Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19

增强嵌合抗原受体 T 细胞治疗血液恶性肿瘤：超越 CART 19

基本信息

批准号：
10713199
负责人：
CARL H. JUNE
金额：
$ 278.23万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713199
关键词：
Acute Myelocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adoptive Transfer Authorization documentation Autoimmune Diseases B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia Back Biological Biometry Blood CAR T cell therapy CD19 gene CRISPR/Cas technology CTLA4 gene Cell Therapy Cells Chronic Lymphocytic Leukemia Clinic Clinical Clinical Trials Collaborations Development Discipline Disease Engineering FDA approved Funding Future Generations Genes Genetic Genetic Engineering Gills Goals Hematologic Neoplasms Hematopoiesis Hematopoietic Neoplasms Hematopoietic System Human Genome Immune Immunologics Immunotherapy In complete remission Individual Interleukin-2 International Joints Journals Laboratories Licensing Lymphoblastic Leukemia Lymphoma Malignant Neoplasms Marrow Mediating Medical Medicine Messenger RNA Modification Monitor Multiple Myeloma Mutate Myeloid Leukemia New England PTPRC gene Paper Patients Persons Publications Publishing Refractory Relapse Research Research Personnel Resistance Resource Sharing Safety Sampling Services Small-Cell Lymphoma Solid Source Surface Antigens T-Lymphocyte Technology Testing Therapeutic Toxic effect Translating United States Vaccines antitumor effect authority base editing bench to bedside cancer cell cancer immunobiology cancer immunotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical investigation efficacy testing engineered T cells gene therapy genome editing improved indexing innovation leukemia leukemia/lymphoma lipid nanoparticle manufacturing facility multidimensional data next generation novel novel therapeutics overexpression preclinical study programs rational design standard of care synthetic biology tool tumor

项目摘要

OVERALL PROJECT SUMMARY / ABSTRACT The long-term goals of this renewal P01 are to develop next generation immunotherapy with chimeric antigen receptor (CAR) T cells and to translate this research into new therapies with curative potential for patients with blood cancer. The CAR developed at our center was the first cell and gene therapy to ever receive approval from the FDA, initially for refractory/relapsed pre-B cell acute lymphocytic leukemia (ALL) in 2017 and lymphoma in 2018. However, multiple myeloma (MM), acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) remain as the major unmet medical need in blood cancers. Our central hypothesis is that therapies with combination of CAR T cells and advanced forms of human genome editing will enable this powerful therapy to reach a broader spectrum of patients with blood cancer. We have brought together a cadre of exceptional investigators from multiple disciplines who have collaborated and published together for many years. Each disease-focused project will be led by recognized authorities in the field. To achieve our goals, we have three Projects that build on progress during the previous funding period and will continue to coordinate closely with essential shared resource cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) CAR T cells targeting CD19 will be tested with genetic disruption of CD5, CTLA- 4 and TET2 to address CLL and lymphoma, which is lack of sustained effector CAR T function in these patients. In AML, the central problem in CAR T cell therapy is the lack of a known surface antigen that is present on AML but lacking from normal hematopoiesis. The goal of Project 2 is to open a wide therapeutic window for AML by genetically-modifying normal marrow to make it resistant to killing by anti-AML CAR T cells, and delivering potent anti-leukemic CAR T cells specific for CD45. Engineered HSC that are genetically edited to install a hematopoietic system facilitating non-toxic therapy with these potent CAR T cells will be developed. In Project 3, the overall hypothesis is that anti-myeloma efficacy will be maximized by (i) testing the efficacy of marrow- derived CAR T compared to current standard of care blood-derived CAR T (ii) improving persistence of BCMA CAR T with orthogonally mutated IL-2/IL-2R technology and mRNA/lipid-nanoparticle vaccine technology to overcome suboptimal persistence and efficacy of current BCMA T cells. The Scientific and Administrative Cores for this P01 are essential for our progress including provision of project management for collaboration and biostatistics, clinical safety and monitoring, and fiscal support (Core A), a GMP facility for manufacture of cells and identification of new binders for CAR targets (Core B), and a state-of- the-art platform for GLP analysis to provide high dimensional data of the samples generated in all Projects (Core C). Our renewal application has the potential for paradigm-shifting impact to transform the lessons of CAR T for ALL into meaningful efficacy against all hematologic malignancies, solid cancers and provides direction for extending beyond cancer to autoimmune disorders.

总体项目概要/摘要此次更新P01的长期目标是开发下一代嵌合抗原免疫疗法受体（CAR）T细胞，并将这项研究转化为对患有以下疾病的患者具有治疗潜力的新疗法血癌。我们中心开发的 CAR 是第一个获得 FDA 批准的细胞和基因疗法 FDA 最初用于 2017 年的难治性/复发性前 B 细胞急性淋巴细胞白血病 (ALL) 和 2017 年的淋巴瘤 2018年。然而，多发性骨髓瘤（MM）、急性髓性白血病（AML）和慢性淋巴细胞白血病（CLL）仍然是血癌中未满足的主要医疗需求。我们的中心假设是，治疗 CAR T 细胞与先进形式的人类基因组编辑的结合将使这种强大的疗法能够覆盖更广泛的血癌患者。我们聚集了一支杰出的骨干队伍来自多个学科的研究人员多年来一直合作并共同发表论文。每个以疾病为重点的项目将由该领域公认的权威机构领导。为了实现我们的目标，我们有三个目标在上一个资助期间取得进展的项目将继续与重要的共享资源核心。在项目 1 中，我们将确定治疗的临床和免疫学影响接受两项临床试验的患者：(i) 靶向 CD19 的 CAR T 细胞将通过 CD5、CTLA- 的基因破坏进行测试 4 和 TET2 来治疗 CLL 和淋巴瘤，这些患者缺乏持续效应 CAR T 功能。在 AML 中，CAR T 细胞疗法的核心问题是缺乏 AML 上存在的已知表面抗原但缺乏正常造血功能。项目 2 的目标是通过以下方式为 AML 打开一个广阔的治疗窗口：对正常骨髓进行基因改造，使其能够抵抗抗 AML CAR T 细胞的杀伤，并提供有效的 CD45 特异性的抗白血病 CAR T 细胞。工程 HSC 经过基因编辑以安装将开发促进使用这些强效 CAR T 细胞进行无毒治疗的造血系统。项目中 3，总体假设是，通过（i）测试骨髓瘤的功效，可以最大限度地提高抗骨髓瘤功效衍生 CAR T 与当前护理标准血源 CAR T 相比 (ii) 提高 BCMA 的持久性具有正交突变IL-2/IL-2R技术和mRNA/脂质纳米颗粒疫苗技术的CAR T 克服当前 BCMA T 细胞的次优持久性和功效。 P01 的科学和行政核心对于我们的进步至关重要，包括提供项目协作和生物统计管理、临床安全和监测以及财政支持（核心 A），用于制造细胞和识别 CAR 靶标新结合剂的 GMP 设施（核心 B），以及最新状态最先进的 GLP 分析平台，提供所有项目中生成的样本的高维数据（核心 C）。我们的更新应用程序有可能产生范式转变的影响，从而改变 CAR T 的经验教训 ALL 对所有血液系统恶性肿瘤、实体癌具有有意义的功效，并为范围从癌症延伸到自身免疫性疾病。

项目成果

期刊论文数量（72）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adoptive T-cell therapy for Hodgkin lymphoma.

DOI：
10.1182/bloodadvances.2021005304
发表时间：
2021-10-26
期刊：
Blood advances
影响因子：
7.5
作者：
Ho C;Ruella M;Levine BL;Svoboda J
通讯作者：
Svoboda J

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults With Acute Lymphoblastic Leukemia.

DOI：
10.1200/jco.19.01892
发表时间：
2020-02-10
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
0
作者：
Frey NV;Shaw PA;Hexner EO;Pequignot E;Gill S;Luger SM;Mangan JK;Loren AW;Perl AE;Maude SL;Grupp SA;Shah NN;Gilmore J;Lacey SF;Melenhorst JJ;Levine BL;June CH;Porter DL
通讯作者：
Porter DL

Chimeric Antigen Receptor Therapy.

DOI：
10.1056/nejmra1706169
发表时间：
2018-07-05
期刊：
The New England journal of medicine
影响因子：
0
作者：
June CH;Sadelain M
通讯作者：
Sadelain M

Born to survive: how cancer cells resist CAR T cell therapy.

DOI：
10.1186/s13045-021-01209-9
发表时间：
2021-11-22
期刊：
Journal of hematology & oncology
影响因子：
28.5
作者：
Lemoine J;Ruella M;Houot R
通讯作者：
Houot R

Acute Kidney Injury Following Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma in a Kidney Transplant Recipient.

DOI：
10.1016/j.xkme.2021.03.011
发表时间：
2021-07
期刊：
Kidney medicine
影响因子：
3.9
作者：
Melilli E;Mussetti A;Linares GS;Ruella M;La Salette C;Savchenko A;Taco MDR;Montero N;Grinyo J;Fava A;Gomà M;Meneghini M;Manonelles A;Cruzado J;Sureda A;Bestard O
通讯作者：
Bestard O