41P - Dynamics of the global tumor immunome upon treatment with a novel anti-HER2 anthracycline based antibody drug conjugate in breast cancer

Date 05 November 2016
Event ESMO Symposium on Immuno-Oncology 2016
Session Lunch and general poster viewing
Presenter Lucia D'Amico
Citation Annals of Oncology (2016) 27 (suppl_8): viii4-viii17. 10.1093/annonc/mdw527
Authors L. D'Amico1, U. Haessler2, U. Menzel2, M. Buchi1, N. Stefan3, R. Beerli3, U. Grawunder3, S. Reddy2, A. Zippelius1
  • 1Department Of Biomedicine, Universitätsspital Basel, 4031 Basel - Switzerland - Basel/CH
  • 2Department Of Biosystems Science & Engineering, ETH Zurich, Basel/CH
  • 3Technology Park Basel, Basel, NBE-Therapeutics Ltd, Basel/CH

Abstract

Aim/Background

About 20% of all breast cancer patients have a human epidermal growth factor receptor 2 (Her2)-positive breast tumor. Trastuzumab, the first anti-Her2 antibody, revolutionized the systemic therapy options. However, despite the improved outcome, 70% of all patients develop resistance in the metastatic setting. Therefore, refined approaches are warranted for the treatment of Her2-positive breast cancer. Our group has recently shown that the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) actively stimulates tumor specific immune response, which relies on the direct effect of the payload DM1 in promoting the maturation of dendritic cells. Here we propose a novel mechanism of action for a Her2-targeting antibody drug conjugated (ADC) bearing a potent anthracycline payload (Tras-PNU).

Methods

We established a murine breast cancer cell line expressing human Her2 (EMT6-hHer2 cells). Then, to analyze the effects of our ADC on tumor growth in vivo we injected 106 EMT6-Her2 cells orthotopically into the mammary fat pads of 8 week old Balb/c mice. Next, to further characterize the importance of T-cells for therapeutic efficacy of the ADC, we depleted CD8+ T cells with T cell-depleting antibodies. Finally, we performed gene expression analysis of purified CD45+ cells to comprehensively study the dynamics of the global immune landscape upon exposure to Tras-PNU.

Results

TRAS-PNU anti-tumor efficacy was compared to treatment with T-DM1, which is approved for HER2+refractory breast cancers. While tumors are resistant to T-DM1, Tras-PNU ADC treatment strongly reduces tumor growth. Furthermore, when we rechallenged the tumor free animals, no tumor growth was observed, supporting the development of an immunological memory formation. Thus, CD8+ T cell depletion severely reduces the anti-tumor activity of Tras-PNU, clearly suggesting an important role for T cells in driving anti-cancer activity. Strikingly, the analysis reveals that our signature is significantly enriched for genes involved in the regulation of anti-tumor immune response.

Conclusions

In summary, we provide a novel mechanism for a new ADC to overcome resistance in breast cancer by promoting long-term immune protection.

Clinical trial identification

NONE

Legal entity responsible for the study

Canton Veterinary Office

Funding

KLBB Basel grant

Disclosure

All authors have declared no conflicts of interest.