Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice.
Heat shock protein vaccination and directed IL-2 therapy amplify tumor immunity rapidly following bone marrow transplantation in mice.
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DOI：
10.1182/blood-2013-08-520775
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发表时间：
2014-05
期刊：
影响因子：
20.3
通讯作者：
R. Newman;Michael J. Dee;T. Malek;E. Podack;R. Levy
中科院分区：
文献类型：
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作者：
R. Newman;Michael J. Dee;T. Malek;E. Podack;R. Levy
肿瘤复发是自体造血干细胞移植（HSCT）后血液癌症患者死亡的主要原因。 HSCT 后早期接种疫苗可以利用淋巴细胞减少和微小残留病的状态来产生抗肿瘤免疫力。在此，在充满 T 细胞的同基因 HSCT 后 2 周内，使用经过改造可分泌热休克蛋白融合蛋白 gp96-Ig 的淋巴瘤细胞进行多次疫苗接种，导致交叉呈递并增加了患有淋巴瘤的小鼠的存活率。为了增强疫苗功效，白介素（IL）-2通过与抗IL-2单克隆抗体克隆S4B6（IL-2S4B6）结合施用，主要针对记忆表型CD8（+）T淋巴细胞和自然杀伤（NK）细胞。 gp96-Ig 疫苗接种和 IL-2S4B6 协调输注的联合治疗可显着延长生存期，这与效应 CD8(+) T 细胞数量增加约 500% 直接相关。值得注意的是，这种双重治疗方案使供体 CD8(+) T 细胞和 NK 细胞大幅增加，但 CD4(+) T 淋巴细胞却没有大幅增加。前两个人群对于 HSCT 后的疫苗功效和预防机会性感染至关重要。事实上，感染单核细胞增生李斯特菌的接受 IL-2S4B6 治疗的 HSCT 受者表现出细菌水平下降。这些临床前研究验证了一种特别适合 HSCT 后环境的新策略，该策略可能会增强接受自体 HSCT 的恶性疾病患者的适应性和先天免疫功能。
Tumor relapse is the primary cause of mortality in patients with hematologic cancers following autologous hematopoietic stem cell transplantation (HSCT). Vaccination early after HSCT can exploit both the state of lymphopenia and minimal residual disease for generating antitumor immunity. Here, multiple vaccinations using lymphoma cells engineered to secrete heat shock protein fusion gp96-Ig within 2 weeks of T cell-replete syngeneic HSCT led to cross-presentation and increased survival of lymphoma-bearing mice. To enhance vaccine efficacy, interleukin (IL)-2 was directed to predominantly memory phenotype CD8(+) T lymphocytes and natural killer (NK) cells via administration bound to anti-IL-2 monoclonal antibody clone S4B6 (IL-2S4B6). Combination therapy with gp96-Ig vaccination and coordinated infusions of IL-2S4B6 resulted in marked prolongation of survival, which directly correlated with ~500% increase in effector CD8(+) T-cell numbers. Notably, this dual regimen elicited large increases in both donor CD8(+) T and NK cells, but not CD4(+) T lymphocytes; the former 2 populations are essential for both vaccine efficacy and protection against opportunistic infections after HSCT. Indeed, IL-2S4B6-treated HSCT recipients infected with Listeria monocytogenes exhibited decreased bacterial levels. These preclinical studies validate a new strategy particularly well suited to the post-HSCT environment, which may augment adaptive and innate immune function in patients with malignant disease receiving autologous HSCT.