Article Text

Download PDFPDF

1173 ST101, a peptide antagonist of novel I/O target CEBPβ, reprograms MDSC polarization and decreases tumor-associated Tregs, suggesting an immune component to observed clinical responses
  1. Claudio Scuoppo1,
  2. Gerald Falchook2,
  3. Elisa Fontana2,
  4. Anja Williams2,
  5. Nehal Lakhani3,
  6. Jeff Evans4,
  7. Fabio Iwamoto5,
  8. Meredith McKean2,
  9. Stefan Symeonides6,
  10. Alistair McLaren4,
  11. Jason Henry2,
  12. Gina Capiaux1,
  13. Robert Michel7,
  14. Stephen Kaesshaefer7,
  15. Alice Bexon1 and
  16. Jim Rotolo1
  1. 1Sapience Therapeutics, Harrison, NY, USA
  2. 2Sarah Cannon Research Institute, Denver, CO, USA
  3. 3START MIdwest, Grand Rapids, MI, USA
  4. 4University of Glasgow, Glasgow, UK
  5. 5Columbia University, New York, NY, USA
  6. 6University of Edinburgh, Edinburgh, UK
  7. 7Bexon Clinical Consulting, LLC, Montclair, NJ, USA


Background CCAAT/Enhancer Binding Protein β (C/EBPβ) is a basic leucine zipper (bZIP) transcription factor that causes aberrant gene activation in many cancers. Upregulated or overactivated C/EBPβ drives oncogenesis by promoting tumor survival and proliferation1 and is a critical regulator of the immunosuppressive environment.2 Specifically, C/EBPβ regulates macrophage differentiation, promoting the expression of M2 myeloid-derived suppressor cells (MDSCs) that contribute to suppression of antitumor immunity and correlate with poor prognosis.3 Reprogramming tumor-associated macrophages (TAMs) from M2 to M1 phenotype represents a potential strategy to enhance antitumor immunity. ST101 is a novel peptide antagonist that prevents C/EBPβ dimerization and inhibits C/EBPβ-dependent gene expression. Confirmed responses in melanoma and other tumors prompted evaluation of ST101 impact on macrophage differentiation.

Methods Primary human macrophages were cultured from peripheral blood mononuclear cells (hPBMCs) and activated toward the M1 or M2 phenotype by LPS and IFNγ (M1) or IL-4 (M2), respectively, in the presence of ST101. Macrophage M1 (CD80, CD86) and M2 (CD163, CD206) expression were analyzed by flow cytometry and rtPCR. Paired biopsy tissue from the ST101 Phase 1-2 clinical study in patients with advanced unresectable and metastatic solid tumors were collected during screening (prior to ST101 exposure) and within 24 hrs of ST101 administration during cycle 2 of therapy. Nanostring gene expression analysis was peformed to determine differential gene expression and the impact of ST101 on the tumor microenvironment.

Results Treatment with pharmacologically relevant concentrations of ST101 (2.5, 5 or 10 µM) resulted in dose-dependent reduction in M2+ macrophage and corresponding induction of M1+ macrophage. At the highest ST101 concentration, a 12-fold reduction in the M2 to M1 ratio was observed without substantial impact on cell viability. Paired patient biopsy tissue from the ST101 Phase 1-2 clinical study indicates a decrease in C/EBPβ target gene IL-6 signaling, an important driver of the M2 macrophage phenotype. Decreased IL-6 signaling resulted in an increase in the tumor-infiltrating macrophage vs. tumor-infiltrating lymphocyte (TIL) ratio, and a decrease in the regulatory T cell (Treg) vs. TIL ratio in tumor samples of treated patients.

Conclusions Overall, these results validate the potential of ST101 in reprogramming M2 macrophages to M1, support a novel, macrophage-driven mechanism of action for ST101 as an anticancer agent and support future exploration of ST101 in immune-oncology therapeutic strategies.

Trial Registration ClinicalTrials. gov Identifier: NCT04478279


  1. Homma J, Yamanaka R, Yajima N, Tsuchiya N, Genkai N, Sano M, Tanaka R. Increased expression of CCAAT/enhancer binding protein ß correlates with prognosis in glioma patients. Oncology Reports 2005;15:595–601.

  2. Ruffell D, Mourkioti F, Gambardella A, Kirstetter P, Lopez RG, Rosenthal N, Nerlov C. A CREB-C/EBPß cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair. PNAS 2009;106:17475–17480.

  3. Marigo I, Bosio E, Solito S, Mesa C, Fenandez A, Dolcetti L, Ugel S, Sonda N, Bicciato S, Falisi E, Calabrese F, Basso G, Zanovello P, Cozzi E, Mandruzzato S, Bronte V. Tumor-induced tolerance and immune suppression depend on the C/EBPß transcription factor. Immunity. 2010;32:790–802.

Ethics Approval ST101 study sites all have obtained ethics approval prior to study start. All participants gave consent prior to starting the study. Advarra’s IRB Organization (IORG) Number is 0000635; Columbia University Medical Center Institutional Review Board FWA# 00002636; North East – Newcastle & North Tyneside 1 Research Ethics Committee DUKE UNIVERSITY HEALTH SYSTEM Institutional Review Board for Clinical Investigations.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.