2238P - Tebentafusp reprograms immunosuppressive tumor-associated M2 macrophages towards anti-tumoral M1 macrophages

Background

Tebentafusp, a gp100-directed ImmTAC bispecific (gp100 x CD3), is the first TCR therapeutic to demonstrate survival benefit and is approved for the treatment of HLA-A*02:01+ adults with unresectable or metastatic uveal melanoma (mUM)¹. High CD3⁺ T cell: CD163⁺ M2 macrophage ratio was associated with therapeutic benefit from tebentafusp despite the immunosuppressive effects of M2 macrophages². Here we explored the effects of ImmTAC-redirected T cell activation on macrophage reprogramming in vitro and in vivo.

Methods

M2 macrophages were generated in vitro from healthy donor monocytes (n=4). Their effect on ImmTAC-mediated T cell activation and redirection against antigen positive HLA-A*02:01+ THP-1 tumor cells was assessed. Gene expression and phenotypic changes were assessed by bulk RNA-seq and flow cytometry. Baseline and on-treatment tumor biopsies from a phase II trial of mUM HLA-A*02:01+ patients treated with tebentafusp (NCT02570308) were used to quantify CD163⁺ and CD3⁺ cells by immunohistochemistry (n=112), and to measure gene expression by bulk RNAseq (n=35), and single cell RNAseq (n=1).

Results

In vitro, M2 macrophages inhibited ImmTAC-mediated T cell killing of tumor cells in a dose dependent manner. M2 macrophages were reprogrammed to downregulate M2 markers (e.g. CD206, CD163) and express M1 markers (e.g. CD40, CD80) in the presence of T cells activated by ImmTAC. This M2 to M1 reprogramming was confirmed by single cell RNAseq of paired biopsies from a tebentafusp-treated patient (55% increase in M1 macrophages 1 year post tebentafusp-treatment). M1 gene signatures³ were significantly upregulated in on-treatment biopsies (n=35) after 3 doses of tebentafusp (2.2 fold change).

Conclusions

ImmTAC-mediated redirection of T cells reprograms pro-tumoral M2 macrophages towards anti-tumoral M1 macrophages in vitro and in tebentafusp-treated mUM patients. These results demonstrate how tebentafusp re-shapes the tumor microenvironment to enhance the anti-tumor activity of T cells.

Clinical trial identification

1. Nathan et al. NEJM 2021 2. Piperno-Neumann et al. AACR 2022 3. Chen et al. Cell 2021.

Editorial acknowledgement

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd.

Disclosure

J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati. E. Guc, A. Treveil, A. Camera, J. Clubley S. Stanhope, L. Collins, K. Ranade, A. Benlahrech: Financial Interests, Personal, Full or part-time Employment: Immunocore Ltd.; Financial Interests, Personal, Stocks/Shares: Immunocore Ltd. H. Heyn: Other, co-founder and equity holder of Omniscope: Omniscope; Other, Advisory Board, Scientific Advisory Board member: MiRXES; Other, Consultant: Moderna. All other authors have declared no conflicts of interest.