1772P - Demonstration of T cell redirection and immune activation in skin rash following tebentafusp treatment

Background

Tebentafusp (tebe) is an investigational TCR–anti-CD3 bispecific fusion protein that targets gp100 and activates T cells. In a recent phase 3 study, tebe improved overall survival (OS) in metastatic uveal melanoma patients (pts)¹. Most pts developed skin rash after dose 1, an expected adverse event since melanocytes also express gp100; however, rash was not an independent predictor of OS benefit².

Methods

12/14 pts developed >1 grade rash within 7 days post 1^st dose. Paired skin biopsies from pts with metastatic melanoma (NCT01211262) were collected pre and post the 1^st (N=12) or 4^th (N=2) dose of tebe. Fixed samples were assessed by hematoxylin and eosin and CD3 immunohistochemistry (IHC). On 5 additional skin biopsies, dual IHC for Melan-A and CD4/8 was performed. RNAlater® samples were analyzed by RNAseq. Differential gene expression, pathway and cell type composition analysis were performed using R software.

Results

Biopsies from these pts showed increase in lymphocytic infiltrate, exocytosis of lymphocytes and basal cell vacuolization (p=0.002) along the dermo-epidermal junction (DEJ) and upper dermal perivascular inflammatory infiltrate (p=0.01) post treatment compared to baseline. The DEJ inflammatory infiltrate consisted of CD3+ T cells, which were predominantly CD8+ and localized close to melanocytes. RNAseq identified 1786 differentially expressed genes (threshold: p-adj≤0.05, log2-ratio≥0.75), with enrichment of innate and adaptive pathways, including IFNγ signaling, post treatment compared to baseline (p-adj<10^-17). An increase in macrophage and CD8+ T cell genes was accompanied by upregulation of the cytotoxic genes GZMB and PRF1 (p-adj<10^-6). Chemokines CXCL9/10/11 and cytokines IL-10/15/32 were overexpressed (p-adj<10^-7). Expression of melanocyte markers, PMEL, MLANA and DCT were decreased.

Conclusions

Tebe induced rapid recruitment of T cells in the proximity of intraepidermal melanocytes in addition to macrophage activation. Thus tebe-induced skin rash is an on-target effect and may be an important pharmacodynamic tool to better understand the precise molecular and cellular cascades of T cell redirection in the tumor. ¹Piperno-Neumann S. AACR 2021 CT002. ²Hassel J. ASCO 2021 #9527.

Clinical trial identification

NCT01211262.

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

S. Stanhope: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. A. Greenshields-Watson: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. L. Collins: Financial Interests, Institutional, Full or part-time Employment: Immunocore Ltd. E. Ramelyte: Financial Interests, Institutional, Full or part-time Employment: University Hospital Zurich; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Board: Sunpharma. R. Dummer: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Merck Sharp & Dhome (MSD); Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb (BMS); Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Sun Pharma; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Catalym; Financial Interests, Personal, Advisory Role: Second Genome; Financial Interests, Personal, Advisory Role: Regeneron; Financial Interests, Personal, Advisory Role: Alligator; Financial Interests, Personal, Advisory Role: T3 Pharma; Financial Interests, Personal, Advisory Role: MaxiVAX SA; Financial Interests, Personal, Advisory Role: touchIME. All other authors have declared no conflicts of interest.