Dissecting the mechanistic basis of response to combined decitabine and ipilimumab following hematopoietic stem cell transplantation for relapsed acute myelogenous leukemia

剖析造血干细胞移植治疗复发性急性髓性白血病后联合地西他滨和伊匹单抗反应的机制基础

• 批准号: 430138413
• 负责人: Dr. Livius Penter
• 金额: --
• 依托单位: Department of Medical Oncology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/430138413?language=en
• 关键词: Dissecting; mechanistic; basis; response; combined

Allogeneic hematopoietic stem cell transplantation (HCT) provides potentially curative therapy for high-risk acute myelogenous leukemia (AML), mainly based on potent graft-versus-leukemia effects (GvL). Relapse of AML after HCT remains the key source of mortality, and hence efforts to enhance GvL are of high priority. At the same time, despite the long-established clinical track record of HCT, the mechanistic basis of GvL remains not fully elucidated.The recent clinical availability of immunomodulatory agents such as checkpoint blockade along with existing active therapeutics, for example hypomethylating agents, opens new doors for enhancing GvL. Clinical trials with single use of these agents have demonstrated promising clinical activity in addressing post-HCT AML relapse, suggesting combination of these treatment modalities could provide even greater effectiveness. This was the rationale for an ongoing NCI ETCTN/CTEP phase I study (#10026) at DFCI which seeks to probe the combination of ipilimumab and decitabine in AML relapse post-HCT. Early data indicate that this approach is clinically active.We hypothesize that responders to combined decitabine and ipilimumab will have distinct disease and immune microenvironment properties and show activated T cell responses against tumor antigens. The dedicated longitudinal biospecimen collection from this study provides a rich opportunity to dissect the basis of response following this novel therapeutic combination. Today powerful research tools are available to study cancer immunology at unprecedented depth. Massively parallel sequencing, high throughput single cell technologies and computationally guided antigen discovery approaches provide exciting foundations for comprehensive evaluation of samples from study subjects. Through application of advanced immunogenomic tools and building on my experience in single T cell receptor (TCR) analysis of tumor-reactive T cells, my objective is to elucidate the immune mechanisms underlying GvL effects.Aim 1 will thus undertake genomic evaluation of tumor samples to link response to disease-specific properties such as tumor antigen load and expression of genes critical to immune signaling pathways. Aim 2 will track quantitative and qualitative changes in the immune microenvironment using flow cytometry, single-cell RNA sequencing and mass cytometry. Aim 3 will exploit single TCR sequencing and methods to uncover cognate antigens of tumor-reactive TCRs to understand tumor antigen-T cell interactions driving responses.Completion of these aims is expected to reveal important principles of immune responses after HCT and will shed light on how checkpoint blockade and hypomethylating agents enhance GvL. This will have direct clinical implications as the results could aid in identifying patients that benefit from this therapeutic combination and might pave the way for developing novel therapeutic approaches like vaccination or adoptive T cell transfer strategies.

异基因造血干细胞移植（HCT）为高危急性髓性白血病（AML）提供了潜在的治愈性治疗，主要基于有效的移植物抗白血病效应（GvL）。HCT后AML的复发仍然是死亡率的主要来源，因此努力提高GvL具有高度优先性。免疫调节剂如检查点阻断剂沿着现有的活性治疗剂如低甲基化剂的最近临床可用性为增强GvL打开了新的大门。单次使用这些药物的临床试验已经证明了在解决HCT后AML复发方面有前景的临床活性，表明这些治疗方式的组合可以提供更大的有效性。这是DFCI正在进行的NCI ETCTN/CTEP I期研究（#10026）的基本原理，该研究旨在探索伊匹单抗和地西他滨联合治疗HCT后AML复发的效果。早期的数据表明，这种方法是临床上active.我们假设，联合地西他滨和ipilimumab的反应者将有不同的疾病和免疫微环境的属性，并显示针对肿瘤抗原的活化T细胞反应。本研究的专用纵向生物标本采集提供了丰富的机会来剖析这种新型治疗组合后的反应基础。今天，强大的研究工具可用于以前所未有的深度研究癌症免疫学。大规模并行测序、高通量单细胞技术和计算引导的抗原发现方法为全面评估来自研究对象的样品提供了令人兴奋的基础。通过应用先进的免疫基因组学工具和建立在我的经验，在单一的T细胞受体（TCR）的肿瘤反应性T细胞的分析，我的目标是阐明免疫机制的GvL的影响。因此，目的1将进行肿瘤样本的基因组评估，以连接响应疾病的特异性属性，如肿瘤抗原负荷和基因的表达，免疫信号通路的关键。目标2将使用流式细胞术、单细胞RNA测序和质谱仪跟踪免疫微环境的定量和定性变化。目标3将利用单个TCR测序和方法来发现肿瘤反应性TCR的同源抗原，以了解肿瘤抗原-T细胞相互作用驱动的应答。这些目标的完成有望揭示HCT后免疫应答的重要原理，并将阐明检查点阻断和低甲基化剂如何增强GvL。这将具有直接的临床意义，因为结果可以帮助识别从这种治疗组合中受益的患者，并可能为开发新的治疗方法（如疫苗接种或过继性T细胞转移策略）铺平道路。

项目成果

Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History.

• DOI: 10.1158/2159-8290.cd-21-0276
• 发表时间: 2021-12-01
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Penter L;Gohil SH;Lareau C;Ludwig LS;Parry EM;Huang T;Li S;Zhang W;Livitz D;Leshchiner I;Parida L;Getz G;Rassenti LZ;Kipps TJ;Brown JR;Davids MS;Neuberg DS;Livak KJ;Sankaran VG;Wu CJ
• 通讯作者: Wu CJ

Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer.

• DOI: 10.1158/1078-0432.ccr-21-2834
• 发表时间: 2022-08-02
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Liu, Min;Tayob, Nabihah;Penter, Livius;Sellars, MacLean;Tarren, Anna;Chea, Vipheaviny;Carulli, Isabel;Huang, Teddy;Li, Shuqiang;Cheng, Su-Chun;Le, Phuong;Frackiewicz, Laura;Fasse, Julia;Qi, Courtney;Liu, Joyce F.;Stover, Elizabeth H.;Curtis, Jennifer;Livak, Kenneth J.;Neuberg, Donna;Zhang, Guanglan;Matulonis, Ursula A.;Wu, Catherine J.;Keskin, Derin B.;Konstantinopoulos, Panagiotis A.
• 通讯作者: Konstantinopoulos, Panagiotis A.

Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case.

• DOI: 10.1182/bloodadvances.2021004335
• 发表时间: 2021-11-23
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Penter L;Gohil SH;Huang T;Thrash EM;Schmidt D;Li S;Severgnini M;Neuberg D;Hodi FS;Livak KJ;Zeiser R;Bachireddy P;Wu CJ
• 通讯作者: Wu CJ