Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle
Abstract
:Simple Summary
Abstract
1. Introduction
2. Doublets: The Current Strategy
3. Triplets: A Strategy under Investigation
3.1. Anti PD1 + Anti CTLA4 + Anti-Angiogenics
3.2. Anti PD1 + Anti-VEGF + Alternative Immunity Targets
4. Immunotherapy beyond ICIs: Future Perspectives
4.1. Chimeric Antigen Receptor T Cell Therapy
4.2. Vaccines
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Determinant | Biological Role | Specificity to HCC | Putative Mechanism of Resistance | Ref. |
---|---|---|---|---|
WNT/CTNNTB1 | Evolutionary conserved transcriptional pathway, cell-cell adhesion, pivotal hepatic functions since embryonal life. | Its activating mutation relates to over-expression of wnt-target genes, enrichment in beta-catenin, and PTK2-related immune exclusion. More represented in viral etiology. | Lower enrichment score of immune signatures: T-cell exclusion, and down-regulation of CCL4. Down-regulation of NKG2D ligand hampering NK-mediated response. | [19,20,21] |
LAG-3 | Type-I trans-membrane protein acts as a negative immune counterweight during prolonged exposure to tumor antigens and is constitutively expressed by T-regs. | More expressed and more frequently mutated (15%) in HCC tissues than non-malignant livers in TGCA samples; positively correlated with the oncogenic transcription factor E2F1. | High correlation between its expression and immune-suppressive or exhausted tumor environment. | [17,22,23,24] |
FGL1 | Liver-secreted protein and main functional ligand to LAG-3 inhibiting antigen-specific T cell activation | Significantly down-regulated in HCC samples and correlated with higher grades, presence of metastases and poorer outcomes. FGL1-positive CTC patients showed resistance to ICIs treatment in a limited retrospective case-series | High expression of FGL1 is correlated with higher density of LAG3+: blocking the FGL1/LAG3 can promote T cytotoxicity immunity. | [14,25,26] |
TIGIT | Co-inhibitor receptor expressed on T cells and NK, functionally similar to PD-1 | Co-factor for T cells functional exhaustion in chronic viral hepatotropic infections; hallmark of immune suppressed HCC TGCA sub-group. | TIGIT, CTLA4 and ICOS are co-regulated and co-expressed; TIGIT interaction with NECTIN2 shapes a cancer-promoting immune suppressive environment | [14,27,28] |
Strategy | Trial Name and/or CTC Identification | Recruitment | Phase | Comparator | Interventions targets |
---|---|---|---|---|---|
Anti-PD(L)1/anti CTLA4 | NCT04720716 | China | III | Sorafenib a | IBI-310 b (ipilimumab bio-similar) + sintilimab c |
NCT04039607/ CheckMate 9DW | global | III | Sorafenib or Lenvatinib d | Ipilimumab b + nivolumab c | |
Anti-PD(L)1/anti-VEGF | NCT04605796 | China | II | - | JS001, toripalimab c + bevacizumab e |
NCT04560894 | China | II/III | Sorafenib a | SCT-I10Ac + SCT510 (bevacizumab bio-similar) e | |
NCT04741165 | China | II | - | HX008 c + bevacizumab e | |
NCT03973112, arm IV | China | II | - | HLX10, serplulimab c + HLX04 (bevacizumab biosimilar) e | |
Anti PD(L)1/TKIs | NCT04443309 | China | I/II | - | Camrelizumab c + lenvatinib d |
NCT04401800 | China | II | - | Tislelizumab c + Lenvatinib d | |
NCT04183088 | Taiwan | II | Regorafenib f | tislelizumab c + regorafenib f | |
NCT04523493 | global | III | Lenvatinib d | JS001, toripalimab c + lenvatinib d | |
NCT03841201/IMMUNIB | Germany | II | - | Nivolumab c + lenvatinib d | |
NCT04741165 | China | II | - | HX008 c + lenvatinib d | |
NCT05441475, part b | China | II | - | Atezolizumab g + ABSK-011 h | |
NCT03439891 | USA | II | - | nivolumab c + sorafenib a | |
NCT04443322 | China | II | - | Durvalumab h + lenvatinib d |
Trial Identification | Study Phase | Treatment Arms | Targets | Primary End-Point |
---|---|---|---|---|
NCT05363722 | Ib | IBI 310 (ipilimumab biosimilar) + bevacizumab + sintilimab | anti PD1 + anti CTLA4 + anti-VEGF | ORR |
NCT04740307 MK-1308A-004 | II | pembrolizumab/quavonlimab (MK-1308A) + lenvatinib | Coformulated anti PD1/anti CTLA4 + TKI | DLTs ORR |
NCT05363722 | III | Camrelizumab + Folfox4 | anti PD1 + chemotherapy | OS |
Camrelizumab + placebo | ||||
NCT04948697 AdvanTIG-206 | II | ociperlimab + tislelizumab + BAT1706 | Anti-TIGIT + anti PD1 + anti- VEGF | ORR |
tislelizumab + BAT1706 | anti PD1 + anti- VEGF | ORR | ||
NCT05337137 Relativity-106 | I/II | Relatlimab + Nivolumab + Bevacizumab | Anti-LAG + anti PD1 + anti-VEGF | DLTs ad PFS |
Placebo + Nivolumab + Bevacizumab | anti PD1 + anti-VEGF | |||
NCT05359861 | II | SRF388 + Atezolizumab + bevacizumab | Anti-IL27 + anti PDL1 + anti-VEGF | PFS |
Placebo + Atezolizumab + bevacizumab | anti PDL1 + anti-VEGF | |||
NCT05249569 | II | Axitinib + Avelumab + Bavituximab | Anti-VEGFR + anti PDL1 + anti-phosphatidylserine | RR |
Treatment Strategy | Trial Identification | Study Phase | Treatment Arms | Primary End-Point |
---|---|---|---|---|
CAR-T cells therapy | NCT02905188 GLYCAR trial | I | GPC3-CAR (GLYCAR T cells) + lymphodepleting chemotherapy (Cyclophosphamide and Fludarabine) | DLT |
NCT03884751 | I | CAR-GPC3 T Cells | DLT + MTD | |
NCT03980288 | I | CAR-GPC3 T Cells (in part II: combination with TKI or anti- PD(L)1) | DLT + MTD | |
NCT04121273 | I | CAR-GPC3 T Cells | DLT | |
NCT03993743 | I | CD147-CART hepatic artery infusion | AEs | |
Vaccine + RFA/surgery | NCT03067493 RAMEC trial | II | RFA or surgery +/− Neo-MASCT | DFS + immune response rate |
Vaccine + ICIs | NCT04248569 | I | DNAJB1-PRKACA peptide vaccine + Nivolumab + Ipilimumab | AEs + change in INF-producing DNAJB1-PRKACA-specific CD8/CD4 T cells |
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Salani, F.; Genovesi, V.; Vivaldi, C.; Massa, V.; Cesario, S.; Bernardini, L.; Caccese, M.; Graziani, J.; Berra, D.; Fornaro, L.; et al. Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle. Cancers 2022, 14, 4896. https://doi.org/10.3390/cancers14194896
Salani F, Genovesi V, Vivaldi C, Massa V, Cesario S, Bernardini L, Caccese M, Graziani J, Berra D, Fornaro L, et al. Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle. Cancers. 2022; 14(19):4896. https://doi.org/10.3390/cancers14194896
Chicago/Turabian StyleSalani, Francesca, Virginia Genovesi, Caterina Vivaldi, Valentina Massa, Silvia Cesario, Laura Bernardini, Miriam Caccese, Jessica Graziani, Dario Berra, Lorenzo Fornaro, and et al. 2022. "Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle" Cancers 14, no. 19: 4896. https://doi.org/10.3390/cancers14194896