Tebentafusp (tebe) is a novel bispecific fusion protein redirecting T cells against gp100 (a melanocytic antigen) expressing cells, approved for metastatic uveal melanoma. Skin adverse events (incl. maculopapular rash, depigmentation) are frequent and were shown to be an off-tumor/on-target effect against gp100+ epidermal melanocytes. Thus, analysis of tebe-induced cellular and molecular processes in patient skin samples may improve mechanistic understanding.
Skin biopsies from patients treated with tebe were collected at baseline and development of skin rash (n=11), as well as from depigmented areas (n=5). Spatial analysis was performed by histology and multiplex immunohistochemistry (7-plex, Akoya Opal). On paired samples (n=6, baseline and rash) from 3 patients, single cell RNA sequencing was conducted. Furthermore, proliferation of T cell subsets (naïve and memory of each CD4+ and CD8+) treated with tebe or anti-CD3 antibody was assessed in vitro (3 healthy donors).
Rash showed increased numbers of CD4+ and CD8+ T cells and markers of activation/proliferation (IFNG, GZMB, IL2RA, MKI67) were upregulated in T cells. In vitro, tebe’s capacity to induce T cell proliferation was validated, predominantly in the CD8+ memory subset, in contrast to the unselective effect observed by high affinity anti-CD3. Recruitment of monocyte-derived macrophages and plasmacytoid dendritic cells (DC) was found. Interestingly, increased activity in regulatory T cells and immunoregulatory DC suggested early homeostatic regulation. Melanocyte numbers remained unchanged in rash but were reduced in 4/5 depigmented lesions. Upregulation of interferon type I/II responses and downregulation of pigment synthesis was seen, resulting in an increased fraction of gp100-negative melanocytes.
Longitudinal skin biopsies are a promising and minimally-invasive tool to study the pharmacodynamics of anti-melanocytic bispecifics. The skin microenvironment on tebe treatment is characterized by T cell proliferation and cytotoxic activity, recruitment of myeloid cells as well as downregulation of the target gp100 in melanocytes and their partial loss in depigmented skin areas.
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R. Dummer: Financial Interests, Personal, Other, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. All other authors have declared no conflicts of interest.