PD-1 阻断疗法与肿瘤内接种治疗性 HPV 蛋白疫苗协同作用，并在临床前模型中引发肿瘤消退。
PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model.
机构信息
Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA.
Department of Otolaryngology, The Johns Hopkins University, Baltimore, MD, USA.
出版信息
Cancer Immunol Immunother. 2021 Apr;70(4):1049-1062. doi: 10.1007/s00262-020-02754-x. Epub 2020 Oct 27.
INTRODUCTION
The human papillomavirus (HPV) encoded oncoproteins E6 and E7 are constitutively expressed in HPV-associated cancers, making them logical therapeutic targets. Intramuscular immunization of patients with HPV16 L2E7E6 fusion protein vaccine (TA-CIN) is well tolerated and induces HPV-specific cellular immune responses. Efficacy of PD-1 immune checkpoint blockade correlates with the level of tumor-infiltrating CD8 + T cells, yet most patients lack significant tumor infiltration of immune cells making immune checkpoint blockade suboptimal. We hypothesized that intratumoral vaccination with TA-CIN could increase the number of tumor-infiltrating CD8 + T cells, synergize with PD-1 blockade and result in better control of tumors compared with either PD-1 blockade or vaccination alone.
METHODS
We examined the immunogenicity and antitumor effects of intratumoral vaccination with TA-CIN alone or in combination with PD-1 blockade in the TC-1 syngeneic murine tumor model expressing HPV16 E6/E7.
RESULTS
Intratumoral vaccination with TA-CIN induced stronger antigen-specific CD8 + T cell responses and antitumor effects. Intratumoral TA-CIN vaccination generated a systemic immune response that was able to control distal TC-1 tumors. Furthermore, intratumoral TA-CIN vaccination induced tumor infiltration of antigen-specific CD8 + T cells. Knockout of Batf3 abolished antigen-specific CD8 + T cell responses and antitumor effects of intratumoral TA-CIN vaccination. Finally, PD-1 blockade synergizes with intratumoral TA-CIN vaccination resulting in significantly enhanced antigen-specific CD8 + T cell responses and complete regression of tumors, whereas either alone failed to control established TC-1 tumor.
CONCLUSIONS
Our results provide rationale for future clinical testing of intratumoral TA-CIN vaccination in combination with PD-1 blockade for the control of HPV16-associated tumors.
简介
人乳头瘤病毒（HPV）编码的癌蛋白 E6 和 E7 在 HPV 相关癌症中持续表达，使其成为合理的治疗靶点。HPV16 L2E7E6 融合蛋白疫苗（TA-CIN）的肌内免疫接种在 HPV 相关癌症患者中耐受性良好，并诱导 HPV 特异性细胞免疫反应。PD-1 免疫检查点阻断的疗效与肿瘤浸润 CD8+T 细胞的水平相关，但大多数患者缺乏免疫细胞对肿瘤的显著浸润，使免疫检查点阻断效果不佳。我们假设，与单独使用 PD-1 阻断或单独接种疫苗相比，用 TA-CIN 进行肿瘤内接种可以增加肿瘤浸润 CD8+T 细胞的数量，与 PD-1 阻断协同作用，并更好地控制肿瘤。
方法
我们在表达 HPV16 E6/E7 的 TC-1 同基因鼠肿瘤模型中，研究了 TA-CIN 单独或与 PD-1 阻断联合进行肿瘤内接种的免疫原性和抗肿瘤作用。
结果
用 TA-CIN 进行肿瘤内接种可诱导更强的抗原特异性 CD8+T 细胞反应和抗肿瘤作用。肿瘤内 TA-CIN 接种产生了全身性免疫反应，能够控制远处的 TC-1 肿瘤。此外，肿瘤内 TA-CIN 接种诱导了抗原特异性 CD8+T 细胞的肿瘤浸润。Batf3 敲除消除了肿瘤内 TA-CIN 接种的抗原特异性 CD8+T 细胞反应和抗肿瘤作用。最后，PD-1 阻断与肿瘤内 TA-CIN 接种协同作用，显著增强了抗原特异性 CD8+T 细胞反应，使肿瘤完全消退，而单独使用任何一种方法都无法控制已建立的 TC-1 肿瘤。
结论
我们的研究结果为进一步临床测试 TA-CIN 瘤内接种联合 PD-1 阻断治疗 HPV16 相关肿瘤提供了依据。
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