Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers

儿童癌症最佳免疫治疗策略的发现和开发

• 批准号: 10578310
• 负责人: JOHN M MARIS
• 金额: $ 26.4万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578310
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adaptive Immune System; Address; Adolescent and Young Adult; Adult; Antigens; Basic Science; Binding Proteins; Brain Neoplasms; CD19 gene; Cancer Center; Cancer Model; Cancer Patient; Cell surface; Chemoresistance; Child; Childhood; Clinic; Clinical; Clinical Trials; Collaborations; Credentialing; Dependence; Development; Disease; Effector Cell; Engineering; FDA approved; Functional disorder; Funding Opportunities; Goals; Heterogeneity; High-Risk Cancer; Immune; Immune Evasion; Immune system; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inter-tumoral heterogeneity; Interdisciplinary Study; Intrinsic factor; Leadership; Life; Lymphocyte; MHC Class I Genes; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Membrane; Mission; Modernization; Molecular; Morbidity - disease rate; Neuroblastoma; Oncogenic; Outcome; Patients; Pediatric Neoplasm; Peptides; Phase I Clinical Trials; Phenotype; Physicians; Pre-Clinical Model; Proteins; Public Health; Publications; Records; Refractory; Regimen; Relapse; Research; Research Personnel; Resistance; Resistance development; Scientist; Signal Transduction; Solid; Subgroup; Survivors; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Translating; Tumor-infiltrating immune cells; United States National Institutes of Health; Work; adaptive immune response; adaptive immunity; anti-tumor immune response; anticancer research; base; cancer immunotherapy; cancer therapy; checkpoint inhibition; chemoradiation; clinical application; design; efficacy testing; exhaustion; experience; high risk; immune resistance; improved; innovation; mortality; multidisciplinary; neoplastic cell; novel; novel therapeutics; pediatric immuno-oncology; pediatric patients; preclinical efficacy; prevent; rational design; sarcoma; success; tumor; tumorigenesis

OVERALL SUMMARY/ABSTRACT There is a major paradox confronting the field of childhood cancer research. Several decades ago, pioneering investigators focused on children with cancer led a revolution resulting in previously incurable malignancies becoming curable. In contrast, over the last two decades, basic science has continued to advance fundamental understanding of the oncogenesis of pediatric cancers, but cure rates for most pediatric malignancies have plateaued, and the field has witnessed first-hand that current standard therapies often saddle survivors with life threatening therapy-induced morbidities. It is sobering that for most children who suffer relapse, few if any novel therapeutic options exist, and most patients receive the same type of therapy that failed them in the first place. The funding opportunity arising out of the Beau Biden Cancer Moonshot initiative directly addresses this paradox by forming a Pediatric Immunotherapy Discovery and Development Network (PI-DDN). Immunotherapy for B-ALL and neuroblastoma is now credentialed, with CD19 directed immunotherapies showing unprecedented activity in highly refractory cases of lymphoid malignancies. The field is now poised for a focused and sustained multi-disciplinary effort to extend these early successes, and rethink our approach to childhood cancer therapy in general. Here, we propose a pediatric immuno-oncology Center entitled Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers. We envision this Center providing a central hub for the PI-DDN, creating additional opportunities for multi-disciplinary research with the common goal of creating new cancer immunotherapies for children. This Center embodies three highly integrated multi-institutional Projects supported by a single Administrative and Statistical Core. The overarching hypothesis to be tested here is that childhood cancers harbor lineage-specific mechanisms of oncogenesis and immune evasion that can be precisely and effectively targeted by rationally designed and developed immunotherapeutic regimens. Project 1 will discover lineage specific cell surface molecules that have project-defined optimal attributes for synthetic immunotherapeutic based targeting, and use this to create and credential new therapeutics based upon preclinical efficacy in high-risk childhood cancer models. Project 2 will focus on major mechanisms of immunotherapy resistance by developing approaches to circumvent the fundamental issues of intra- and inter-tumoral heterogeneity and T cell dysfunction due to both intrinsic and extrinsic factors. Project 3 will focus on a major difference between pediatric and many adult malignancies, with pediatric cancers typically eliciting little adaptive immunity, and develop approaches to enhance adaptive immune responses against pediatric cancer-specific antigenic targets. The proposed Center will discover and develop effective immunotherapeutic strategies that will be immediately translatable to the clinic, is designed to have a major direct impact on childhood cancer outcomes, and as part of the PI-DDN it will catalyze research advances across the spectrum of high-risk pediatric malignancies.

整体总结/文摘

项目成果

FOXO1 is a master regulator of CAR T memory programming.

FOXO1是CAR T内存编程的主调节器。

• DOI: 10.21203/rs.3.rs-2802998/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Doan,Alexander;Mueller,KatherineP;Chen,Andy;Rouin,GeoffreyT;Daniel,Bence;Lattin,John;Chen,Yingshi;Mozarsky,Brett;Markovska,Martina;Arias-Umana,Jose;Hapke,Robert;Jung,Inyoung;Xu,Peng;Klysz,Dorota;Bashti,Malek;Quinn,Patrick
• 通讯作者: Quinn,Patrick

Human antibodies targeting ENPP1 as candidate therapeutics for cancers.

• DOI: 10.3389/fimmu.2023.1070492
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Chu, Xiaojie;Baek, Du-San;Li, Wei;Shyp, Taras;Mooney, Brian;Hines, Margaret G.;Morin, Gregg B.;Sorensen, Poul H.;Dimitrov, Dimiter S.
• 通讯作者: Dimitrov, Dimiter S.

Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma.

• DOI: 10.1158/2159-8290.cd-20-1690
• 发表时间: 2021-11
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Zhang HF;Hughes CS;Li W;He JZ;Surdez D;El-Naggar AM;Cheng H;Prudova A;Delaidelli A;Negri GL;Li X;Ørum-Madsen MS;Lizardo MM;Oo HZ;Colborne S;Shyp T;Scopim-Ribeiro R;Hammond CA;Dhez AC;Langman S;Lim JKM;Kung SHY;Li A;Steino A;Daugaard M;Parker SJ;Geltink RIK;Orentas RJ;Xu LY;Morin GB;Delattre O;Dimitrov DS;Sorensen PH
• 通讯作者: Sorensen PH

NOT-Gated CD93 CAR T Cells Effectively Target AML with Minimized Endothelial Cross-Reactivity.

• DOI: 10.1158/2643-3230.bcd-20-0208
• 发表时间: 2021-11
• 期刊: Blood cancer discovery
• 影响因子: 11.2
• 作者: Richards RM;Zhao F;Freitas KA;Parker KR;Xu P;Fan A;Sotillo E;Daugaard M;Oo HZ;Liu J;Hong WJ;Sorensen PH;Chang HY;Satpathy AT;Majzner RG;Majeti R;Mackall CL
• 通讯作者: Mackall CL

Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.

• DOI: 10.1016/j.tcb.2022.02.009
• 发表时间: 2022-09
• 期刊: TRENDS IN CELL BIOLOGY
• 影响因子: 19
• 作者: Zhang, Hai-Feng;Geltink, Ramon I. Klein;Parker, Seth J.;Sorensen, Poul H.
• 通讯作者: Sorensen, Poul H.