Off-the-shelf engineered NK cells for the treatment of AML

用于治疗 AML 的现成工程 NK 细胞

• 批准号: 10162818
• 负责人: Katy Rezvani
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162818
• 关键词: Address; Adenoviruses; Adoptive Immunotherapy; Adrenal Cortex Hormones; Adult Respiratory Distress Syndrome; Algorithms; Antiviral Agents; Apoptosis; Attention; BK Virus; Blood donor; Blood specimen; COVID-19; COVID-19 pandemic; CRISPR/Cas technology; Cancer Patient; Cell Line; Cell Therapy; Cells; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Communities; Coronavirus; Correlative Study; Cryopreservation; Cytomegalovirus; Development; Dose; Effectiveness; Engineering; FDA approved; Funding; Funding Agency; Generations; Genes; Glucocorticoid Receptor; Glucocorticoids; Health; Hematopoietic Stem Cell Transplantation; Immune; Immunocompromised Host; Immunotherapeutic agent; Individual; Infection; Infusion procedures; Institutional Review Boards; Knock-out; Laboratories; Life; Literature; Lymphocyte; Mechanical ventilation; Medical; Middle East Respiratory Syndrome Coronavirus; NK cell therapy; NR3C1 gene; Natural Killer Cells; Nuclear Receptors; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Pneumonia; Preparation; Prevention; Production; Protocols documentation; Resistance; Respiratory Failure; Role; SARS coronavirus; Safety; Savings; Severities; Source; Steroid Resistance; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Transplantation; Treatment Efficacy; Umbilical Cord Blood Transplantation; University of Texas M D Anderson Cancer Center; Viral; Virus; Virus Diseases; biobank; chimeric antigen receptor; chimeric antigen receptor T cells; comorbidity; cytotoxic; engineered NK cell; improved outcome; innovation; mortality; novel; novel strategies; peripheral blood; phase I trial; respiratory; response; safety and feasibility; scale up; transmission process

ABSTRACT The coronavirus (COVID-19) pandemic has spread rapidly and globally to infect over 3 million individuals, with no effective therapeutic options for patients with serious and life-threatening complications. The impact of this infection is likely to be especially serious in patients undergoing hematopoietic stem cell transplant (HSCT), in particular umbilical cord blood transplant (CBT) recipients or those receiving chimeric antigen receptor (CAR) T or NK cell therapies, given their immunocompromised state, presence of medical comorbidities, and concerns for higher infection-related severity and mortality. Our team has developed robust clinical banks of HLA-typed GMP-grade viral-specific T lymphocytes (VSTs) targeting cytomegalovirus (CMV), BK virus (BKV) and adenovirus. We have treated over 100 HSCT recipients, 49% of whom had received CB or haploidentical transplants, with these partially HLA-matched and off-the-shelf VSTs on FDA-approved clinical protocols with a >80% response rate and no toxicity. We have successfully applied this platform to establish the protocols for the manufacture of GMP-grade COVID-19 specific T cells. We propose to generate a biobank of COVID-19 specific T cells from donors who have recovered from COVID-19 infections using IRB-approved protocols (MDACC Lab02-0630) in the MDACC GMP Facility. We will then conduct a phase I/II clinical trial to evaluate the safety, feasibility and antiviral activity of third-party, off-the-shelf, most closely HLA-matched COVID-19 specific T cells in HSCT including CBT/haploidentical transplant or cell therapy recipients with severe COVID-19 infections (Aim 1). To expedite the approval of this trial for our patients, we recently amended another VST protocol to include treatment with COVID-19 specific T cells (MDACC #2017-0350, IND 17761). One of the most severe manifestations of the COVID-19 viral infection is acute respiratory distress syndrome (ARDS), often requiring mechanical ventilation and high dose corticosteroid therapy due to respiratory failure. Indeed, there is increasing evidence that the use of corticosteroids may reduce mortality in patients with COVID- 19 related ARDS, especially if administered early in the treatment algorithm. However, COVID-19 specific T-cell therapy is not an option in such patients as corticosteroids induce apoptosis of adoptively transferred T cells, thus, significantly limiting the efficacy of this approach. To address this challenge, our group has developed an efficient and novel strategy to inactivate the glucocorticoid receptor (GR) in viral-specific T cells, using CRISPR- Cas9 gene editing of the Nuclear Receptor Subfamily 3 Group C Member1 gene (NR3C1- the gene encoding the GR). In Aim 2 of this proposal, we will perform the IND-enabling studies for the production of GMP-grade NR3C1 knockout COVID-19 specific T-cells in preparation for a subsequent phase 1 trial, to be funded through alternative sources. Given our track-record of generating clinically effective viral-specific T-cells, we are optimistic that our approach of adoptive immunotherapy with COVID-19 specific T cells will be successful in HSCT or cell therapy recipients with life-threating COVID-19 related infections.

摘要 冠状病毒(新冠肺炎)大流行迅速在全球蔓延，感染了300多万人，其中 对于有严重和危及生命的并发症的患者，没有有效的治疗选择。这件事的影响 在接受造血干细胞移植(HSCT)的患者中，感染可能尤其严重。 特定的脐血移植(CBT)受者或接受嵌合抗原受体(CAR)者 T或NK细胞疗法，考虑到它们的免疫受损状态，存在医学上的并存，以及关注的问题 更高的感染相关严重程度和死亡率。我们的团队已经开发出了强大的HLA型临床库 针对巨细胞病毒(CMV)、BK病毒(BKV)和巨细胞病毒(BKV)的GMP级病毒特异性T淋巴细胞(VST) 腺病毒。我们已经治疗了100多名HSCT受者，其中49%接受了脐带血或半相合移植 将这些部分相合的和现成的VST移植到FDA批准的临床方案中 &gt；80%有效率，无毒性。我们已经成功地将该平台应用于制定网络通信协议 制造颗粒膜蛋白等级的新冠肺炎特异性T细胞。我们建议生成一个特定于新冠肺炎的生物库 使用IRB批准的方案(MDAcc)从新冠肺炎感染康复的捐赠者的T细胞 Lab02-0630)。然后我们将进行I/II期临床试验，以评估安全性， 第三方、现成、与人类白细胞抗原最匹配的新冠肺炎特异性T细胞的可行性和抗病毒活性 在造血干细胞移植中，包括CBT/半相合移植或细胞治疗受者中严重的新冠肺炎感染(目的 1)。为了加快我们患者对这项试验的批准，我们最近修改了另一项VST方案，以包括 使用新冠肺炎特异性T细胞治疗(MDAC2017-0350IND 17761)。 新冠肺炎病毒感染最严重的表现之一是急性呼吸窘迫综合征 (ARDS)，由于呼吸衰竭，通常需要机械通气和大剂量皮质激素治疗。 事实上，越来越多的证据表明，使用皮质类固醇可以降低COVID患者的死亡率。 19个相关的ARDS，特别是如果在治疗算法早期使用的话。然而，新冠肺炎特异的T细胞 对于这样的患者，治疗不是一种选择，因为皮质类固醇会诱导过继转移的T细胞凋亡， 因此，极大地限制了这种方法的有效性。为了应对这一挑战，我们团队开发了一种 使用CRISPR-1灭活病毒特异性T细胞中糖皮质激素受体(GR)的有效和新策略 核受体亚家族3组C成员1基因(NR3C1-编码基因)的Cas9基因编辑 GR)。在本提案的目标2中，我们将为GMP级的生产进行IND使能研究 NR3C1号基因敲除新冠肺炎特异性T细胞，为后续的第一阶段试验做准备，资金来源为 另一种来源。鉴于我们在产生临床有效的病毒特异性T细胞方面的记录，我们 乐观地认为，我们的新冠肺炎特异性T细胞过继免疫疗法将在 造血干细胞移植或细胞治疗受者患有威胁生命的新冠肺炎相关感染。

项目成果

Optimizing natural killer cell doses for heterogeneous cancer patients on the basis of multiple event times

• DOI: 10.1111/rssc.12271
• 发表时间: 2019-02-01
• 期刊: JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES C-APPLIED STATISTICS
• 影响因子: 1.6
• 作者: Lee, Juhee;Thall, Peter F.;Rezvani, Katy
• 通讯作者: Rezvani, Katy

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.

• DOI: 10.1016/j.celrep.2021.109432
• 发表时间: 2021-07-20
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Basar R;Uprety N;Ensley E;Daher M;Klein K;Martinez F;Aung F;Shanley M;Hu B;Gokdemir E;Nunez Cortes AK;Mendt M;Reyes Silva F;Acharya S;Laskowski T;Muniz-Feliciano L;Banerjee PP;Li Y;Li S;Melo Garcia L;Lin P;Shaim H;Yates SG;Marin D;Kaur I;Rao S;Mak D;Lin A;Miao Q;Dou J;Chen K;Champlin RE;Shpall EJ;Rezvani K
• 通讯作者: Rezvani K

Chimeric antigen receptor (CAR) natural killer (NK)-cell therapy: leveraging the power of innate immunity.

嵌合抗原受体 (CAR) 自然杀伤 (NK) 细胞疗法：利用先天免疫的力量。

• DOI: 10.1111/bjh.17186
• 发表时间: 2021-04
• 期刊: BRITISH JOURNAL OF HAEMATOLOGY
• 影响因子: 6.5
• 作者: Rafei, Hind;Daher, May;Rezvani, Katayoun
• 通讯作者: Rezvani, Katayoun