Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy.
Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy.
复制标题
DOI：
10.1136/jitc-2020-001191
复制
发表时间：
2020-10
影响因子：
10.9
通讯作者：
van Montfoort N
中科院分区：
文献类型：
--
作者：
Groeneveldt C;Kinderman P;van den Wollenberg DJM;van den Oever RL;Middelburg J;Mustafa DAM;Hoeben RC;van der Burg SH;van Hall T;van Montfoort N
t细胞结合cd3双特异性抗体（CD3-bsAbs）是一种很有前途的癌症免疫治疗方式。尽管这种疗法已经进入了血液系统恶性肿瘤的临床实践，但缺乏足够的浸润性T细胞是影响实体肿瘤疗效的主要障碍。在这项研究中，我们利用溶瘤呼肠孤病毒作为一种策略来增强cd3 - bsab在免疫沉默实体肿瘤中的疗效。突变型p53和K-ras诱导的小鼠胰腺癌模型KPC3与人胰腺导管腺癌相似，肿瘤微环境呈纤维组织增生，t细胞密度低，免疫治疗耐药。采用纳米链分析、定量RT-PCR和多色流式细胞术分析呼肠孤病毒3型毒株对KPC3荷瘤小鼠瘤内免疫功能的影响，观察呼肠孤病毒诱导肿瘤微环境和脾脏随时间的变化。呼肠孤病毒联合全身注射cd3 - bsab的效果在已建立KPC3或B16的免疫能力小鼠中进行了评估。F10肿瘤和接近患者的人表皮生长因子受体2 (HER2)+乳腺癌模型BT474植入免疫功能低下小鼠，以人T细胞作为效应细胞。复制能力强的呼肠孤病毒诱导早期干扰素信号，随后自然杀伤细胞和CD8+ T细胞大量涌入，代价是FoxP3+ Tregs。病毒复制在7天后下降，并与淋巴细胞的全身性激活和肿瘤内呼肠孤病毒特异性CD8+ T细胞的出现有关。尽管肿瘤浸润性T细胞大多是呼肠孤病毒特异性的，而不是肿瘤特异性的，但它们作为随后系统给药的cd3 - bsab的非耗尽效应细胞。呼肠孤病毒与cd3 - bsab联合治疗可导致大的、已建立的KPC3、B16的消退。F10和BT474肿瘤。呼肠孤病毒作为预处理方案的效果明显优于同时或早期给药cd3 - bsab。这种联合治疗导致未注射呼肠孤病毒的远处病变消退，呼肠孤病毒和cd3 - bsab的全身给药也导致肿瘤控制。这表明这种疗法可能对转移性疾病也有效。溶瘤呼肠孤病毒给药是一种有效的策略，可以诱导局部干扰素反应和强烈的t细胞内流，从而使肿瘤微环境敏感化，以便后续的CD3-bsAb治疗。这种联合疗法值得在非炎症性实体瘤患者中进一步研究。
T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors. The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells. Replication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease. Oncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors.
登录
查看更多内容
通过RIG-I介导的5'-二磷酸RNA识别的抗病毒药免疫。
影响因子：
64.8
作者：
Goubau, Delphine;Schlee, Martin;Deddouche, Safia;Pruijssers, Andrea J.;Zillinger, Thomas;Goldeck, Marion;Schuberth, Christine;Van der Veen, Annemarthe G.;Fujimura, Tsutomu;Rehwinkel, Jan;Iskarpatyoti, Jason A.;Barchet, Winfried;Ludwig, Janos;Dermody, Terence S.;Hartmann, Gunther;Reis e Sousa, Caetano
通讯作者：
Reis e Sousa, Caetano
影响因子：
3.5
作者：
Baum, Alina;Garcia-Sastre, Adolfo
通讯作者：
Garcia-Sastre, Adolfo
影响因子：
11.1
作者：
Freedman JD;Hagel J;Scott EM;Psallidas I;Gupta A;Spiers L;Miller P;Kanellakis N;Ashfield R;Fisher KD;Duffy MR;Seymour LW
通讯作者：
Seymour LW
影响因子：
--
作者：
Lee JW;Komar CA;Bengsch F;Graham K;Beatty GL
通讯作者：
Beatty GL
影响因子：
8
作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry