Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona.
Division of Hematology, Health Sciences Campus, University of Southern California, Los Angeles, California.
Clin Cancer Res. 2023 Dec 15;29(24):5087-5103. doi: 10.1158/1078-0432.CCR-23-0229.
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.
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。我们开展了一项由研究者发起的临床试验，以评估 PELA 联合地塞米松（Dex）和硼替佐米（BZ）在接受该方案治疗的多发性骨髓瘤患者中的疗效，并确定肿瘤免疫微环境（TiME）。
我们招募了 14 名复发/难治性多发性骨髓瘤患者，开展了一项 PELA 剂量递增的 Ib 期临床试验（ClinicalTrials.gov：NCT02514382），患者在第 1、2、8、9、15 和 16 天接受 PELA 治疗，剂量分别为 3 个递增剂量。患者在第 1、8 和 15 天接受 40 mg Dex 和 1.5 mg/m2 BZ 治疗。每 28 天重复一个周期。在治疗前和治疗后采集骨髓标本（免疫组化，n=9；成像质谱流式细胞术，n=6）和外周血样本（流式细胞术，n=5；T 细胞受体克隆性，n=7；细胞因子测定，n=7）进行分析。
所有患者均耐受良好。治疗相关毒性短暂，未发生剂量限制性毒性。11 例可评价疗效的患者中，6 例（55%）的异常蛋白减少。治疗后，骨髓中 T 细胞和自然杀伤细胞的激活、炎症细胞因子的释放以及程序性死亡配体 1 的表达增加。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更接近，以及更大比例的新型免疫原性多发性骨髓瘤表型（CD138+IDO1+HLA-ABCHigh），提示免疫调节作用。
PELA/BZ/Dex 耐受性良好，与部分应答患者的抗多发性骨髓瘤活性相关，其特征为免疫重编程和 TiME 改变，这支持进一步研究 PELA 作为免疫调节剂的作用。
