Tinostamustine Plus Nivolumab Linked to Immune Responses in Advanced Melanoma

A longitudinal immune monitoring study conducted in 15 of 17 patients enrolled in the ENIgMA phase IB trial demonstrated that the combination of tinostamustine and nivolumab is linked with preserved adaptive immune competence and detectable cellular and humoral immune activation in heavily pre-treated patients with advanced melanoma. The ENIgMA trial (NCT03903458; SNCTP000003243) evaluated the safety and preliminary activity of the first-in-class alkylating deacetylase inhibitor tinostamustine in combination with nivolumab (3 mg/kg) in patients with predominantly immune checkpoint inhibitor-resistant, advanced melanoma.

In evaluable patients, previous findings demonstrated that combining tinostamustine with nivolumab induced disease stabilization in 54% and confirmed partial responses in 23%. To evaluate systemic immunologic shifts associated with an immunomodulatory dose of tinostamustine, researchers collected peripheral blood samples longitudinally during treatment and analyzed them by flow cytometry, serum antigen-specific IgG enzyme-linked immunosorbent assay (ELISA), and intracellular cytokine staining following ex vivo peptide stimulation. Longitudinal flow cytometric analyses revealed dynamic changes in peripheral immune subsets, including T cells, natural killer (NK) cells, and monocytes, suggesting ongoing immune engagement during therapy.

Antigen-specific adaptive immune responses remained detectable despite extensive prior treatment and high tumour burden. CD4+ T cell responses directed against melanoma-associated antigens, particularly those associated with TNFα, represented the dominant pattern of cellular immune activation, alongside treatment-related increases in melanoma-associated antigen-specific IgG responses observed in several patients. Among progressors, elevated baseline lactate dehydrogenase (LDH) levels significantly and inversely correlated with circulating T cell frequencies, highlighting distinct immune profiles associated with poor clinical outcome.

Subject of Research: Immune responses to tinostamustine and nivolumab in advanced melanoma

Article Title: Tinostamustine–nivolumab therapy is associated with antigen-specific cellular and humoral immune responses in heavily pre-treated patients with advanced melanoma

Article References: Mane, S., Walter, V., Abdou, M.-T., Diem, S., Wyss, N., Koster, K.-L., Besse, L., Hess, D., Metaxas, Y., Flynn, M.-C., Aeppli, S., El Saadany, T., Hiendlmeyer, E., von Moos, R., Joerger, M., & Flatz, L. (2026). Tinostamustine–nivolumab therapy is associated with antigen-specific cellular and humoral immune responses in heavily pre-treated patients with advanced melanoma. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04608-4

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04608-4

Keywords: Advanced Melanoma, Tinostamustine, Nivolumab, Cancer Immunology, Phase IB Trial, Immune Checkpoint Inhibitors, Adaptive Immunity, Flow Cytometry, therapy, associated, antigen-specific, cellular