Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle
Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4896 |
| _version_ | 1797480110728675328 |
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| author | Francesca Salani Virginia Genovesi Caterina Vivaldi Valentina Massa Silvia Cesario Laura Bernardini Miriam Caccese Jessica Graziani Dario Berra Lorenzo Fornaro Gianluca Masi |
| author_facet | Francesca Salani Virginia Genovesi Caterina Vivaldi Valentina Massa Silvia Cesario Laura Bernardini Miriam Caccese Jessica Graziani Dario Berra Lorenzo Fornaro Gianluca Masi |
| author_sort | Francesca Salani |
| collection | DOAJ |
| description | Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises. |
| first_indexed | 2024-03-09T21:55:40Z |
| format | Article |
| id | doaj.art-57cae989600f4d2f8323eff4faa9d23b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:55:40Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-57cae989600f4d2f8323eff4faa9d23b2023-11-23T19:58:26ZengMDPI AGCancers2072-66942022-10-011419489610.3390/cancers14194896Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the HurdleFrancesca Salani0Virginia Genovesi1Caterina Vivaldi2Valentina Massa3Silvia Cesario4Laura Bernardini5Miriam Caccese6Jessica Graziani7Dario Berra8Lorenzo Fornaro9Gianluca Masi10Institute of Interdisciplinary Research “Health Science”, Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56124 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyUnit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, ItalyImmune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.https://www.mdpi.com/2072-6694/14/19/4896immune-checkpoint inhibitors (ICIs)advanced hepatocellular carcinoma (aHCC)first lineprimary resistanceprimary progressorsTIGIT |
| spellingShingle | Francesca Salani Virginia Genovesi Caterina Vivaldi Valentina Massa Silvia Cesario Laura Bernardini Miriam Caccese Jessica Graziani Dario Berra Lorenzo Fornaro Gianluca Masi Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle Cancers immune-checkpoint inhibitors (ICIs) advanced hepatocellular carcinoma (aHCC) first line primary resistance primary progressors TIGIT |
| title | Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle |
| title_full | Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle |
| title_fullStr | Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle |
| title_full_unstemmed | Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle |
| title_short | Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle |
| title_sort | primary resistance to immunotherapy based regimens in first line hepatocellular carcinoma perspectives on jumping the hurdle |
| topic | immune-checkpoint inhibitors (ICIs) advanced hepatocellular carcinoma (aHCC) first line primary resistance primary progressors TIGIT |
| url | https://www.mdpi.com/2072-6694/14/19/4896 |
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