Current Advances

New Data Suggest Inhibition of STAT3 with ISIS-STAT3-2.5Rx May Promote Immune Activation Against Tumor Cells

Data on ISIS-STAT3-2.5Rx presented by AstraZeneca scientists at the 2015 American Association for Cancer Research Annual Meeting

At the 2015 American Association for Cancer Research Annual Meeting held in Philadelphia, PA, Dr. Patricia McCoon, a researcher from AstraZeneca, presented clinical and pre-clinical data on ISIS-STAT3-2.5Rx. In an oral presentation titled, “Clinical and Preclinical Evidence of Immune Modulating Role for the STAT3-targeting ASO AZD9150 and Potential to Enhance Clinical Responses to Anti-PDL1 Therapy,” results from two separate clinical studies of ISIS-STAT3-2.5Rx (also referred to as AZD9150) were presented, one study was in patients with diffuse large B cell lymphoma (DLBCL) and the other was in patients with advanced/metastatic hepatocellular carcinoma (HCC). Results from these studies showed:

  • Durable clinical responses were observed in both patient groups treated with ISIS-STAT3-2.5Rx.
  • In patients treated with ISIS-STAT3-2.5Rx, levels of STAT3 were reduced in multiple cell types relevant to cancer growth and survival, including stroma cells, myeloids cells and leukocytes.
  • An analysis of clinical biomarker data suggested that the antitumor activity of ISIS-STAT3-2.5Rx observed in these studies is at least partly achieved through a well-known role of STAT3 in immune cells, where inhibition of STAT3 reactivates a patient’s own immune system to attack cancer cells.
  • Consistent with this mechanism, preclinical studies in animal models of cancer showed that co-treatment of ISIS-STAT3-2.5Rx and MEDI4736, an antibody immune checkpoint inhibitor, resulted in significantly greater antitumor activity than when either drug was administered alone.

These data support AstraZeneca’s plan to broaden its evaluation of ISIS-STAT3-2.5Rx to include combination therapy with MEDI4726. Later this year, AstraZeneca plans to initiate two separate Phase 1/2 clinical studies evaluating the combination of ISIS-STAT3-2.5Rx and MEDI4736 in cancer patients. The first study will be conducted in patients with head and neck squamous cell carcinoma and the second study will be conducted in patients with DLBCL.

About ISIS-STAT3-2.5Rx
ISIS-STAT3-2.5Rx is a generation 2.5 antisense drug designed to reduce the production of signal transducer and activator of transcription 3, or STAT3, for the treatment of patients with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma. Over activity in STAT3 is believed to prevent cell death and promote tumor cell growth.

In 2012, we licensed ISIS-STAT3-2.5Rx to AstraZeneca as a part of our collaboration to discover and develop anti-cancer drugs. ISIS-STAT3-2.5Rx is our first drug to incorporate our new generation 2.5 chemistry. We believe the significant potency we observed in our preclinical studies with ISIS-STAT3-2.5Rx broadens the therapeutic opportunities for ISIS-STAT3-2.5Rx into many different types of cancer where STAT3 is implicated. We are conducting a Phase 2 study in patients with advanced lymphoma and AstraZeneca is conducting a Phase 1/2 study in patients with metastatic HCC.

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