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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘