Novel CART Cells for Treating AML

用于治疗 AML 的新型 CART 细胞

• 批准号: 10366752
• 负责人: Xianxin Hua
• 金额: $ 52.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366752
• 关键词: Acute Myelocytic Leukemia; Adoptive Immunotherapy; Adult Acute Myeloblastic Leukemia; Animal Model; B-Cell Acute Lymphoblastic Leukemia; Binding; Blast Cell; CD19 gene; Cell Line; Cell Surface Proteins; Cells; Chemoresistance; Clinic; Clinical Research; Data; Development; Disease remission; Drug resistance; FDA approved; Face; Future; Generations; Hematopoietic; Hematopoietic stem cells; Human; IL3RA gene; Immune; Immune system; Immunotherapy; In Vitro; Leukemic Cell; Lymphoma; Medical; Mus; Normal Cell; Normal tissue morphology; Patients; Prognosis; Refractory; Relapse; Safety; Specificity; Specimen; Surface; System; T-Lymphocyte; Technology; Testing; Toxic effect; Translations; acute myeloid leukemia cell; alanine aminopeptidase; cancer cell; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; effective therapy; improved; in vivo; innovation; leukemia; leukemic stem cell; mortality; nanobodies; novel; patient derived xenograft model; pre-clinical; receptor; tumor

Project Summary Chemotherapy resistance remains a major barrier to successful treatment of patients with acute myeloid leukemia (AML), contributing to high rates of relapse and mortality. Development of more effective treatments for AML is imperative, particularly therapies with alternative mechanisms of action to circumvent chemoresistance. Adoptive cellular immunotherapy using CD19-targeting chimeric antigen receptor (CAR)- expressing T cells has drastically improved the treatment of patients with multiply relapsed/refractory B-cell lymphoblastic leukemia (B-ALL) and lymphoma and was approved by the FDA. However, successful translation of AML immunotherapies has lagged behind and remains a significant unmet medical need. To date, CAR T cells targeting CD33 or CD123 for AML have shown potent preclinical anti-AML activity, but also induced severe myelotoxicity via on target/off tumor damage to hematopoietic stem cells (HSCs). We have developed an innovative system to isolate single-domain nanobodies (Nb) that preferentially bind AML cells and enable cognate CAR T cells to kill the cancer cells. One of these nanobodies, Nb157, specifically binds to the cell surface protein CD13 (aminopeptidase N), which is often upregulated in adult AML specimens and leukemia stem cells (LSCs). In preliminary studies, we demonstrated that Nb157/CD13 CAR T cells (CD13CARTs) potently eradicated AML cells in preclinical animal models. TIM-3, an inhibitory receptor of certain immune cells, is upregulated in AML blast cells and LSCs, but not expressed in human HSCs. Thus, we generated the 1st generation bispecific and split CD13/TIM-3 CARTs (1st G bCARTs) and demonstrated that the bCARTs potently eradicated AML cells in preclinical animal models, with significantly reduced toxicity to HSCs. To further improve the safety profile of the bCARTs, the 2nd generation bCARTs were generated and they did not induce obvious toxicity to HSCs in our ex vivo analysis. We hypothesize that further development of the bispecific or inducible bispecific CARTs can eradicate AML in patient-derived xenograft (PDX) models with little or tolerable off-tumor toxicity. Three specific aims are proposed to test this hypothesis. Aim 1 will evaluate the 2nd generation bispecific CD13/TIM-3CARTs (bCARTs) in maximizing selective AML killing. Aim 2 will investigate efficacy and specificity of inducible CD13/TIM-3CARTs (ibCARTs) in killing AML cells. Aim 3 will develop bispecific CLL-1/TIM-3 bCARTs to selectively killing AML cells. Results obtained from these studies are imminently translatable to the clinic in the near future for patients with relapsed/refractory AML.

项目摘要 耐化疗仍然是成功治疗急性髓样患者的主要障碍 白血病（AML），导致了高复发和死亡率。开发更有效的治疗方法 对于AML是势在必行的，尤其是具有替代作用机理的疗法 化学抗性。使用CD19靶向嵌合抗原受体（CAR） - 表达T细胞大大改善了用倍数复发/难治性B细胞的患者的治疗 淋巴细胞白血病（B-ALL）和淋巴瘤，并由FDA批准。但是，成功翻译 AML免疫疗法已落后，并且仍然是巨大的未满足的医疗需求。迄今为止，汽车T 针对AML CD33或CD123的细胞已显示出有效的临床前抗AML活性，但也诱导了严重的 骨毒性通过目标/关闭肿瘤对造血干细胞的损害（HSC）。我们已经开发了 隔离单域纳米型（NB）的创新系统，该系统优先结合AML细胞并启用 同源汽车T细胞杀死癌细胞。这些纳米生物结构之一NB157特别结合了细胞表面 蛋白CD13（氨基肽酶N），通常在成年AML标本和白血病干细胞中上调 （LSC）。在初步研究中，我们证明了NB157/CD13 CAR T细胞（CD13CARTS）有效 临床前动物模型中根除的AML细胞。 Tim-3是某些免疫细胞的抑制受体，是 在AML爆炸细胞和LSC中上调，但在人HSC中不表达。因此，我们生成了第一 一代双特异性和分裂CD13/TIM-3推车（第1 G BCARTS），并证明了BCARTS有效 根除临床前动物模型中的AML细胞，对HSC的毒性显着降低。进一步改善 BCARTS的安全性，第二代BCART是生成的，它们并未引起明显的 在我们的离体分析中对HSC的毒性。我们假设双特异性或诱导的进一步发展 双特异性推车可以在患者衍生的异种移植（PDX）模型中消除AML，该模型很少或无法忍受。 毒性。提出了三个特定目标来检验这一假设。 AIM 1将评估第二代双特异性 CD13/TIM-3CARTS（BCARTS）在最大化选择性AML杀戮方面。 AIM 2将研究功效和特异性 诱导CD13/TIM-3CARTS（IBCARTS）杀死AML细胞。 AIM 3将开发双特异性CLL-1/TIM-3 BCARTS选择性杀死AML细胞。从这些研究中获得的结果即将转换为 诊所在不久的将来针对患有复发/难治性AML的患者。