Oncolytic Maraba virus armed with tumor antigen boosts vaccine priming and reveals diverse therapeutic response patterns when combined with checkpoint blockade in ovarian cancer
Oncolytic Maraba virus armed with tumor antigen boosts vaccine priming and reveals diverse therapeutic response patterns when combined with checkpoint blockade in ovarian cancer
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DOI：
10.1186/s40425-019-0641-x
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发表时间：
2019-07-17
影响因子：
10.9
通讯作者：
Odunsi, Kunle
中科院分区：
文献类型：
--
作者：
McGray, A. J. Robert;Huang, Ruea-Yea;Odunsi, Kunle
背景资料：癌症免疫疗法正在成为一线治疗后经历疾病复发的卵巢癌患者的有希望的治疗策略。因此，确定战略，以加强抗肿瘤免疫和限制免疫抑制，同时认识到不同模式的肿瘤免疫治疗的反应是至关重要的选择治疗组合，导致持久的therapeutic benefit.Methods：使用临床前小鼠模型，我们评估了异源的总理/加强疫苗结合检查点封锁治疗转移性腹膜内卵巢癌。分析疫苗诱导的CD 8（+）T细胞应答和治疗后肿瘤微环境的变化，并与治疗结果进行比较。腹腔内肿瘤生长的动力学进行了评估，使用非侵入性磁共振成像（MRI）。结果：疫苗引发抗原武装溶瘤Maraba病毒加强引发了强大的肿瘤特异性CD 8（+）T细胞反应，提高肿瘤控制，并导致独特的免疫学变化的肿瘤，包括签名，与卵巢癌患者的临床预后改善。然而，这种治疗不是治愈性的，并且肿瘤微环境（TME）中的T细胞在功能上受到抑制。联合PD-1阻断部分克服了在对初免/加强疫苗接种的反应中观察到的肿瘤中的适应性抗性，恢复了TME中的CD 8（+）T细胞功能并增强了治疗反应。在联合治疗过程中，肿瘤的非侵入性MRI显示了治疗后的异质性放射学反应模式，包括假进展，这与复发前肿瘤控制的改善有关。我们的研究结果指出，PD-1信号传导和卵巢TME中的适应性免疫抵抗在决定肿瘤特异性CD 8（+）T细胞的功能命运方面具有关键的分层作用，即使在稳健的治疗介导的抗肿瘤免疫的情况下，以及多种独特的治疗反应模式的能力导致持久的肿瘤控制。
Background: Cancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy. As such, identifying strategies to bolster anti-tumor immunity and limit immune suppression, while recognizing diverse patterns of tumor response to immunotherapy is critical to selecting treatment combinations that lead to durable therapeutic benefit.Methods: Using a pre-clinical mouse model, we evaluated a heterologous prime/boost vaccine in combination with checkpoint blockade to treat metastatic intraperitoneal ovarian cancer. Vaccine-elicited CD8(+) T cell responses and changes in the tumor microenvironment following treatment were analyzed and compared to treatment outcome. Kinetics of intraperitoneal tumor growth were assessed using non-invasive magnetic resonance imaging (MRI).Results: Vaccine priming followed by antigen-armed oncolytic Maraba virus boosting elicited robust tumor-specific CD8(+) T cell responses that improved tumor control and led to unique immunological changes in the tumor, including a signature that correlated with improved clinical outcome of ovarian cancer patients. However, this treatment was not curative and T cells in the tumor microenvironment (TME) were functionally suppressed. Combination PD-1 blockade partially overcame the adaptive resistance in the tumor observed in response to prime/boost vaccination, restoring CD8(+) T cell function in the TME and enhancing the therapeutic response. Non-invasive MRI of tumors during the course of combination treatment revealed heterogeneous radiologic response patterns following treatment, including pseudo-progression, which was associated with improved tumor control prior to relapse.Conclusions: Our findings point to a key hierarchical role for PD-1 signaling and adaptive immune resistance in the ovarian TME in determining the functional fate of tumor-specific CD8(+) T cells, even in the context of robust therapy mediated anti-tumor immunity, as well as the ability of multiple unique patterns of therapeutic response to result in durable tumor control.