Development of a Curative Therapeutic Vaccine (TheraVac) for the Treatment of Large Established Tumors.
Development of a Curative Therapeutic Vaccine (TheraVac) for the Treatment of Large Established Tumors.
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开发用于治疗大型肿瘤的治愈性治疗疫苗 (TheraVac)
DOI：
10.1038/s41598-017-14655-8
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发表时间：
2017-10-27
影响因子：
4.6
通讯作者：
Oppenheim JJ
中科院分区：
文献类型：
--
作者：
Nie Y;Yang D;Trivett A;Han Z;Xin H;Chen X;Oppenheim JJ
利用免疫系统治疗癌症需要同时产生肿瘤特异性CTL和削减肿瘤免疫抑制环境。在这里，我们开发了一种免疫治疗方案，能够消除大型建立小鼠肿瘤使用HMGN 1，DC激活TLR 4激动剂能够诱导抗肿瘤免疫。瘤内递送HMGN 1与低剂量环磷酰胺治愈了携带小（约0.5 cm）但不携带大（约1.0 cm）CT 26肿瘤的小鼠。筛选能够与HMGN 1协同活化DC的活化剂，鉴定为R848。瘤内递送HMGN 1和R848加上环磷酰胺根除了大的已建立的CT 26肿瘤。所得到的无肿瘤小鼠对随后的CT 26攻击具有抗性，表明产生了CT 26特异性保护性免疫。这种免疫刺激方案导致肿瘤浸润DC归巢至引流淋巴结，并增加T细胞向肿瘤组织的浸润。该方案中的环磷酰胺可被抗CTLA 4或抗PD-L1替代。重要的是，这种免疫治疗方案也能治愈已建立的大型小鼠Renca和EG 7肿瘤。因此，我们开发了一种名为“TheraVac”的治疗性疫苗接种方案，由HMGN 1和R848加上检查点抑制剂组成，可以在不使用外源性肿瘤相关抗原的情况下消除各种大肿瘤并诱导肿瘤特异性免疫。
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.
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影响因子：
11.2
作者：
Birger, Y;Catez, F;Bustin, M
通讯作者：
Bustin, M
影响因子：
30.5
作者：
Chiba, Shigeki;Baghdadi, Muhammad;Akiba, Hisaya;Yoshiyama, Hironori;Kinoshita, Ichiro;Dosaka-Akita, Hirotoshi;Fujioka, Yoichiro;Ohba, Yusuke;Gorman, Jacob V.;Colgan, John D.;Hirashima, Mitsuomi;Uede, Toshimitsu;Takaoka, Akinori;Yagita, Hideo;Jinushi, Masahisa
通讯作者：
Jinushi, Masahisa
影响因子：
15.9
作者：
Carpentier, Alexandre;Metellus, Philippe;Carpentier, Antoine F.
通讯作者：
Carpentier, Antoine F.
DOI：
10.1007/978-1-4419-1603-7_10
发表时间：
2009-01-01
期刊：
LIPID A IN CANCER THERAPY
影响因子：
--
作者：
Cluff, Christopher W.
通讯作者：
Cluff, Christopher W.
影响因子：
29.4
作者：
Keenan BP;Saenger Y;Kafrouni MI;Leubner A;Lauer P;Maitra A;Rucki AA;Gunderson AJ;Coussens LM;Brockstedt DG;Dubensky TW Jr;Hassan R;Armstrong TD;Jaffee EM
通讯作者：
Jaffee EM