Xue Wei, Metheringham Rachael L, Brentville Victoria A, Gunn Barbara, Symonds Peter, Yagita Hideo, Ramage Judith M, Durrant Lindy G
Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, City Hospital Campus , Nottingham, UK.
Department of Immunology, Juntendo University School of Medicine , Tokyo, Japan.
Oncoimmunology. 2016 Apr 22;5(6):e1169353. doi: 10.1080/2162402X.2016.1169353. eCollection 2016 Jun.
Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.
检查点阻断疗法已在约10%-40%的患者中展现出有前景的抗肿瘤反应。然而，大多数患者对其肿瘤并未产生有效的免疫反应，对检查点阻断疗法也无反应。这些患者可能会受益于一种有效的疫苗，该疫苗能刺激高亲和力T细胞反应并与检查点阻断疗法联合使用。我们之前已表明，将TRP-2和gp100表位纳入人IgG1 DNA的互补决定区（免疫体®：IB），在动物模型和患者中均能导致显著的肿瘤消退。这种疫苗接种策略优于其他策略，因为它将抗原靶向抗原呈递细胞并刺激高亲和力T细胞反应。为了拓宽这种疫苗接种策略的应用范围，将覆盖超过80% HLA表型的16个NY-ESO-1表位纳入IB（SCIB2）。它们产生的T细胞反应频率和亲和力高于肽疫苗接种。这些T细胞具有足够的亲和力来杀死表达NY-ESO-1的肿瘤细胞，并且在体内能控制已建立的B16-NY-ESO-1肿瘤的生长，从而实现长期存活（35%）。当SCIB2与调节性T细胞耗竭、CTLA-4阻断或PD-1阻断联合使用时，已建立肿瘤的长期存活率分别显著提高到56%、67%和100%。通过联合使用SCIB2疫苗接种和检查点阻断疗法将这些反应转化到临床中，只会进一步改善临床反应。
