CD27 Agonist Antibodies Mediate Clinical Responses through Intratumoral Stimulation in B-cell Malignancies: Multicenter RiVa Trial.

Preclinical studies show that agonistic CD27 antibodies can activate intratumoral T cells to release chemokines and cytokines to augment macrophage-dependent tumor killing induced by CD20 antibodies, i.e., rituximab, in B-cell lymphoma.

临床前研究表明，激动性 CD27 抗体可以激活肿瘤内的 T 细胞，释放趋化因子和细胞因子，以增强由 CD20 抗体（例如利妥昔单抗）诱导的巨噬细胞依赖性肿瘤杀伤作用，在 B 细胞淋巴瘤中。

This clinical trial evaluated the safety and efficacy of rituximab and varlilumab in patients with previously treated B-cell non-Hodgkin lymphoma.

这项临床试验评估了利妥昔单抗和varlilumab在先前接受过治疗的B细胞非霍奇金淋巴瘤患者中的安全性和有效性。

patients_and_methods

This multicenter phase IIa trial recruited patients with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma.

这项多中心的IIa期试验招募了复发或难治性CD20+ B细胞非霍奇金淋巴瘤患者。

Patients were randomized to arm A or B.

患者被随机分配到A组或B组。

All patients received rituximab on day 1 of cycles 1 to 6 and varlilumab on day 2 (arm A) or day 8 (arm B) of cycle 1 and day 2 of cycles 3 and 5.

所有患者在第1至第6个周期的第1天接受利妥昔单抗治疗，并在第1个周期的第2天（A组）或第8天（B组）以及第3个和第5个周期的第2天接受瓦利单抗治疗。

Tumor biopsies were collected before treatment and on-treatment (after varlilumab in arm A and before varlilumab in arm B).

在治疗前和治疗期间（A组在varlilumab治疗后，B组在varlilumab治疗前）收集了肿瘤活检样本。

The primary objective was to assess safety and antitumor activity.

主要目的是评估安全性及抗肿瘤活性。

Results

Twenty-seven participants were evaluable, with modest overall response and disease control rates of 15.4% (4/27) and 38.8% (8/27), respectively.

共有27名参与者可进行评估，总体反应率和疾病控制率分别为15.4%（4/27）和38.8%（8/27），差异不大。

Intratumoral bulk RNA sequencing analysis demonstrated that adding varlilumab to rituximab enhanced CD4+ T-cell infiltration and increased T- and innate-cell signatures; inflamed tumor signatures were observed before treatment in responders.

肿瘤内RNA测序分析显示，将varlilumab添加到利妥昔单抗中增强了CD4+ T细胞浸润，并增加了T细胞和先天性细胞标志物；在治疗前，观察到反应者的肿瘤炎症标志物。

Single-cell analysis further showed that higher levels of CD27-expressing T and NK cells, along with activated γδ T-cell signatures, were associated with response, whereas CD27-expressing B cells correlated with nonresponse.

单细胞分析进一步显示，CD27表达的T细胞和NK细胞水平较高，以及激活的γδ T细胞特征与反应相关，而CD27表达的B细胞与无反应相关。

Conclusions

Rituximab and varlilumab show modest activity.

利妥昔单抗和varlilumab显示出适度的活性。

However, CD27 agonist antibodies may elicit meaningful antitumor responses when tumors express sufficient intratumoral targets and exhibit existing immune priming.

然而，当肿瘤表达足够的肿瘤内靶点并表现出已有的免疫启动时，CD27激动性抗体可能会引发有意义的抗肿瘤反应。