Abstract 1529: Development of lymphoid aggregates in metastatic uveal melanoma tumors treated with tebentafusp

Abstract

Abstract Tebentafusp (tebe), targeting gp100, is the first TCR-CD3 bispecific to demonstrate overall survival (OS) benefit and is approved for the treatment of metastatic uveal melanoma (mUM). We have previously shown B cell recruitment into the tumor associates with OS on tebe [1]. We explored further the formation of lymphoid aggregates (LA) within the tumor microenvironment in response to tebe. HLA-A*02:01+ 2L+ adult patients (pts) with mUM were treated with tebe (NCT02570308). Paired tumor biopsies were collected at baseline (n=70), after 3 doses of tebe (n=48), and at radiographical progression (n=17). Presence of B cells, T cells and macrophages was assessed by immunohistochemistry, using antibodies against CD20, CD3 and CD163 respectively, and digitally quantified. Using digital density analysis, aggregates of ≥10 CD20+ B cells within CD3+ T cell area in a 100µm radius were defined as LA. At progression pts were categorized by OS ≥12 or <12 months. Mean fold change (FC) was used. At baseline, B cells were detected in 90% of pts (median 5 B cells/mm2) with those pts having no more than 2 LA/mm2 (17% pts with 1 LA/mm2 and 3% pts with 2 LA/mm2). The median number of B cells in the biggest LA per sample was 24.B cells were recruited into the tumor after 3 doses of tebe (median 32 B cells/mm2, FC 3, p=6.5e-05). The LA density increased up to 6 LA/mm2 (23% pts with 1 LA/mm2, 8% pts with 2 LA/mm2, 6% pts with 3 LA/mm2 and 2% pts with 6 LA/mm2) with a trend for an increase in LA size (median B cell number in biggest LA = 30, p = 0.67). Tumors with a low baseline CD163+ macrophage to CD3+ T cell ratio, which was previously associated with longer OS on tebe, tended to have more LA/mm2 at baseline and on-treatment than those with a high ratio. At progression, pts with long OS had more B cells in the tumor compared to short OS (median 20 vs 2 B cells/mm2; FC 5, p=0.05). Additionally, more pts with long OS had LA than pts with short OS (6/12 pts vs 1/5 pts respectively) with a density not exceeding 1 LA/mm2. LA size was larger in pts with long OS compared to short OS (median B cell number in biggest LA 30 vs 10 respectively). LA in the short OS patient was found in the normal adjacent tissue compared to the LA in long OS patients which were located in the tumor and invasive margin. Tebe enhanced the formation of LA in the tumor microenvironment, notably in the low immunosuppressed tumors, which is consistent with the hypothesis that it results in epitope spread. These observations provide deeper insight into the mechanism of action of tebe and helps to explain prolonged survival of mUM pts beyond radiographical progression. [1] Greenshields-Watson A. et al., 619, SITC 2022 Citation Format: Takami Sato, Camille Britton-Rivet, Sophie Khakoo, Alistair Easton, Anastasiya Kazachenka, Laura Collins, Emma Leach, Adel Benlarech, Sarah Stanhope, Marcus O. Butler. Development of lymphoid aggregates in metastatic uveal melanoma tumors treated with tebentafusp [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1529.