Sandra Cauwenberghs

Abstract 4863: PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors

Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase-1 (IDO-1) to induce an immunosuppressive microenvironment. IDO-1 expression is upregulated in many cancers and described to be a resistance mechanism to immune checkpoint therapies. IDO-1 is induced in response to inflammatory stimuli such as IFN-a and promotes immune tolerance through the catabolism of tryptophan and accumulation of tryptophan catabolites including kynurenine. IDO-1 activity leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3. As such, IDO1 is a nexus for the induction of key immunosuppressive mechanisms and represents an important immunotherapeutic target in oncology. We have identified and characterized a new IDO-1 inhibitor. PF-06840003 is a highly selective orally bioavailable IDO-1 inhibitor. PF-06840003 reversed IDO-1-induced T-cell anergy in vitro. In vivo, PF-06840003 reduced intratumoral kynurenine levels in mice by >80% and inhibited tumor growth in multiple preclinical syngeneic models in mice, in combination with immune checkpoint inhibitors. PF-0684003 has favorable predicted human pharmacokinetic properties, including a predicted t1/2 of 16-19 hours. These studies highlight the strong potential of PF-06840003 as a clinical candidate in Immuno-Oncology. Citation Format: Joseph Tumang, Bruno Gomes, Martin Wythes, Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Helene Cannelle, Sandra Cauwenberghs, Jenny Chaplin, Deepak Dalvie, Sofie Denies, Coraline De Maeseneire, Peter Folger, Kim Frederix, Jie Guo, James Hardwick, Ken Hook, Katti Jessen, Erick Kindt, Marie-Claire Letellier, Kai-Hsin Liao, Wenlin Li, Karen Maegley, Reece Marillier, Nichol Miller, Brion Murray, Romain Pirson, Julie Preillon, Virginie Rabolli, Chad Ray, Stephanie Scales, Jay Srirangam, Jim Solowiej, Nicole Streiner, Vince Torti, Konstantinos Tsaparikos, Paolo Vicini, Gregory Driessens, Manfred Kraus. PF-06840003: a highly selective IDO-1 inhibitor that shows good in vivo efficacy in combination with immune checkpoint inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4863.

Preclinical assessment of a novel small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1).

iTeos leverages the science of the LICR to target the metabolism of the tumor microenvironment and develops small-molecule inhibitors. Tryptophan catabolism can suppress the anti-tumor immune response through expression of the rate-limiting enzyme IDO1. Local tryptophan reduction and metabolite production by the kynurenine pathway are associated with anergy/apoptosis of tumor-infiltrating lymphocytes. Two IDO1 inhibitors (Incyte INCB24360/NewLink NLG919) are currently tested in clinical trials for treatment of relapsed/refractory solid tumors but exhibit therapeutic limitations.

Preclinical assessment of a novel small molecule inhibitor of tryptophan 2,3-dioxygenase 2 (TDO2)

iTeos leverages the science of LICR to target metabolism of the tumor microenvironment and develops small molecule immunomodulators. TDO2 is a heme-containing enzyme highly expressed in the liver, in specific brain regions and liver/brain tumors. It catalyses the first and rate-limiting step of tryptophan catabolism along the kynurenine pathway and thereby regulates systemic tryptophan levels. Tryptophan (Trp) degradation by TDO2 suppresses anti-tumor immune responses and promotes tumor cell survival.

Abstract B030: Development and validation of a phenotypic screening platform for the identification of novel immuno-oncology targets

iTeos Therapeutics developed a target discovery and drug repurposing platform based on phenotypic screening assays that mimic the immunosuppressive tumor microenvironment. Here, we present an immunosuppressive cell line/T cell co-culture assay that enables chemical and genomic screening. Multi-parameter readouts are combined to assess both T cell activity as well as tumor cell death. T cell activity is measured through high content imaging of cluster formation complemented with detection of INFγ secretion. Tumor cell death is assessed using a cytotoxicity assay. The current format of the assay (96-well) allows medium-throughput testing of up to 3,000 samples/screen. As proof-of-concept we evaluated the assay for its ability to detect metabolic immune-oncology targets like indoleamine-2,3-dioxygenase 1 (IDO1). IDO1 is expressed in a wide range of cancers and mediates local T cell suppression through depletion of the essential amino acid tryptophan. The assay conditions were validated with an IDO1 inhibitor as positive control and subsequently scaled up for automation. A commercially available small molecule library [Selleck Bioactive Compound Library (cat number L1700), 1902 compounds] with a high percentage of clinically tested drugs was screened. The library was tested at two different concentrations (0.3 μM and 3 μM), with two independent T cell donors and spiked with IDO1 inhibitors as internal control. The combined analysis of T-cell activity and tumor killing led to the identification of 42 compounds with activity on multiple, potential immune suppressive pathways, including metabolism, epigenetics, autophagy, and TGFβ signaling. This assay is also suitable for gene modulation strategy using shRNA or cDNA libraries enriched for genes expressed specifically in immune suppressive cells and tissues. Moreover the assay can be adapted to additional cell types such as MDSC or Treg, opening up opportunities for identification of novel immune suppressive targets. In conclusion, this approach allows rapid identification of mechanisms and targets contributing to tumor resistance. Phenotypic screens allow higher confidence in the selection of targets with a potential for clinical translation. [V.R., M.M., J.M.S., and S.C. contributed equally to this work.] Citation Format: Virginie Rabolli, Murielle Martini, Ariane Scoumanne, Marie-Claire Letellier, Stefano Crosignani, Christophe Queva, Michel Detheux, Jakub M. Swiercz, Sandra Cauwenberghs. Development and validation of a phenotypic screening platform for the identification of novel immuno-oncology targets [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B030.