New BGB324 study points to novel mechanism to enhance immunotherapy efficacy
Bergen, Norway, September 25, 2016 – Leading oncology biopharmaceutical company BerGenBio AS, today released important new preclinical study data on its first-in-class AXL inhibitor, BGB324. The study showed AXL to be a key factor in tumour resistance to the emerging class of new immune checkpoint inhibitors that can be targeted through combination therapy with BGB324. The study data was presented in a poster today at CRI-CIMT-EATI-AACR – The 2nd International Cancer Immunotherapy Conference, in New York.
The new study evaluated whether BGB324 used in combination with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) in mouse carcinoma models enhanced the effect of immune checkpoint blockade in aggressive adenocarcinomas displaying limited immunogenicity. BGB324 is a highly selective small molecule inhibitor of the AXL receptor tyrosine kinase. An important regulator of the tumour cell plasticity related to EMT (Epithelial-to-Mesenchymal Transition), AXL signalling is also a key suppressor of the innate anti-tumour immune response. Thus Axl contributes uniquely to both tumour intrinsic and extrinsic mechanisms that suppress anti-tumour immunity. The new study shows that AXL was induced in tumours by immune checkpoint inhibitor treatment and postulated that this could limit their efficacy.
The poster was entitled “BGB324, a selective small molecule inhibitor of AXL receptor tyrosine kinase, enhances immune checkpoint inhibitor efficacy”, and presented in Poster Session B on September 26. In the study, immune therapy with anti-PD-1/anti-PD-L1 or anti-CTLA-4/anti-PD-1 increased AXL and EMT-marker expression in the murine lung cancer (Lewis lung, LL2) and mammary adenocarcinoma (4T1) syngeneic models, and correlated with a lack of response to immune checkpoint therapy. However, combination treatment with BGB324 significantly enhanced durable responsiveness to anti-PD-1/anti-PD-L1 or anti-CTLA-4/anti-PD-1 treatment in mice bearing established LL2 or 4T1 tumors. BGB324 in combination with anti-PD1/PDL1 increases the number of tumor infiltrating cytotoxic T-lymphocytes, natural killer (NK) and NKT cells and decreases levels of myeloid derived suppressor cells (mMDSCs) in the Lewis Lung cancer model.
Studies with human non-small cell lung cancer (NSCLC) indicated that BGB324 blocks a critical protective mechanism used by cancer cells to avoid destruction by effector immune cells. Targeting this mechanism resulted in a highly immunogenic cell death and increased cytotoxicity by human NK cells. Further, BGB324 blocked tumour suppressive (M2) polarization of primary human macrophages in vitro. BGB324 treatment in combination with PD-1 pathway inhibition reduced mouse lung tumor expression of the key macrophage stimulating cytokine CSF-1, emphasizing how Axl targeting abrogates anti-tumour immune suppressive macrophage action.
BGB324 is the only selective AXL inhibitor currently in clinical development. Phase Ib clinical trials are underway as single agent and in combination with standard of care drug (cytarabine) in acute myeloid leukaemia (AML), and in combination with erlotinib in non-small cell lung cancer (NSCLC).
Richard Godfrey, Chief Executive Officer of BerGenBio, commented -We believe this strong new preclinical data clearly demonstrates the rationale for combining BGB324 with immune checkpoint inhibitors to treat aggressive cancers. This study shows that these inhibitors actually increase AXL expression that supports immune evasion. Treatment with BGB2324 counters this, increasing tumor immunogenicity and promoting the anti-tumour response. In addition to the ongoing development of BGB324 in AML and NSCLC, this data suggests that BGB324 could also be used in combination with cancer immunotherapeutic agents to enhance their efficiency.
BGB324 is a first-in-class, highly selective small molecule inhibitor of the Axl receptor tyrosine kinase. It blocks the epithelial-mesenchymal transition (EMT), which is a key driver in immune evasion, drug-resistance and metastasis.
About BerGenBio AS
BerGenBio AS is a clinical stage biopharmaceutical company focused on developing first-in-class drugs for aggressive cancers. The company is a world leader in understanding the biology of epithelial-mesenchymal transition (EMT), a widely recognised key pathway in immune evasion, acquired cancer drug-resistance and metastasis. BerGenBio AS is founded on proprietary platform technology, CellSelect™, to identify and validate novel drug targets and biomarkers. The company has progressed its lead drug candidate BGB324, an EMT inhibitor, into clinical trials in AML and NSCLC, while pursuing the pre-clinical development of additional compounds and proprietary EMT drug targets.