Department of Medical Oncology/Laboratory of Medical and Molecular Oncology (LMMO), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
Department of Medical Oncology/Laboratory of Medical and Molecular Oncology (LMMO), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.
J Immunother Cancer. 2022 Sep;10(9). doi: 10.1136/jitc-2022-005141.
Intratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces immunogenic cell death, thereby providing maturation signals and enhancing the release of tumor antigens that can be captured and processed by CD1c (BDCA-1) / CD141 (BDCA-3) myDCs, in order to reinvigorate the cancer-immunity cycle.
In this phase I trial, patients with advanced melanoma who failed standard therapy were eligible for IT injections of ≥1 non-visceral metastases with T-VEC on day 1 followed by IT injection of CD1c (BDCA-1) myDCs +/- CD141 (BDCA-3) myDCs on day 2. T-VEC injections were repeated on day 21 and every 14 days thereafter. The number of IT administered CD1c (BDCA-1) myDCs was escalated from 0.5×10, to 1×10, to a maximum of 10×10 cells in three sequential cohorts. In cohort 4, all isolated CD1c (BDCA-1) / CD141 (BDCA-3) myDCs were used for IT injection. Primary objectives were safety and feasibility. Repetitive biopsies of treated lesions were performed.
In total, 13 patients were enrolled (cohort 1 n=2; cohort 2 n=2; cohort 3 n=3; cohort 4 n=6). Patients received a median of 6 (range 3-8) T-VEC injections. The treatment was safe with most frequent adverse events being fatigue (n=11 (85%)), fever (n=8 (62%)), and chills/influenza-like symptoms (n=6 (46%)). Nine (69%) and four patients (31%), respectively, experienced pain or redness at the injection-site. Clinical responses were documented in injected and non-injected lesions. Two patients (cohort 3) who previously progressed on anti-PD-1 therapy (and one patient also on anti-CTLA-4 therapy) developed a durable, pathologically confirmed complete response that is ongoing at 33 and 35 months following initiation of study treatment. One additional patient treated (cohort 4) had an unconfirmed partial response as best response; two additional patients had a mixed response (with durable complete responses of some injected and non-injected lesions). On-treatment biopsies revealed a strong infiltration by inflammatory cells in regressing lesions.
IT coinjection of autologous CD1c (BDCA-1) +/- CD141 (BDCA-3) myDCs with T-VEC is feasible, tolerable and resulted in encouraging early signs of antitumor activity in immune checkpoint inhibitor-refractory melanoma patients.
NCT03747744.
肿瘤内（IT）髓样树突状细胞（myDCs）在启动抗肿瘤免疫反应和重新许可肿瘤微环境中的抗肿瘤细胞毒性 T 淋巴细胞方面发挥着关键作用。替莫唑胺拉帕替尼（T-VEC）诱导免疫原性细胞死亡，从而提供成熟信号并增强肿瘤抗原的释放，这些抗原可被 CD1c（BDCA-1）/CD141（BDCA-3）myDCs 捕获和处理，以重振癌症免疫周期。
在这项 I 期试验中，标准治疗失败的晚期黑色素瘤患者符合条件，可在第 1 天接受 T-VEC 的 IT 注射，然后在第 2 天接受 CD1c（BDCA-1）myDCs +/- CD141（BDCA-3）myDCs 的 IT 注射。T-VEC 注射在第 21 天和此后每 14 天重复一次。IT 给予的 CD1c（BDCA-1）myDC 数量从 0.5×10 逐渐增加到 1×10，再增加到三个连续队列中的最高 10×10 个细胞。在队列 4 中，所有分离的 CD1c（BDCA-1）/CD141（BDCA-3）myDCs 都用于 IT 注射。主要目标是安全性和可行性。对治疗病变进行了重复活检。
共有 13 名患者入组（队列 1 n=2；队列 2 n=2；队列 3 n=3；队列 4 n=6）。患者接受了中位数为 6（范围 3-8）次 T-VEC 注射。治疗是安全的，最常见的不良事件是疲劳（n=11（85%））、发热（n=8（62%））和寒战/流感样症状（n=6（46%））。9（69%）和 4 名患者（31%）分别在注射部位出现疼痛或发红。在注射和未注射的病变中均记录了临床反应。两名先前在抗 PD-1 治疗中进展的患者（其中一名也接受了抗 CTLA-4 治疗）（队列 3）出现了持久的、经病理证实的完全缓解，在开始研究治疗后 33 和 35 个月仍在持续。一名额外接受治疗的患者（队列 4）的最佳反应为未经确认的部分缓解；另外两名患者的反应为混合反应（一些注射和未注射的病变有持久的完全缓解）。治疗中的活检显示，在消退的病变中有强烈的炎症细胞浸润。
用 T-VEC 对自体 CD1c（BDCA-1） +/- CD141（BDCA-3）myDCs 进行 IT 共注射是可行的、耐受的，并在免疫检查点抑制剂难治性黑色素瘤患者中产生了令人鼓舞的早期抗肿瘤活性迹象。
NCT03747744。
Zotero 插件
