肿瘤细胞治疗研究
英文原题：Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.
Comprehensive Single-Cell Immune Profiling Defines the Patient Multiple Myeloma Microenvironment Following Oncolytic Virus Therapy in a Phase Ib Trial.
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PELA/BZ/Dex 耐受性良好，并在部分应答患者中与抗多发性骨髓瘤活性相关，其特征为免疫重编程和 TiME 变化，值得进一步研究 PELA 作为免疫调节剂的作用。
我们的临床前研究表明，溶瘤呼肠孤病毒制剂pelareorep（PELA）具有显著的免疫调节抗骨髓瘤活性。我们开展了一项研究者发起的临床试验，评估PELA联合地塞米松（Dex）和硼替佐米（BZ）的疗效，并明确接受该方案治疗的多发性骨髓瘤患者的肿瘤免疫微环境（TiME）。
复发/难治性多发性骨髓瘤患者（n = 14）入组了一项Ib期临床试验（ClinicalTrials.gov：NCT02514382），在第1、2、8、9、15和16天接受三个递增剂量的PELA。患者在第1、8和15天接受40 mg Dex和1.5 mg/m2 BZ。周期每28天重复一次。收集治疗前和治疗后骨髓标本（IHC，n = 9；成像质谱流式，n = 6）和外周血样本进行分析（流式细胞术，n = 5；T细胞受体克隆性，n = 7；细胞因子检测，n = 7）。
PELA/BZ/Dex 在所有患者中耐受良好。治疗中出现的不良反应为暂时性，未发生剂量限制性毒性。11 例可评估疗效的患者中，6 例（55%）显示副蛋白减少。治疗增加了 T 细胞和NK 细胞活化、炎性细胞因子释放以及骨髓中程序性死亡配体 1 的表达。与无应答者相比，应答者的呼肠孤病毒蛋白水平更高，治疗后细胞毒性 T 细胞浸润增加，细胞毒性 T 细胞与多发性骨髓瘤细胞的距离显著更近，并且一种新型免疫致敏多发性骨髓瘤表型（CD138+ IDO1+HLA-ABCHigh）的群体更大，表明存在免疫调节。
Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen.
Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7).
PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation.
PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.
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