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Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

1281 - OT-1096, a first-in-class immunoactivating small molecule that targets the thioredoxin reductase/thioredoxin axis causes strong tumor growth inhibition by downregulating intratumoral Tregs in a humanized TNBC-PDX model.

Date

22 Oct 2018

Session

Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

Topics

Clinical Research

Tumour Site

Breast Cancer

Presenters

Owe Orwar

Citation

Annals of Oncology (2018) 29 (suppl_8): viii133-viii148. 10.1093/annonc/mdy279

Authors

O. Orwar, I. Lowstedt, K. Andersson, G. Gannedahl, G. Willman, M. Davidsson, W. Stafford, C. Trkulja

Author affiliations

  • N/a, Oblique Therapeutics AB, 413 46 - Gothenburg/SE
More

Resources

Abstract 1281

Background

Triple-negative breast cancer is an aggressive subtype associated with poor prognosis and limited treatment options, and new effective medicines are needed. We have developed a novel class of SecTRAP- forming small molecules that lead to a change-of-function of thioredoxin reductase that is cytotoxic to cancer cells (Staffort et al. Sci Transl Med, 2018). However, the immunomodulatory effects of OT-1096 are unknown. This study examined the efficacy of OT-1096 in humanized CD34+ NSG mice bearing patient-derived TNBC xenografts and compared the efficacy of OT-1096 to pembrolizumab. Additionally, the immunoactivating effects of OT-1096 were analyzed.

Methods

NSG mice, humanized with CD34+ stem cells from 3 different human donors were engrafted with TNBC invasive ductal carcinoma patient-derived xenografts. The mice were treated with OT-1096 (10mg/kg IV) tiwk and was compared to treatment with pembrolizumab (10mg/kg initial dose, thereafter 5mg/kg IP) biwk, single agent and in combination with OT-1096. Tumor volume was measured using calipers for 31 days and xenografts were analyzed with FACS to determine immune cell infiltration at day 41(sacrifice).

Results

OT-1096 showed statistically significant tumor growth inhibition (TGI: 63%) when comparing treatments arms with all three donors combined. OT-1096 also presented improved tumor growth control compared to pembrolizumab. FACs analysis of xenografts showed OT-1096-treated tumors to have a lower fraction of Tregs within the TIL population as compared to controls. OT-1096 treatment was both safe and well tolerated.

Conclusions

OT-1096 shows promising results in a humanized mouse TNBC PDX model with improved tumor growth inhibition compared to pembrolizumab. The results suggest that OT-1096 possesses both redox system modulation and beneficial immunomodulatory potential, and warrants further investigations of OT-1096 in TNBC and other malignancies.

Clinical trial identification

Legal entity responsible for the study

Oblique Therapeutics AB.

Funding

Oblique Therapeutics AB.

Editorial Acknowledgement

Disclosure

O. Orwar: Stock owner, board of directors, CEO: Oblique Therapeutics. I. Lowstedt, G. Willman, M. Davidsson: Full-time employee: Oblique Therapeutics. W. Stafford: Employee and shareholder: Oblique Therapeutics. C. Trkulja: Stock owner, board of directors, full-time employee: Oblique Therapeutics. All other authors have declared no conflicts of interest.

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