Güç et al. investigated the effects of TAMs on the efficacy of the bispecific ImmTAC tebentafusp, targeting CD3 and gp100-HLA-A*02:01, in patients with metastatic uveal melanoma (mUM). In vitro, M2 TAMs suppressed ImmTAC-mediated tumor cell killing in a dose- and contact-dependent way that did not rely on known checkpoint inhibitors, while pretreatment of T cells with IL-2, combined with ImmTAC, overcame the suppression and enhanced killing by promoting M2-to-M1 TAM reprogramming. As a high baseline TAM:T cell ratio is associated with shorter OS in tebentafusp-treated mUM patients, combining tebentafusp with IL-2 might have translational potential.
Contributed by Katherine Turner
ABSTRACT: Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01(+) adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR_=_2.09, 95% CI, 1.31-3.33, p_=_0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM.
Author Info: (1) Immunocore Ltd, Abingdon-on-Thames, UK. (2) Immunocore Ltd, Abingdon-on-Thames, UK. (3) Immunocore Ltd, Abingdon-on-Thames, UK. (4) Immunocore Ltd, Abingdon-on-Thames, UK. (5)
Author Info: (1) Immunocore Ltd, Abingdon-on-Thames, UK. (2) Immunocore Ltd, Abingdon-on-Thames, UK. (3) Immunocore Ltd, Abingdon-on-Thames, UK. (4) Immunocore Ltd, Abingdon-on-Thames, UK. (5) Immunocore Ltd, Abingdon-on-Thames, UK. (6) Immunocore Ltd, Abingdon-on-Thames, UK. (7) Centro Nacional de Anlisis Genmico (CNAG), Barcelona, Spain. (8) Immunocore Ltd, Abingdon-on-Thames, UK. (9) Immunocore Ltd, Abingdon-on-Thames, UK. (10) Institut Catal d'Oncologia (ICO)-Cancer Immunotherapy Group at'Institut d'Investigaci Biomdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. (11) Centro Nacional de Anlisis Genmico (CNAG), Universitat de Barcelona (UB), ICREA, Barcelona, Spain. (12) Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), Heidelberg University, NCT Heidelberg, Heidelberg, Germany. (13) University of Liverpool & Clatterbridge Cancer Centre, Liverpool, UK. (14) Immunocore Ltd, Abingdon-on-Thames, UK. (15) Immunocore Ltd, Abingdon-on-Thames, UK. (16) Institut Catal d'Oncologia (ICO)-Cancer Immunotherapy Group at'Institut d'Investigaci Biomdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. (17) Immunocore Ltd, Rockville, MD, USA. (18) Immunocore Ltd, Abingdon-on-Thames, UK. adel.benlahrech@immunocore.com.
