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571 IL-2 combination with ImmTAC overcomes CD163+ TAM-like M2 macrophage inhibition of ImmTAC-mediated T cell killing of tumor cells
  1. Rahul Khanolkar,
  2. Revashnee Naidoo,
  3. Esra Güç,
  4. Emma Leach,
  5. Sarah Stanhope,
  6. Duncan Gascoyne,
  7. Laura Collins,
  8. Koustubh Ranade and
  9. Adel Benlahrech
  1. Immunocore, Abingdon, UK


Background ImmTAC molecules are bispecific fusion proteins consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target cells. Tebentafusp, a gp100-directed ImmTAC, has demonstrated survival benefit in metastatic uveal melanoma [1]. We previously reported that a tumor microenvironment with a high immunosuppressive CD163+ tumor-associated macrophage (TAM): CD3 T cell ratio was associated with reduced benefit from tebentafusp [2]. Here, we explored whether IL-2 could potentiate T cells to overcome inhibition of ImmTAC-mediated killing by TAM-like M2 macrophages.

Methods Tumor biopsies from a Phase 2 trial of metastatic uveal melanoma HLA-A*02:01+ patients treated with tebentafusp (NCT02570308) were used to quantify CD163+ TAMs and CD3+ T cells by immunohistochemistry (N=107) and to measure gene expression by bulk RNAseq (N=70). Pro-inflammatory M1 and TAM-like M2 macrophages were generated in vitro from healthy donors (N=5) and their effect on ImmTAC-mediated T cell activation and tumor killing was assessed against THP-1 tumor cells. T cells were untreated or pre-treated for 4 days with commercially sourced IL-2 or IL-15.

Results In vitro, ImmTAC-mediated T cell killing of tumor cells was reduced by 85±5% in the presence of TAM-like M2 but not M1 macrophages. Consistent with this finding, below median CD163:CD3 ratio was associated with greater tumor shrinkage (TS) (odds ratio OR=2.9, p=0.014) and longer overall survival (OS) (hazard ratio HR=0.4, p=0.001) in tebentafusp-treated patients. We next explored in vitro whether the T cell activating cytokines IL-2 and IL-15 could overcome TAM-mediated inhibition of T cell redirection by ImmTAC. At clinically relevant doses, IL-2 but not IL-15 treatment resulted in dose dependent restoration of ImmTAC-mediated T cell killing of tumor cells in the presence of TAM-like M2 macrophages—60% and 83% restoration of killing at 50 and 150 U/ml of IL-2, respectively. Consistent with this observation, increased expression of IL2RB (HR 0.3, p<0.001) and IL2RG (HR 0.4, p=0.002), but not IL2RA (HR 0.8, p=0.5) in tumors was associated with longer OS on tebentafusp.

Conclusions Low CD163+ TAM to CD3 T cell ratio and high IL2RB/G expression in tumors at baseline were associated with longer OS and greater TS in tebentafusp-treated metastatic uveal melanoma patients in a Phase 2 trial. In vitro, TAM-like M2 macrophages suppressed ImmTAC-mediated T cell killing of tumor cells, an effect abrogated by IL-2. These observations provide strong rationale for combining IL-2 biased to IL2RB/G with ImmTAC molecules to enhance benefit in tumors with high levels of TAMs.

Trial Registration NCT02570308


  1. Piperno-Neumann S, Hassel JC, Rutkowski P et al. Abstract CT002: Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Cancer Res. 2021; 81 (13 Supplement) CT002.

  2. Hassel JC, Benlahrech A, Stanhope S, et al. Abstract 1673: Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp. Cancer Res. 2021; 81 (13 Supplement) 1673.

Ethics Approval The Oxford A REC approved protocol 13/SC/0226 was used to obtain written consent for all blood donations and was fully approved by the National Research Ethics Committee South Central.

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