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

• 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
• 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

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.

总体项目总结/摘要 该更新P01的长期目标是开发使用嵌合抗原的下一代免疫疗法 受体（CAR）T细胞，并将这项研究转化为具有治疗潜力的新疗法， 血癌我们中心开发的CAR是第一个获得批准的细胞和基因疗法 FDA最初于2017年针对难治性/复发性前B细胞急性淋巴细胞白血病（ALL）， 2018.然而，多发性骨髓瘤（MM）、急性髓细胞白血病（AML）和慢性淋巴细胞白血病（CLL） 仍然是血癌的主要未满足的医疗需求。我们的中心假设是， CAR T细胞和先进形式的人类基因组编辑的组合将使这种强大的疗法， 接触到更广泛的血癌患者。我们召集了一批杰出的 来自多个学科的研究人员多年来一直合作并共同发表。每个 以疾病为重点的项目将由该领域公认的权威领导。为了实现我们的目标，我们有三个 在上一个供资期取得进展的基础上开展的项目，将继续与 核心共享资源。在项目1中，我们将确定治疗的临床和免疫学影响。 （i）靶向CD 19的CAR T细胞将用CD 5、CTLA-1的遗传破坏进行测试。 4和TET 2来解决CLL和淋巴瘤，其在这些患者中缺乏持续的效应子CAR T功能。 在AML中，CAR T细胞治疗的中心问题是缺乏AML上存在的已知表面抗原。 但缺乏正常的造血功能。项目2的目标是为AML打开一个广阔的治疗窗口， 对正常骨髓进行基因修饰，使其对抗AML CAR T细胞的杀伤具有抗性， 对CD 45特异的抗白血病CAR T细胞。经过基因编辑的工程HSC， 将开发促进使用这些有效CAR T细胞的无毒治疗的造血系统。在项目 3，总体假设是，抗骨髓瘤功效将通过以下方式最大化：（i）测试骨髓-骨髓抑制剂的功效， （ii）改善BCMA的持久性 CAR T与正交突变的IL-2/IL-2 R技术和mRNA/脂质纳米颗粒疫苗技术， 克服当前BCMA T细胞的次优持久性和功效。 本P01的科学和行政核心对我们的进展至关重要，包括提供项目 合作和生物统计学、临床安全性和监测以及财政支持管理（核心A），a 用于生产细胞和鉴定CAR靶标（核心B）的新结合剂的GMP设施，以及 先进的GLP分析平台，提供所有项目（核心）中生成的样本的高维数据 C）。我们的更新应用程序有可能产生范式转变的影响，将CAR T的经验教训转化为 ALL对所有血液恶性肿瘤、实体癌有意义的疗效，并为 从癌症扩展到自身免疫性疾病

项目成果

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
• 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
• 作者: June CH;Sadelain M
• 通讯作者: Sadelain M

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

Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell.

通过转导单个白血病B细胞诱导对嵌合抗原受体T细胞疗法的抗性。

• DOI: 10.1038/s41591-018-0201-9
• 发表时间: 2018-10
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Ruella M;Xu J;Barrett DM;Fraietta JA;Reich TJ;Ambrose DE;Klichinsky M;Shestova O;Patel PR;Kulikovskaya I;Nazimuddin F;Bhoj VG;Orlando EJ;Fry TJ;Bitter H;Maude SL;Levine BL;Nobles CL;Bushman FD;Young RM;Scholler J;Gill SI;June CH;Grupp SA;Lacey SF;Melenhorst JJ
• 通讯作者: Melenhorst JJ