Review of bi-specific therapies in uveal melanoma

Orloff, Marlana; Seedor, Rino S.; Sato, Takami

doi:10.1038/s41417-022-00442-9

Cited by 6 publications

(7 citation statements)

References 33 publications

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“…The T cell receptor part targets cells presenting tumor neoantigens or intracellular antigens presented by HLA. The anti-CD3 domain recruits immune cells, mainly (CD3 (+)) T cells [66,67]. Tebentafusp is a drug in the class of ImmTAC described above.…”

Section: Novel Immunotherapy Approachesmentioning

confidence: 99%

From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma

Synoradzki,

Paduszyńska,

Solnik

et al. 2024

Current Oncology

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Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp—a T cell–redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research.

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Section: Novel Immunotherapy Approachesmentioning

confidence: 99%

From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma

Synoradzki,

Paduszyńska,

Solnik

et al. 2024

Current Oncology

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“…Although the cell biology of uveal melanoma has been extensively studied [2,4], this breadth of knowledge has not translated into better treatments and outcomes for UM patients. While brachytherapy and surgical procedures are initially effective treatments for primary uveal melanoma [3,4], 50% of all patients still develop metastases [5,6]. Metastatic uveal melanoma (MUM) is highly aggressive and lethal, often with an overall survival (OS) of <1 year [1,4].…”

Section: Introductionmentioning

confidence: 99%

“…However, 44% of patients exhibited grade ≥3 adverse events, including 89% with cytokine release syndrome [11]. Importantly, 55% of people in the USA and Europe are HLA-A*02:01-negative, and thus a large portion of the MUM patient population is unlikely to derive benefit from tebentafusp [6]. While this initial success with tebentafusp is exciting and it is the first systemic therapy to show any OS benefit and be FDA approved for MUM [6], there is still a significant need for a broadly applicable, safe, and effective therapy for MUM.…”

Section: Introductionmentioning

confidence: 99%

The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma

Boudreau,

Tonogai,

Schane

et al. 2023

Melanoma Research

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The treatment of metastatic uveal melanoma remains a major clinical challenge. Procaspase-3, a proapoptotic protein and precursor to the key apoptotic executioner caspase-3, is overexpressed in a wide range of malignancies, and the drug PAC-1 leverages this overexpression to selectively kill cancer cells. Herein, we investigate the efficacy of PAC-1 against uveal melanoma cell lines and report the synergistic combination of PAC-1 and entrectinib. This preclinical activity, tolerability data in mice, and the known clinical effectiveness of these drugs in human cancer patients led to a small Phase 1b study in patients with metastatic uveal melanoma. The combination of PAC-1 and entrectinib was tolerated with no treatment-related grade ≥3 toxicities in these patients. The pharmacokinetics of entrectinib were not affected by PAC-1 treatment. In this small and heavily pretreated initial cohort, stable disease was observed in four out of six patients, with a median progression-free survival of 3.38 months (95% CI 1.6–6.5 months). This study is an initial demonstration that the combination of PAC-1 and entrectinib may warrant further clinical investigation. Clinical trial registration: Clinical Trials.gov: NCT04589832.

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“…Furthermore, whereas 42–45% of primary cutaneous melanomas carry a BRAF V600E mutation and are therefore predicted to respond to targeted BRAF-/MEK inhibition [ 6 ], UM do not carry BRAF V600E mutations [ 7 ]. Recently, tebentafusp, an HLA-A specific T-cell redirecting agent targeting the melanocytic protein gp100, was demonstrated to improve the overall survival over pembrolizumab or ipilimumab or dacarbazine, which are relatively suboptimal “standard” choices, in patients with metastatic UM who had an HLA-A 02:01 allele [ 8 , 9 ]. Unfortunately, owing to the restricted HLA background, only half of all patients will ever have this therapeutic option, and the vast majority of patients are still likely to succumb to this disease even with the availability of tebentafusp.…”

Section: Introductionmentioning

confidence: 99%

Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

Kraehenbuehl

Holland

Armstrong

et al. 2022

Cancers

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Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.

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Review of bi-specific therapies in uveal melanoma

Cited by 6 publications

References 33 publications

From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma

From Molecular Biology to Novel Immunotherapies and Nanomedicine in Uveal Melanoma

The combination of PAC-1 and entrectinib for the treatment of metastatic uveal melanoma

Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

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