Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research (FNLCR), Frederick, Maryland, USA.
Guizhou Provincial Peoples' Hospital, Guiyang, Guizhou Province, China.
Sci Rep. 2017 Oct 27;7(1):14186. doi: 10.1038/s41598-017-14655-8.
Harnessing immune system to treat cancer requires simultaneous generation of tumor-specific CTLs and curtailment of tumor immunosuppressive environment. Here, we developed an immunotherapeutic regimen capable of eliminating large established mouse tumors using HMGN1, a DC-activating TLR4 agonist capable of inducing anti-tumor immunity. Intratumoral delivery of HMGN1 with low dose of Cytoxan cured mice bearing small (∅ ≈ 0.5 cm), but not large (∅ ≈ 1.0 cm) CT26 tumors. Screening for activators capable of synergizing with HMGN1 in activating DC identified R848. Intratumoral delivery of HMGN1 and R848 plus Cytoxan eradicated large established CT26 tumors. The resultant tumor-free mice were resistant to subsequent challenge with CT26, indicating the generation of CT26-specific protective immunity. This immunotherapeutic regimen caused homing of tumor-infiltrating DC to draining lymph nodes and increased infiltration of T cells into tumor tissues. Cytoxan in this regimen could be replaced by anti-CTLA4) or anti-PD-L1. Importantly, this immunotherapeutic regimen was also curative for large established mouse Renca and EG7 tumors. Thus, we have developed a curative therapeutic vaccination regimen dubbed 'TheraVac' consisting of HMGN1 and R848 plus a checkpoint inhibitor, that can, without using exogenous tumor-associated antigen(s), eliminate various large tumors and induce tumor-specific immunity.
利用免疫系统治疗癌症需要同时产生肿瘤特异性 CTL 并抑制肿瘤免疫抑制环境。在这里，我们开发了一种免疫治疗方案，该方案使用 HMGN1（一种能够诱导抗肿瘤免疫的 DC 激活 TLR4 激动剂），能够消除使用低剂量环磷酰胺治疗的具有大肿瘤的小鼠中的大已建立的小鼠肿瘤。HMGN1 与低剂量环磷酰胺的肿瘤内递送可治愈携带小（∅≈0.5cm）但不携带大（∅≈1.0cm）CT26 肿瘤的小鼠。筛选出与 HMGN1 协同激活 DC 的激动剂，鉴定出 R848。HMGN1 和 R848 加环磷酰胺的肿瘤内递送可消除大已建立的 CT26 肿瘤。由此产生的无肿瘤小鼠对 CT26 的后续挑战具有抗性，表明产生了 CT26 特异性保护免疫。这种免疫治疗方案导致肿瘤浸润 DC 归巢到引流淋巴结，并增加 T 细胞浸润到肿瘤组织中。该方案中的环磷酰胺可以被抗 CTLA4 或抗 PD-L1 取代。重要的是，这种免疫治疗方案对大已建立的小鼠 Renca 和 EG7 肿瘤也具有治疗作用。因此，我们开发了一种名为“TheraVac”的治愈性治疗性疫苗方案，该方案由 HMGN1 和 R848 加一种检查点抑制剂组成，无需使用外源性肿瘤相关抗原即可消除各种大肿瘤并诱导肿瘤特异性免疫。
