Kwilas Anna R, Ardiani Andressa, Donahue Renee N, Aftab Dana T, Hodge James W
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive; Room 8B13, Bethesda, MD, 20892, USA.
Exelixis, Inc., South San Francisco, CA, USA.
J Transl Med. 2014 Nov 13;12:294. doi: 10.1186/s12967-014-0294-y.
Growing awareness of the complexity of carcinogenesis has made multimodal therapies for cancer increasingly compelling and relevant. In recent years, immunotherapy has gained acceptance as an active therapeutic approach to cancer treatment, even though cancer is widely considered an immunosuppressive disease. Combining immunotherapy with targeted agents that have immunomodulatory capabilities could significantly improve its efficacy.
We evaluated the ability of cabozantinib, a receptor tyrosine kinase inhibitor, to modulate the immune system in vivo as well as alter the phenotype of tumor cells in vitro in order to determine if this inhibitor could act synergistically with a cancer vaccine.
Our studies indicated that cabozantinib altered the phenotype of MC38-CEA murine tumor cells, rendering them more sensitive to immune-mediated killing. Cabozantinib also altered the frequency of immune sub-populations in the periphery as well as in the tumor microenvironment, which generated a more permissive immune environment. When cabozantinib was combined with a poxviral-based cancer vaccine targeting a self-antigen, the combination significantly reduced the function of regulatory T cells and increased cytokine production from effector T cells in response to the antigen. These alterations to the immune landscape, along with direct modification of tumor cells, led to markedly improved antitumor efficacy.
These studies support the clinical combination of cabozantinib with immunotherapy for the treatment of cancer.
对癌症发生复杂性的认识不断提高，使得癌症的多模式治疗越来越具有吸引力和相关性。近年来，免疫疗法已被认可为一种积极的癌症治疗方法，尽管癌症被广泛认为是一种免疫抑制性疾病。将免疫疗法与具有免疫调节能力的靶向药物联合使用可能会显著提高其疗效。
我们评估了受体酪氨酸激酶抑制剂卡博替尼在体内调节免疫系统以及在体外改变肿瘤细胞表型的能力，以确定该抑制剂是否能与癌症疫苗协同作用。
我们的研究表明，卡博替尼改变了MC38-CEA小鼠肿瘤细胞的表型，使其对免疫介导的杀伤更敏感。卡博替尼还改变了外周以及肿瘤微环境中免疫亚群的频率，从而产生了更有利于免疫的环境。当卡博替尼与靶向自身抗原的痘病毒基癌症疫苗联合使用时，该组合显著降低了调节性T细胞的功能，并增加了效应T细胞对抗原的细胞因子产生。这些对免疫格局的改变，以及对肿瘤细胞的直接修饰，导致抗肿瘤疗效显著提高。
这些研究支持卡博替尼与免疫疗法联合用于癌症治疗的临床应用。
