Multi-functional cellular therapies to overcome tumor heterogeneity and limit toxicity in acute myeloid leukemia

多功能细胞疗法克服肿瘤异质性并限制急性髓系白血病的毒性

• 批准号: 10679763
• 负责人: CORYNN KASAP
• 金额: $ 8.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2026-09-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679763
• 关键词: Ablation; Acute Myelocytic Leukemia; Address; Affect; Allogenic; American; Antibodies; Antibody Therapy; Antigen Targeting; Antigens; Automobile Driving; B lymphoid malignancy; Bispecific Antibodies; Blood; Bone Marrow; Bone Marrow Purging; Cell Therapy; Cell secretion; Cells; Cessation of life; Data; Development; Disease; Drug resistance; Elements; Engineering; Face; Future; Genetic Transcription; Goals; Hematologic Neoplasms; Hematology; Hematopoietic Neoplasms; Heterogeneity; Home; Homing; IL3RA gene; Immune system; Immunotherapy; In Vitro; Malignant Neoplasms; Marrow; Measurable; Myeloid Cells; Myelosuppression; Neoadjuvant Therapy; Normal Cell; Patients; Pharmacy facility; Physicians; Population; Positioning Attribute; Relapse; Reporter; Research; Residual Neoplasm; Residual state; Resistance; Risk; Scientist; Stem cell transplant; Surface; Surface Antigens; Survival Rate; Synthetic immunology; System; T cell therapy; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Training; Work; Xenograft Model; acute myeloid leukemia cell; antibody engineering; antibody immunotherapy; cellular engineering; chemotherapy; chimeric antigen receptor T cells; cytokine release syndrome; design; engineered T cells; experience; experimental study; feasibility testing; in vivo; in vivo Model; innovation; leukemic stem cell; mouse model; neoplastic cell; next generation; novel strategies; novel therapeutic intervention; patient derived xenograft model; relapse prediction; small molecule; stem cell niche; success; systemic toxicity; targeted treatment; therapeutic protein; therapeutic target; therapeutically effective; tumor; tumor heterogeneity

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease with only 30% 5-year overall survival. As a blood cancer, AML appears poised to benefit from the revolution in engineered cellular therapies and bispecific antibodies. These agents are making an enormous impact in B-cell malignancies. However, extending this success to AML faces two significant hurdles: 1) lack of highly disease-specific targets, where engaging current AML therapeutic targets leads to severe cytokine release syndrome and severe myeloablation, precluding an effective therapeutic index; and 2) significant intratumoral heterogeneity, where targeting a single surface antigen is likely to lead to antigen-negative relapse. In practice, these two challenges leave few therapeutic targets sufficient to achieve cures in most patients. Here, my long-term goal is to develop a new therapeutic approach to overcome these hurdles. This proposal will be led by myself under the sponsorship of Dr. Arun Wiita, an expert in hematologic malignancies and drug resistance, with collaborative support from Dr. Kole Roybal, expert in advanced cellular engineering; and Dr. Jim Wells, expert in antibody engineering. Specifically, I hypothesize that employing SNIPR, the newly-described, next-generation, humanized platform based on the SynNotch cellular engineering technology (Zhu et al., Cell 2022), will enable development of a multi-functional T-cell therapy that can eliminate residual AML after induction chemotherapy, clearing relapse- driving leukemic stem cells and increasing cure rates, while avoiding toxicities of systemic therapeutics. My major design pillars include 1) develop engineered T-cells that home specifically to the leukemic stem cell niche; and 2) locally, but not systemically, have SNIPR T-cells secrete multiple protein therapeutics to ablate heterogenous leukemic stem cells and AML blasts in and near this niche. In Specific Aim 1, I test the feasibility and initial in vitro and in vivo potency of SNIPR engineered T-cells designed to simultaneously secrete functional bispecific antibodies against 3 AML targets. In Specific Aim 2, I use PDX models to test whether SNIPR T-cells can selectively home to the bone marrow niche, with CD70 as the optimal leukemic stem cell “trigger”. Successful completion of these Aims will set the stage for subsequent work, outside the scope of this proposal, to validate, using additional in vitro and in vivo models, the ability of CD70-sensing, multi-bispecific- secreting T-cells to eliminate AML more completely than other therapies while minimizing toxicities. Furthermore, this approach will ultimately enable delivery of other therapeutic payloads to the leukemic stem cell niche, ideally targeting this disease-driving cellular population with unprecedented precision. Success here may also outline a new therapeutic strategy for use across cancers, to eliminate heterogeneous tumor in the microenvironment while sparing normal cells. Completion of the work in this proposal in conjunction with the associated training plan will provide critical expertise and experience to support my goal of becoming an independent physician-scientist focused on translational immunotherapy research.

项目摘要/摘要 急性髓样白血病（AML）是一种毁灭性疾病，仅5年5年总生存期。作为鲜血 癌症，AML似乎有毒，从工程蜂窝疗法和双特异性的革命中受益 抗体。这些药物对B细胞恶性肿瘤产生巨大影响。但是，扩展了这一点 AML的成功面临两个重大障碍：1）缺乏高度疾病的目标，其中引人入胜 当前的AML热靶标会导致严重的细胞因子释放综合征和严重的骨髓化， 排除有效的治疗指数； 2）明显的肿瘤内异质性，其中靶向单个 表面抗原可能导致抗原阴性缓解。实际上，这两个挑战几乎没有 在大多数患者中，治疗靶标足以实现治疗方法。在这里，我的长期目标是开发一个新的 克服这些障碍的治疗方法。该提议将由我自己领导 血液系统恶性肿瘤和耐药性专家Arun Wiita博士在博士的合作支持下 高级蜂窝工程专家Kole Royal；抗体工程专家Jim Wells博士。 具体而言，我假设使用SNIPR，新描述的，下一代，人性化的平台 基于Synnotch细胞工程技术（Zhu等人，Cell 2022），将使能够发展 多功能的T细胞疗法可以消除诱导化疗后残留AML，清除继电器 - 驱动白血病干细胞并增加治愈率，同时避免了全身治疗的毒性。我的 主要设计支柱包括1）开发专门用于白血病干细胞的工程T细胞 利基； 2）在本地但不是系统地，SNIPR T细胞秘密多种蛋白质治疗以消融 异质性白血病干细胞和AML在该利基市场内外爆炸。在特定目标1中，我测试可行性 以及初始体外和体内效力，用于简单地分泌的SNIPR工程T细胞 针对3个AML靶标的功能双特异性抗体。在特定目标2中，我使用PDX模型测试是否 SNIPR T细胞可以选择性地回到骨髓小裂，CD70作为最佳的白血病干细胞 “扳机”。这些目标的成功完成将为后续工作奠定基础，之外 提案，使用其他体外和体内模型来验证CD70感应，多双特异性的能力 与其他疗法相比，分泌T细胞以更全面地消除AML，同时最大程度地减少毒性。 此外，这种方法最终将使其他治疗有效载荷交付给白血病STEM 细胞生态位，理想情况下，针对这种疾病驱动的细胞种群，具有前所未有的精度。在这里成功 还可以概述一种新的理论策略，用于跨癌症，以消除异质性肿瘤 微环境在保留正常细胞的同时。在本提案中完成工作与 相关培训计划将提供重要的专业知识和经验，以支持我成为一个目标的目标 独立的身体科学家专注于翻译的免疫疗法研究。