Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma
Abstract
:1. Introduction
2. ICI Therapy for OMM
3. Immunotherapy Resistance
3.1. Mechanism of Intrinsic Resistance to Immune-Checkpoint-Blockade Therapy in Melanoma
3.1.1. Impairments in the Antigen Processing–Presenting Machinery
3.1.2. Alterations in Signaling Pathways
3.1.3. Absence of Tumor Antigens and Lack of Antigenic Mutation
3.1.4. Expression of PD-L1 and Other Contributing Factors to Resistance
3.2. Role of the Extrinsic Tumor Resistance Mechanism
4. Future Directions
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Clinical Trial İdentifier | Trıal Name | Phase | Location(s) | Status | Target Disease | Target Accrual | Intervention | Primary Outcome Measures | Secondary Outcome Measures |
---|---|---|---|---|---|---|---|---|---|
NCT03178123 | A phase II Randomized, Control, Multi-center Study of Recombinant Humanized Anti-PD-1 mAb For Injection Compared to High-dose Interferon in Patients with Mucosal Melanoma That Has Been Removed by Surgery | Phase II | Beijing Cancer Hospital | ACTIVE, NOT RECRUITING | Mucosal melanoma that has been removed by surgery | 220 | Humanized anti-PD-1 monoclonal antibody toripalimab or high-dose recombinant interferon a-2B | Recurrence-free survival time (RFS) | Distant metastasis-free survival, recurrence—free survival rate at 3 years, overall survival (OS), number of participants with treatment-related adverse events |
NCT05384496 | Phase 2 Study of Axitinib + PD-1 Blockade in Mucosal Melanoma With Pilot Addition of Stereotactic Body Radiotherapy or Ipilimumab in Select Progressors | Phase II | Memorial Sloan Kettering Cancer Center USA | RECRUITING | Advanced or metastatic mucosal melanoma that has not been treated before | 20 | Combination of axitinib and nivolumab with or without SBRT/Ipilimumab | Best objective response | – |
NCT05169957 | Hepatic Ablation of Melanoma Metastases to Enhance Immunotherapy Response, a Phase I Clinical Trial (HAMMER I) | Phase I | University of Michigan Rogel Cancer Center, USA | RECRUITING | Metastatic melanoma with liver metastases who are at significant risk of not benefiting from systemic therapy alone | 18 | Ipilimumab + Nivolumab + Stereotactic Body Radiation Therapy (SBRT) | Percentage of patients who receive all planned radiotherapy. | Proportion of patients who develop grade 3 or higher toxicity, OS, PFS, proportion of patients with local control, objective response rate, BoR |
NCT05089370 | Oral Decitabine/Cedazuridine (DEC-C) in Combination With Nivolumab as a Strategy to Enhance the Efficacy of Immune Checkpoint Blockade in Unresectable or Metastatic Mucosal Melanoma | Phase Ib/II | University of Colorado Hospital, USA | RECRUITING | Unresectable or metastatic mucosal melanoma | 30 | Oral decitabine/cedazuridine (DEC-C) in combination with nivolumab | Safety of DEC-C in combination with nivolumab | The response rate to DEC-C in combination with nivolumab, to determine if the addition of DEC-C to nivolumab increases PFS and OS |
NCT05111574 | A Randomized Phase II Trial of Adjuvant Nivolumab With or Without Cabozantinib in Patients with Resected Mucosal Melanoma | Phase II | Multicenter, USA, CANADA | SUSPENDED | Mucosal melanoma | 99 | Nivolumab and cabozantinib or nivolumab and placebo | RFS | OS, RFS, PFS, overall response rate, duration of response, incidence of adverse events |
NCT03033576 | A Phase II Randomized Study of Nivolumab (NSC-748726) With Ipilimumab (NSC-732442) or Ipilimumab Alone in Advanced Melanoma Patients Refractory to an Anti-PD1 or Anti-PD-L1 Agent | Phase II | Multicenter, USA | ACTIVE, NOT RECRUITING | Unresectable stage IV or stage III melanoma and refractory to an anti-PD1 or anti-PD-L1 agent | 94 | Ipilimumab or nivolumab and ipilimumab | Progression free survival | Change in CD8+ expression, overall objective response rate, OS, number of participants with Gr 3 through 5 adverse events that are related to study drugs |
NCT03235245 | Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation: an EORTC Randomized Phase II Study (EBIN) | Phase II | Multicenter, International | ACTIVE, NOT RECRUITING | BRAF V600 mutation-positive stage III or IV cutaneous or mucosal melanoma | 271 | Nivolumab + Ipilimumab, or Encorafenib + Binimetinib + Nivolumab + Ipilimumab | Progression free survival | OS, CR rate, time to CR, duration of CR, best overall response rate, time to best response, duration of best response, occurrence of adverse events, PFS2 |
NCT04511013 | A Randomized Phase 2 Trial of Encorafenib + Binimetinib + Nivolumab vs Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases | Phase II | Multicenter, USA | RECRUITING | BRAF-V600 mutant melanoma that has spread to the brain | 112 | Encorafenib+ Binimetini+ Nivolumab or Nivolumab+ Ipilimumab | Progression-free survival | OS, ICRR, objective response rate, duration of response |
NCT05341349 | Safety and Efficacy of SRS and Immune Checkpoint Inhibitors (ICI) Concurrent With NovoTTF-100M in Melanoma Brain Metastases | Phase I | Emory University Hospital/Winship Cancer Institute, USA | RECRUITING | Melanoma with brain metastasis | 10 | SRS, pembrolizumab, TTFields or nivolumab, ipilimumab, SRS, TTFields | The percentage of patients developing grade 3 CNS toxicity | Rates of skin toxicity, rates of alopecia, time to progression, intracranial control, PFS, OS |
NCT05545969 | A Multicentre, Open Label, Phase II Study to Determine the Response to Neoadjuvant Pembrolizumab and Lenvatinib Followed by Adjuvant Treatment With Pembrolizumab and Lenvatinib in Mucosal Melanoma | Phase II | Multicenter, Australia | NOT YET RECRUITING | Fully-resectable mucosal melanoma | 44 | Neoadjuvant pembrolizumab & Lenvatinib + definitive surgery + adjuvant pembrolizumab | Change in immune cell expression of HIF1 and immune cell densities, pathological response rate | RECIST response rate |
NCT05436990 | A Phase II Multicenter Study to Assess the Antitumor Activity of Vactosertib in Combination With Pembrolizumab in Acral and Mucosal Melanoma Patients Progressed From Prior Immune Check Point Inhibitor | Phase II | Multicenter, Severance Hospital, Yonsei University Healthy System | NOT YET RECRUITING | Acral or mucosal melanoma with stage IV or unresectable stage III disease, progressed on treatment with an anti-PD-1/L1 mAb | 30 | Vactosertib in combination with pembrolizumab | Overall response rate | – |
NCT05420324 | A Multicenter, Single-arm, Open-label Phase II Study to Evaluate the Efficacy and Safety of YH003 in Combination With Pebolizumab and Albumin Paclitaxel in First-line Treatment of Patients With Unresectable/Metastatic Mucosal Melanoma | Phase II | Multicenter, China | RECRUITING | Advanced or cytologically confirmed metastatic or unresectable mucosal melanoma | 43 | YH003 in combination with pebolizumab and albumin paclitaxel in first-line treatment | Confirmed objective response rate | – |
NCT03313206 | Phase II Multicentric Study: Efficacy Evaluation of Neoadjuvant Treatment Associated With Maintenance Therapy by Anti-PD1 Immunotherapy on Disease-free-survival (DFS) in Patients With Resectable Head and Neck Mucosal Melanoma | Phase II | Multicenter, France | RECRUITING | Resectable head and neck mucosal melanoma. | 60 | Neoadjuvant pembrolizumab + Surgery + IMRT or neoadjuvant pembrolizumab + Surgery + IMRT + Lenvatinib | Disease free survival | – |
NCT04622566 | A Phase II Study of Neoadjuvant Lenvatinib and Pembrolizumab in Resectable Mucosal Melanoma | Phase II | Beijing Cancer Hospital | NOT YET RECRUITING | Resectable mucosal melanoma | 26 | Lenvatinib and pembrolizumab | Pathological complete response (pCR) rate | 1 year RFS rate per RECIST1.1 as assessed by investigator, OS, incidence of AEs/SAEs |
NCT04318717 | Adjuvant Pembrolizumab and Hypofractionated Radiation Therapy for the Treatment of Mucosal Melanoma | Phase II | Washington University School of Medicine | RECRUITING | Mucosal melanoma that has undergone surgical resection | 16 | Pembrolizumab + Hypofractionated radiation therapy | Local tumor control rate | Number of treatment-related grade 3 or greater adverse events, number of treatment discontinuations due to treatment-related adverse events, RFS, distant metastasis-free survival, OS |
NCT02506153 | A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma | Phase III | Multicenter, USA, CANADA, IRELAND | ACTIVE, NOT YET RECRUITING | Stage IIIA (N2a), IIIB, IIIC, or stage IV melanoma | 1378 | High-dose recombinant interferon alfa-2B, ipilimumab or pembrolizumab | OS, RFS, PD-L1 status | Incidence of toxicity, post-relapse therapy, BRAF mutation status, long-term survival, change in quality of life |
NCT03698019 | A Phase II Randomized Study of Adjuvant Versus NeoAdjuvant Pembrolizumab (MK-3475) for Clinically Detectable Stage III-IV High-Risk Melanoma | Phase II | Multicenter, USA | ACTIVE, NOT YET RECRUITING | Detectable stage III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or stage IV resectable melanoma | 323 | Adjuvant pembrolizumab or adjuvant and neoadjuvant pembrolizumab | Two-year event-free survival rate | Number of participants with grade 3 through 5 adverse events that are related to study drug, two-year OS rate, response rate, number of participants receiving surgery |
NCT05549297 | Phase 2/3 Randomized Study of Tebentafusp as Monotherapy and in Combination With Pembrolizumab Versus Investigator’s Choice in HLA-A*02:01-positive Participants With Previously Treated Advanced Melanoma (TEBE-AM) | Phase II/III | Multicenter, USA | RECRUITING | Unresectable Stage III or stage IV non-ocular melanoma | 460 | Tebentafusp or tebentafusp in combination with pembrolizumab or investigators choice of therapy | ctDNA reduction on treatment relative to baseline, OS | Safety; adverse events and severe adverse events, safety: tolerability, serum pharmacokinetics, incidence of anti-tebentafusp antibodies |
NCT03241186 | Single Arm Phase II Study of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma (SALVO Study). HCRN: MEL16-252 | Phase II | Multicenter, USA | ACTIVE, NOT YET RECRUITING | Melanoma of any mucosal site, resected within ≤90 days of registration. | 36 | Ipilimumab (1 mg/kg) + Nivolumab (3 mg/kg) IV | Recurrence-free survival time | Adverse Events, OS |
NCT04091217 | Atezolizumab in Combination With Bevacizumab in Patients With Unresectable Locally Advanced or Metastatic Mucosal Melanoma | Phase II | Multicenter, China | COMPLETED | Unresectable locally advanced(stage III) or metastatic(Stage IV) mucosal melanoma | 43 | Atezolizumab + Bevacizumab | Objective response rate | PFS, OS, DOR, DCR, percentage of participants with adverse events |
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Usta, S.Z.; Uchihashi, T.; Kodama, S.; Kurioka, K.; Inubushi, T.; Shimooka, T.; Sugauchi, A.; Seki, S.; Tanaka, S. Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma. Int. J. Mol. Sci. 2023, 24, 17282. https://doi.org/10.3390/ijms242417282
Usta SZ, Uchihashi T, Kodama S, Kurioka K, Inubushi T, Shimooka T, Sugauchi A, Seki S, Tanaka S. Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma. International Journal of Molecular Sciences. 2023; 24(24):17282. https://doi.org/10.3390/ijms242417282
Chicago/Turabian StyleUsta, Sena Zeynep, Toshihiro Uchihashi, Shingo Kodama, Kyoko Kurioka, Toshihiro Inubushi, Takuya Shimooka, Akinari Sugauchi, Soju Seki, and Susumu Tanaka. 2023. "Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma" International Journal of Molecular Sciences 24, no. 24: 17282. https://doi.org/10.3390/ijms242417282