The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell-Mediated Immunotherapies.
The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell-Mediated Immunotherapies.
复制标题
DOI：
10.1158/1535-7163.mct-20-0430
复制
发表时间：
2021-03
影响因子：
5.7
通讯作者：
Vashisht Gopal YN
中科院分区：
文献类型：
--
作者：
Varghese S;Pramanik S;Williams LJ;Hodges HR;Hudgens CW;Fischer GM;Luo CK;Knighton B;Tan L;Lorenzi PL;Mackinnon AL;McQuade JL;Hailemichael Y;Roszik J;Peng W;Vashisht Gopal YN
免疫检查点抑制剂和过继性肿瘤浸润淋巴细胞（TIL）疗法极大地提高了黑色素瘤患者的生存率。然而，大多数患者对这些药物没有反应，并且许多反应者出现疾病复发。虽然正在探索许多创新疗法来抵消这些药物的局限性，但与免疫疗法的新型治疗组合有可能改善患者的反应。在这项研究中，我们评估了与 Telaglenastat (CB-839) 联合免疫治疗的抗黑色素瘤活性，Telaglenastat (CB-839) 是一种有效的谷氨酰胺酶抑制剂 (GLSi)，具有良好的全身耐受性。在体外 TIL：肿瘤共培养研究中，CB-839 治疗提高了自体 TIL 对患者来源的黑色素瘤细胞的细胞毒活性。在这些共培养物中，与 TIL 相比，CB-839 治疗更有效地降低肿瘤细胞中谷氨酰胺向 α-酮戊二酸 (αKGA) 的转化。这些结果表明，CB-839 可以通过差异改变肿瘤和免疫细胞代谢来改善肿瘤微环境中的免疫功能。体内 CB-839 治疗可激活黑色素瘤抗原特异性 T 细胞，并在过继性 T 细胞治疗的免疫活性小鼠模型中提高其肿瘤杀伤活性。此外，CB-839 与抗 PD1 或抗 CTLA4 抗体的组合增加了效应 T 细胞的肿瘤浸润，并提高了这些检查点抑制剂在高突变负荷小鼠黑色素瘤模型中的抗肿瘤活性。对这些治疗的反应还伴随着肿瘤中干扰素γ（IFNγ）相关基因表达的增加。总之，这些结果为将 CB-839 与免疫疗法相结合以提高这些疗法针对黑色素瘤的疗效提供了强有力的理由。
Immune checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of melanoma patients. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. While numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses. In this study, we evaluated the anti-melanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a potent glutaminase inhibitor (GLSi) that has favorable systemic tolerance. In in vitro TIL:tumor co-culture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs in these co-cultures. These results suggest that CB-839 may improve immune function in a tumor microenvironment by differentially altering tumor and immune cell metabolism. In vivo CB-839 treatment activated melanoma antigen–specific T cells, and improved their tumor killing activity in an immune-competent mouse model of adoptive T cell therapy. Additionally, combination of CB-839 with anti-PD1 or anti-CTLA4 antibodies increased tumor infiltration by effector T cells and improved the anti-tumor activity of these checkpoint inhibitors in a high mutation burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNγ)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.