacillus Calmette-Guerin Therapy; Binding; Bladder Neoplasm; Blocking Antibodies; CD40 Ligand; CD8-Positive T-Lymphocytes; Cancer Model; Career Mobility; Cells; Clinic; Clinical; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development Plans; Disease; Engineering; Ensure; Family; Fc Receptor; Fc domain; Foundations; Funding; Future; Gases; Generations; Goals; Human; IgG Receptors; Immune; Immune system; Immunity; Immunocompetent; Immunology; Immunotherapeutic agent; Immunotherapy; International; Knowledge; Laboratories; Lead; Ligands; Ligation; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical Oncology; Mentors; Modeling; Mus; Necrosis; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Phenotype; Physicians; Play; Pre-Clinical Model; Principal Investigator; Proteins; Recombinant Antibody; Research; Research Project Grants; Role; Route; Scientist; Site; Specimen; Strategic Planning; Surface; T cell response; T-Cell Activation; T-Lymphocyte; TNFRSF5 gene; Testing; Therapeutic; Tissues; Toxic effect; Training; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; Universities; Vaccines; Work; anti-PD1 antibodies; anti-PD1 therapy; antibody test; antigen-specific T cells; base; cancer care; cancer immunotherapy; career development; clinical candidate; clinical investigation; crosslink; defined contribution; design; effector T cell; efficacy evaluation; exhaust; experience; human tissue; humanized mouse; immune checkpoint blockade; immunoregulation; improved; improved outcome; in situ vaccination; in vivo; instructor; interest; intravesical; member; mouse model; novel; programmed cell death protein 1; receptor; recruit; response; success; systemic toxicity; targeted agent; targeted treatment; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

Project Summary/Abstract Candidate: The PI, an Instructor in Clinical Investigation at the Rockefeller University, has developed a 5-year career development plan building upon his scientific background in immunology and clinical training in medical oncology. His mentor, Dr. Jeffrey Ravetch, is an internationally recognized expert in Fc receptors. The PI has strategically planned to address the necessary training and mentoring required for his successful career transition to independence through select coursework and a robust mentoring plan. An advisory committee composed of leaders in the field will not only ensure that the PI’s research project progresses as planned, but also is recognized by promotion and leads to independent research funding. This exciting research project is also sufficiently different from that of his mentor’s in order to avoid competition or overlap. Research plan: The recent success of immunotherapy has re-invigorated an interest in harnessing a patient’s own immune system against cancer. While therapies blocking PD-1 have improved the overall survival of patients with bladder cancer, a number of patients don’t derive clinical benefit. My studies have focused on optimizing immune stimulating agents targeting CD40. CD40 plays a key role in the activation of antigen presenting cells (APCs) and the generation of tumor specific T cells. Agonistic anti-CD40 antibodies have been proposed as an efficient approach to promote the maturation of APCs in patients; however, they were toxic with little activity. A likely explanation for this limited activity was provided by our prior studies demonstrating an absolute requirement for the antibody Fc to bind to the inhibitory Fc receptor, FcRIIB. Using this knowledge, we Fc-engineered lead clinical candidate, 2141-V11, which had superior anti-tumor efficacy. Additionally, using an in situ vaccination approach we demonstrated potent anti-tumor activity without evidence of toxicity. We are now investigating the role CD40 in the tumor microenvironment (TME) and how it can be targeted for the treatment of bladder cancer. This is because current immunotherapy in the form of intravesical Bacillus Calmette-Guerin (BCG) is not effective for a large proportion of patients affected by this disease. Our preliminary data support a role for CD40 in bladder tumors and reversal of T cell phenotypes thought to be targeted by anti-PD-1 therapies. Thus, CD40 antibodies, alone or in combination with “checkpoint blockade”, could help improve outcomes in patients not responding to intravesical BCG therapy. Building on our groups extensive experience in studying antibody therapies and access to unique tissue specimens, we now aim to test the hypothesis that 2141-V11 will target dendritic cells in the TME to promote successful anti-tumor immunity.

项目摘要/摘要 候选人：洛克菲勒大学的临床调查讲师PI已经制定了一项为期5年的 在免疫学科学背景和医学临床培训的基础上制定职业发展计划 肿瘤学。他的导师杰弗里·拉维奇博士是国际公认的Fc受体专家。少年派有 有战略规划地解决他成功职业生涯所需的必要培训和指导 通过精选的课程和强大的指导计划过渡到独立。咨询委员会 由该领域的领导者组成的组织不仅将确保国际和平研究所的研究项目按计划进行，而且 也是通过推广得到认可的，并导致独立研究资金。这个令人兴奋的研究项目是 也与他导师的完全不同，以避免竞争或重叠。 研究计划：最近免疫疗法的成功重新激发了人们对利用患者的 拥有抵御癌症的免疫系统。虽然阻断PD-1的治疗提高了患者的总体存活率 对于膀胱癌患者，一些患者得不到临床上的好处。我的研究主要集中在 优化针对CD40的免疫刺激剂。CD40在抗原活化中起关键作用 提呈细胞(APC)和肿瘤特异性T细胞的产生。激动型抗CD40抗体已经被 被认为是促进患者APC成熟的有效方法；然而，它们具有毒性 很少的活动。我们之前的研究表明，对这种有限的活动提供了一个可能的解释 抗体Fc与抑制性Fc受体FcRIIb结合的绝对要求。利用这些知识，我们 2141-V11，具有较好的抗肿瘤效果。此外，使用 在原位接种的方法，我们显示了强大的抗肿瘤活性，而没有毒性的证据。我们现在是 探讨CD40在肿瘤微环境(TME)中的作用及其靶向治疗 膀胱癌。这是因为目前的免疫疗法是以卡介苗膀胱内注射的形式。 卡介苗(BCG)对很大比例受这种疾病影响的患者无效。我们的初步数据支持 CD40在膀胱肿瘤中的作用和逆转被认为是抗PD-1治疗靶点的T细胞表型。 因此，CD40抗体单独使用或与“检查点阻断”联合使用有助于改善预后。 对卡介苗膀胱内治疗无效的患者。建立在我们团队广泛的学习经验基础上 抗体疗法和获得独特的组织样本，我们现在的目标是检验2141-V11将 靶向TME中的树突状细胞以促进成功的抗肿瘤免疫。