Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘STING’

Can STING (stimulator of interferon genes) agonists promote cancer metastasis in some patients?

That’s the intriguing question posed by research published recently in the journal Nature by Dr Samuel Bakhoum @Samuel_Bakhoum and colleagues. (doi:10.1038/nature25432who found that, “chromosomal unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.”

Samuel F. Bakhoum, MD PhD is a Holman research fellow at Weill Cornell Medicine and a senior resident in radiation oncology at Memorial Sloan Kettering Cancer Center in New York. The joint first author of the Nature article is Bryan Ngo, a student in the Weill Cornell Graduate School of Medical Sciences. It’s impressive work from two early career researchers.

The paper raises several important questions that drug developers – several of whom already have STING agonists in the clinic – may need to carefully think about.  It is, however, important to point out that this data is preclinical, so we don’t yet know what may or may not happen in cancer patients.

We first heard about the data published in Bakhoum, Ngo et al’s Nature article, “Chromosomal instability drives metastasis through a cytosolic DNA response,” at last October’s excellent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Philadelphia.

What we learnt at #Targets17 was that chromosomal instability is linked to tumour metastasis through the STING pathway.

Readers of BSB will know that we’ve been covering activation of innate immunity through the STING pathway for several years now (See posts:What we learnt at AACR about Aduro ADU-S100” and “Tom Gajewski takes the STING out of Cancer,” to name but a few.

So how do we reconcile the positive and encouraging data that has led to development of multiple STING agonists, several of which are now in the clinic, with the potential that there might be a harmful aspect to them?

There are some important subtleties and nuances around this critical issue and that is the essence of this post and what we sought to gain more insight into, beyond the obvious superficial answer that there could be harmful effects involved.

The Roman god Janus is depicted as having two faces – one looking to the future and the other to the past.

There are also two faces to cancer immunotherapy: It can be a force for good, we can harness our immune system in a way that results in a positive outcome – people with cancer live longer, some are even cured.  Alternatively, if we harness the immune system in a negative way it can also be a force for harm. 

We heard on the recent Novel Targets Podcast episode that while combination cancer immunotherapies can be effective in a subset of people, they can also lead to rip-roaring toxicities as well as unwanted auto-immune side effects, and in some cases, these can be fatal.  With multiple inhibitory and activating forces at place, cancer immunotherapy can tread a fine line balancing these out.

Dr Bakhoum kindly spoke to BSB about the translational and clinical implications of this latest research.

Given the potential impact of this research, we also sought additional commentary from experts active in STING research such as Jason Luke, MD FACP (@JasonLukeMD). He’s an Assistant Professor in the Department of Medicine at the University of Chicago and a Principal Investigator for early immunotherapy trials, including those with STING agonists.

BSB readers may recall we did an in-depth interview with him at AACR17 (See post: Overcoming Immunotherapy Resistance). This time around, he shared his perspective on Dr Bakhoum’s research and looked at the potential clinical implications.

Like Janus, does the STING pathway really have two faces to it?

Should companies with STING agonists be concerned or not?

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Suburban Station, Philadelphia

Philadelphia – the second day of the AACR-NCI-EORTC molecular targets and cancer therapeutics meeting brought some new data to ponder.

I have to say it’s been the best molecular targets I’ve been to in may ways since 2009.

There were quite a few interesting elements here that cropped up during the day, which are well worth discussing and considering further implications.

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At the recent annual meeting of the American Association for Cancer Research (AACR), one controversial area that arose was centred around targeting OX40, a stimulatory checkpoint. We’ve written extensively about anti-OX40 checkpoint agonists on the blog in the past.

Targeting OX40 is an area of interest to several companies looking to improve the effectiveness of checkpoint inhibitors. As a result, several companies have OX40 agonists in development, including AstraZeneca/MedImmune, Roche/Genentech, Pfizer, GSK and Incyte/Agenus, for example, making it a competitive target and interesting race to market.

Meanwhile, in their recent 1Q earnings call, Roche announced that they expect to present clinical data on their PD-L1/OX40 combination at the forthcoming American Society of Clinical Oncology (ASCO) annual meeting in Chicago from June 4th to 7th. This therefore makes it a timely moment to reflect on the data generated so far and what we can expect next month.

In New Orleans, we spoke to several researchers who are active in the OX40 field, since there were both mouse and human data presented at this year’s conference.

The interviews conducted were wide-ranging and informative, so in our latest mini-series we explore Part 1 today with Part 2 tomorrow.  They are relaxed fireside chats with different experts included in each to discuss their data (and other relevant topics) presented in New Orleans.

This way, you’ll be able to follow along and find out where the common areas are, as well as the differences in perspectives, and even where we could be headed in the near future.

This latest series on OX40 agonists raises many intriguing questions that we hope may be answered at ASCO and other clinical meetings going forward. We also discuss the challenges and opportunities associated with research into cancer immunotherapy combinations.

Dr Bernard Fox at #AACR16

Dr Bernard Fox at #AACR16

Intriguing preclinical data in mice models were presented by Dr David Messenheimer (Portland). We spoke with the senior author of that abstract, Dr Bernard Fox.

He is the Harder Family Chair for Cancer Research and Chief of the Laboratory of Molecular and Tumour Immunology at the Earle A. Chiles Research Institute in Portland, Oregon, and a leading cancer immunotherapy expert. He’s also the CEO of UbiVac, a biotech spin-off from Chiles in 2005 to develop therapeutic vaccines for cancer and infectious diseases.

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Some really intriguing news was announced this morning, with Aduro Biotech issuing a press release on their new global collaboration with Novartis for their “immuno-oncology products derived from its proprietary STING-targeted CDN platform technology.”

Many readers will recall Aduro for its program that inserts genetically engineered lysteria into therapeutics aka the LADD regimen. The lead program, CRS–207, in combination with GVAX Pancreas in pancreatic cancer previously received Breakthrough Therapy designation from the FDA. Their scientific advisers include Drew Pardoll and Frank McCormick, who are immunotherapy and protein pathway specialists, respectively.

The collaboration with Novartis is for a completely different platform based on cyclic dinucleotides (CDNs), which are small molecules that are naturally expressed by bacteria and immune cells and have been recently shown to activate the STING (Stimulator of Interferon Genes) signaling pathway in immune cells.

So what’s the significance of this exciting deal and why does it matter?

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