Monjazeb Arta M, Kent Michael S, Grossenbacher Steven K, Mall Christine, Zamora Anthony E, Mirsoian Annie, Chen Mingyi, Kol Amir, Shiao Stephen L, Reddy Abhinav, Perks Julian R, T N Culp William, Sparger Ellen E, Canter Robert J, Sckisel Gail D, Murphy William J
Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.
Department of Surgical and Radiological Sciences, UC Davis School of Veterinary Medicine, Davis, California.
Clin Cancer Res. 2016 Sep 1;22(17):4328-40. doi: 10.1158/1078-0432.CCR-15-3026. Epub 2016 Mar 15.
Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy.
We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial.
In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects.
These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR.
先前的研究表明，瘤内CpG免疫疗法联合放射疗法可作为一种原位疫苗，诱导能够根除全身疾病的抗肿瘤免疫反应。不幸的是，大多数患者没有反应。我们推测免疫疗法可能反常地上调免疫抑制途径，我们将这种现象称为“反弹免疫抑制”，从而限制临床反应。我们进一步推测，免疫抑制酶吲哚胺-2,3-双加氧酶（IDO）是反弹免疫抑制的一种机制，阻断IDO将提高免疫疗法的疗效。
我们在小鼠模型和一项犬类临床试验中研究了一种由局部放射疗法、瘤内CpG和全身IDO阻断组成的新型三联疗法的疗效和免疫效应。
在小鼠模型中，我们观察到用放射疗法、CpG或其他免疫疗法治疗后瘤内IDO表达显著增加。在放射疗法+CpG基础上加用IDO阻断可降低IDO活性，减少肿瘤生长，并减少免疫抑制因子，如肿瘤微环境中的调节性T细胞。这种三联组合诱导全身抗肿瘤效应，减少转移，并以CD8(+)T细胞依赖的方式提高生存率。我们在一项犬类临床试验中评估了这种新型三联疗法，因为自发性犬类恶性肿瘤与人类癌症密切相关。与我们的小鼠研究结果相似，该疗法耐受性良好，减少瘤内免疫抑制，并诱导强烈的全身抗肿瘤效应。
这些结果表明，IDO在治疗后维持肿瘤中的免疫抑制，阻断IDO可促进局部抗肿瘤免疫反应并产生全身影响。该策略的疗效和有限的毒性对临床转化具有吸引力。《临床癌症研究》；22(17)；4328 - 40。©2016美国癌症研究协会。
