用同种异体肿瘤细胞裂解物脉冲处理的自体树突状细胞可诱导胰腺癌患者产生肿瘤反应性T细胞应答：一项I期研究。

Autologous dendritic cells pulsed with allogeneic tumour cell lysate induce tumour-reactive T-cell responses in patients with pancreatic cancer: A phase I study.

作者信息

Lau S P, Klaase L, Vink M, Dumas J, Bezemer K, van Krimpen A, van der Breggen R, Wismans L V, Doukas M, de Koning W, Stubbs A P, Mustafa D A M, Vroman H, Stadhouders R, Nunes J B, Stingl C, de Miranda N F C C, Luider T M, van der Burg S H, Aerts J G, van Eijck C H J

机构信息

Department of Surgery, Erasmus University Medical Center, 'S-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands; Department of Pulmonary Medicine, Erasmus University Medical Center, 'S-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.

Department of Pulmonary Medicine, Erasmus University Medical Center, 'S-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.

出版信息

Eur J Cancer. 2022 Jul;169:20-31. doi: 10.1016/j.ejca.2022.03.015. Epub 2022 Apr 28.

DOI:10.1016/j.ejca.2022.03.015

PMID:35490565

Abstract

BACKGROUND

Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor prognosis even after curative resection. Responses to immunotherapy are rare and related to inadequate T-cell priming. We previously demonstrated the potency of allogeneic lysate-dendritic cell (DC) vaccination in a preclinical model. Here we translate this concept to patients.

METHODS

In this phase I study, patients with resected PDAC were included when they demonstrated no radiologic signs of recurrence after standard-of-care treatment. Allogeneic tumour lysate-loaded autologous monocyte-derived DCs were injected at weeks 0, 2, 4 and at months 3 and 6. Objectives are feasibility, safety and immunogenicity of allogeneic tumour-DCs. The presence of tumour antigens shared between the vaccine and patient tumours was investigated. Immunological analyses were performed on peripheral blood, skin and tumour.

RESULTS

Ten patients were included. DC production and administration were successful. All patients experienced a grade 1 injection-site and infusion-related reaction. Two patients experienced a grade 2 fever and 1 patient experienced a grade 3 dyspnoea. No vaccine-related serious adverse events were observed. Shared tumour antigens were found between the vaccine and patient tumours. All evaluated patients displayed a vaccine-induced response indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T-cells. In addition, treatment-induced T-cell reactivity to autologous tumour of study patients was detected. Seven out of ten patients have not experienced disease recurrence or progression at a median follow-up of 25 months (15-32 months).

CONCLUSION

Allogeneic tumour lysate-DC treatment is feasible, safe and induces immune reactivity to PDAC expressed antigens.

摘要

背景

胰腺导管腺癌（PDAC）即便在进行根治性切除后，其预后仍很差，这一点众所周知。免疫疗法的反应罕见，且与T细胞启动不足有关。我们之前在临床前模型中证明了同种异体裂解物-树突状细胞（DC）疫苗接种的效力。在此，我们将这一概念应用于患者。

方法

在这项I期研究中，已接受标准治疗且无复发影像学征象的PDAC切除患者被纳入研究。在第0、2、4周以及第3和6个月注射负载同种异体肿瘤裂解物的自体单核细胞衍生DC。目标是评估同种异体肿瘤-DC的可行性、安全性和免疫原性。研究了疫苗与患者肿瘤之间共享的肿瘤抗原的存在情况。对外周血、皮肤和肿瘤进行了免疫分析。

结果

纳入了10名患者。DC的制备和给药均成功。所有患者均经历了1级注射部位和输液相关反应。2名患者出现2级发热，1名患者出现3级呼吸困难。未观察到与疫苗相关的严重不良事件。在疫苗和患者肿瘤之间发现了共享的肿瘤抗原。所有评估患者均表现出疫苗诱导的反应，表现为Ki67+和活化的PD-1+循环T细胞频率增加。此外，还检测到研究患者对自体肿瘤的治疗诱导T细胞反应性。在中位随访25个月（15 - 32个月）时，10名患者中有7名未出现疾病复发或进展。