Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma
Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive condi...
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| Language: | English |
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BMJ Publishing Group
2024-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/10/e009690.full |
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| author | Michael A Curran Joanna Schmidt Ahmed O Kaseb Arthur Liu Madeline Steiner Ricardo DeAzevedo Broderick X Turner Sherwin Newton Rachel Fleming Angelica Tolentino |
| author_facet | Michael A Curran Joanna Schmidt Ahmed O Kaseb Arthur Liu Madeline Steiner Ricardo DeAzevedo Broderick X Turner Sherwin Newton Rachel Fleming Angelica Tolentino |
| author_sort | Michael A Curran |
| collection | DOAJ |
| description | Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with PD-1 blockade. While MET inhibition demonstrated cooperativity with αPD-1 across all three models, the type I MET inhibitor capmatinib showed optimal activity in combination and statistically significantly outperformed the combination with the type II inhibitor cabozantinib in the αPD-1 refractory DEN model. In both HCA-1 and DEN HCC, the capmatinib and αPD-1 combination enhanced CD8 T cell frequency and activation state while limiting intratumoral myeloid immune suppression. In vitro studies of antigen-specific T cell activation reveal significantly less inhibition of effector cytokine production and proliferation by capmatinib versus by type II or type III MET inhibitors. These findings suggest significant potential for clinical HCC combination studies of type I MET inhibitors and PD-1 blockade where prior trials using type II inhibitors have yielded limited benefit. |
| format | Article |
| id | doaj-art-4f6f166e60514a1f81c09fa7eeee67e1 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4f6f166e60514a1f81c09fa7eeee67e12025-08-20T02:27:31ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-10-01121010.1136/jitc-2024-009690Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinomaMichael A Curran0Joanna Schmidt1Ahmed O Kaseb2Arthur Liu3Madeline Steiner4Ricardo DeAzevedo5Broderick X Turner6Sherwin Newton7Rachel Fleming8Angelica Tolentino92The University of Texas MD Anderson Cancer Center, Houston, TX, USAIonis Pharmaceuticals, Carlsbad, California, USADepartment of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAIonis Pharmaceuticals, Carlsbad, California, USAIonis Pharmaceuticals, Carlsbad, California, USABlockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with PD-1 blockade. While MET inhibition demonstrated cooperativity with αPD-1 across all three models, the type I MET inhibitor capmatinib showed optimal activity in combination and statistically significantly outperformed the combination with the type II inhibitor cabozantinib in the αPD-1 refractory DEN model. In both HCA-1 and DEN HCC, the capmatinib and αPD-1 combination enhanced CD8 T cell frequency and activation state while limiting intratumoral myeloid immune suppression. In vitro studies of antigen-specific T cell activation reveal significantly less inhibition of effector cytokine production and proliferation by capmatinib versus by type II or type III MET inhibitors. These findings suggest significant potential for clinical HCC combination studies of type I MET inhibitors and PD-1 blockade where prior trials using type II inhibitors have yielded limited benefit.https://jitc.bmj.com/content/12/10/e009690.full |
| spellingShingle | Michael A Curran Joanna Schmidt Ahmed O Kaseb Arthur Liu Madeline Steiner Ricardo DeAzevedo Broderick X Turner Sherwin Newton Rachel Fleming Angelica Tolentino Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma Journal for ImmunoTherapy of Cancer |
| title | Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma |
| title_full | Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma |
| title_fullStr | Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma |
| title_full_unstemmed | Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma |
| title_short | Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma |
| title_sort | type i met inhibitors cooperate with pd 1 blockade to promote rejection of hepatocellular carcinoma |
| url | https://jitc.bmj.com/content/12/10/e009690.full |
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