preclinical optimization of BCMA directed T cell therapy

BCMA 定向 T 细胞疗法的临床前优化

基本信息

批准号：
10802050
负责人：
Peter Leif Bergsagel
金额：
$ 62.19万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10802050
关键词：
Affect Alkylating Agents Antibodies Antibody Therapy Antigens Biological Models Bispecific Antibodies Bite Bone Marrow Bortezomib CAR T cell therapy CD3 Antigens Cancer Therapy Evaluation Program Cell physiology Cells Clinical Clinical Trials Combined Modality Therapy Complex Credentialing Cyclophosphamide Cytotoxic T-Lymphocytes DNA Data Development Dexamethasone Disease Disease remission Extramedullary Genomics Glucocorticoids Harvest Hematopoietic Neoplasms Human Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunologic Deficiency Syndromes Immunologics Immunooncology Immunotherapy In complete remission Long-Term Effects Longitudinal Studies Malignant - descriptor Mediating Melphalan Modeling Multiple Myeloma Mus Patient-Focused Outcomes Patients Phase Phase II Clinical Trials Plasma Cells Prednisone Proteasome Inhibitor Randomized Refractory Relapse Reporting Research Personnel Resistance Shapes Surface Antigens T cell therapy T-Cell Activation T-Lymphocyte TNFRSF17 gene Thalidomide Toxic effect Transgenes Tumor Burden Tumor Debulking Validation Vertebral column Xenograft Model chimeric antigen receptor T cells clinical development clinical practice clinical predictors clinically relevant co-clinical trial conventional therapy cost cytokine release syndrome cytotoxic design exhaust exhaustion immune modulating agents improved lenalidomide leukemia/lymphoma mouse model neoplastic cell novel drug combination patient response pomalidomide pre-clinical preclinical study receptor reconstitution relapse patients response retransplantation single-cell RNA sequencing standard of care targeted treatment tool treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

PROJECT SUMMARY The pillars of multiple myeloma (MM) therapy are DNA alkylators (cyclophosphamide, melphalan), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), glucocorticoids (dexamethasone, prednisone) and IMiDs (thalidomide, lenalidomide, pomalidomide). Despite achieving an initial response, patients inevitably relapse and MM remains incurable. More recently, remarkable responses have been obtained with immunotherapy: antibodies against CD38 (daratumumab), bi-specific antibodies or BiTEs to BCMA, CAR-T cells against BCMA. However, similarly to what observed with conventional therapy, none of these immune-oncology agents are curative. We believe that in order to improve patient outcome we need to better define the changes induced by the tumor on the surrounding immune cells and the effects that conventional and immunotherapy exert on the tumor and its microenvironment. Unfortunately, most preclinical studies are conducted on xenograft models lacking an immune system, or transiently reconstituted with human immune subsets and fail to capture the complex interaction between tumor and immune cells. Using the clinically predictive, fully immunocompetent Vk*MYChCRBN mouse model of MM we have generated, we discovered that sensitivity to anti-BCMA bispecific antibody is affected by high tumor burden, which drives excessive antigenic stimulation and T cell exhaustion. Combination therapies aimed to boost T cell function increase the short-term activity of the bispecific antibody, but mice eventually relapse with modest improve in overall survival. Surprisingly, the addition of cyclophosphamide proved very effective, by inducing a tempered but durative T cell activation which was curative in a fraction of mice. Based on our results in VkMYChCRBN MM we have designed a phase 1, randomized phase 2 clinical trial of a BCMA/CD3 bispecific antibody teclistamab with the addition either iberdomide or cyclophosphamide. In this proposal we aim to use the results of treating MM patients with either single agent teclistamab, or combinations with iberdomide or cyclophosphamide to credential the Vk*MYChCRBN MM model for T-cell directed immunotherapy. Finally, we will investigate factors that regulate the development of immunologic protection and cure after bispecific antibody therapy. Overall, these data will further credential the Vk*MYChCRBN mouse model of MM and inform the clinical development of bispecific antibodies in MM.

项目摘要多发性骨髓瘤（MM）疗法的支柱是DNA烷基剂（环磷酰胺，Melphalan），蛋白酶体抑制剂（Bortezomib，Carfilzomib，ixazomib），糖皮质激素（地塞米松，泼尼松）和Imids （沙利度胺，勒纳替胺，pomalidomide）。尽管达到了初步反应，但患者不可避免地复发 MM仍然无法治愈。最近，通过免疫疗法获得了显着反应：针对CD38（daratumumab）的抗体，双特异性抗体或对BCMA的叮咬，CAR-T细胞对BCMA。但是，与常规疗法观察到的类似，这些免疫肿瘤剂都不是治愈性。我们认为，为了改善患者的结果，我们需要更好地定义由周围免疫细胞上的肿瘤以及常规和免疫疗法对肿瘤及其微环境。不幸的是，大多数临床前研究是在异种移植模型上进行的缺乏免疫系统，或者用人类免疫子集暂时重构，无法捕获肿瘤和免疫细胞之间的复杂相互作用。使用临床预测性，完全免疫能力的VK*Mychcrbn小鼠模型，我们已经生成我们发现对抗BCMA双特异性抗体的敏感性受高肿瘤负担的影响，该抗体驱动过度的抗原刺激和T细胞耗尽。旨在提高T细胞功能的组合疗法增加双特异性抗体的短期活性，但小鼠最终随着适度的改善而复发总体生存。出乎意料的是，通过诱导调速，可证明环磷酰胺的添加非常有效但是持续的T细胞活化在一小部分小鼠中是治愈性的。根据我们在Vkmychcrbn MM中的结果 BCMA/CD3双特异性抗体teclistamab具有添加的iberdomide或环磷酰胺。在这个提案我们的目标是使用单一药物teclistamab或组合治疗MM患者的结果使用iberdomide或环磷酰胺以凭借定向的T细胞的VK*Mychcrbn MM模型免疫疗法。最后，我们将研究调节免疫保护发展的因素并在双特异性抗体治疗后治愈。总体而言，这些数据将进一步证明VK*mychcrbn鼠标 MM的模型并告知MM中双特异性抗体的临床开发。