Direct activation of STING in the tumour microenvironment leads to potent and systemic tumour regression and immunity
Dr Thomas Dubensky - Aduro Biotech, Berkley, USA
What brings me to this meeting is that we recently announced that we just received FDA clearance to use our small molecule known as ADUS100, which is a synthetic cyclic dinucleotide which binds to inactivate STING. In particular STING itself has, in humans, just five different alleles and we showed and published last summer in Cell Reports that that particular synthetic STING agonist that we developed activates all known human STING alleles and that was in combination with showing a very potent activity in aggressive mouse models of cancer. We could show by local activation of STING within the tumour microenvironment led to development of a T-cell response that was systemically effective.
Are there currently any phase II trials in progress?
What we will be discussing on Wednesday really will be first in human clinical trials to target STING and so that will be the inaugural clinical study targeting the STING pathway.
Could you tell us about your phase I clinical trial?
This programme has been partnered with Novartis which has an exclusive license to all oncology for STING agonists. The phase I clinical trial will be one of the reasons we wanted to partner with pharma, it will be a very large phase I study. It will be a two-part clinical study which in the first part will be in about 25 patients, just a typical dose escalation study to define the therapeutic index. What we found, and I’ll be talking about this on Wednesday, is not surprisingly for an agonist that activates the innate immunity, we see a bell-shaped dose response curve defined by lower doses or you see no activities over what we think is a fairly broad therapeutic index we see a combination of both local activation of innate immunity and priming of T-cells that are systemically effective. Then at too high dose levels, as you would expect, you can induce a cytokine storm that is easy to detect as it’s happening but it’s dose dependent and that defines the bell shaped dose curve. That will be the first part of the clinical study is to define what that therapeutic index is.
What’s really interesting about this programme is that I’m sure you are very familiar with the terminology hot versus cold tumours and why is it that some tumours have a high degree of infiltration. What’s been shown, at least in the melanoma setting, that’s due to the tumour resident phagocytes like macrophages and dendritic cells have an interferon beta transcriptional profile that turns out to be STING dependent. So really in the second part of this phase I study we’ll be segregated into two different patient cohorts, each of which have fifty subjects and they’ll be in both UV induced and non-UV induced tumours. So UV induced tumours like Merkel cell, melanoma, squamous cell cancer of the skin, and then non-UV induced tumours like breast, like for example lymphoma, which is another target that we’ll be evaluating in this phase I. Through heavy biomarker analysis we’ll be able to ask the question in the setting of UV-induced tumours like melanoma do we, for example, induce a higher degree of infiltration or, more importantly, convert a non-inflamed to a T-cell inflamed microenvironment, anticipating that those patients will give a higher response rate than the current 50% or so that’s observed with immune checkpoint inhibitors. But, from our perspective, it’s also very interesting as beyond non-small cell lung, MSI high, colorectal cancer, melanoma, those are all indications where immune checkpoints can work as a single agent; in other malignancies with lower mutational burdens you don’t see that. So what’s really exciting about this study we’ll begin to ask if by activating the STING pathway will this be an opportunity to convert a non-inflamed tumour microenvironment to an inflamed one and that will presumably make those patients more responsive to immune checkpoint inhibitors.
What is your take-home message?
We were very early into the STING pathway and it was actually, I won’t go into it, a derivative from our other programmes and we were able to get a very early insight why it was such a significant and central node of innate immunity in the setting of cancer which is absolutely linked to the development of tumour specific immunity. One of the more powerful aspects of this approach is that we’re using a small molecule via activating what’s the central node of innate immunity to develop a T-cell response that will be unique between different individuals because we all have unique immune systems. So this is, we think, a very powerful way to use a small molecule for patient-specific medicine since we’re ostensibly developing T-cells that are unique to a person’s unique antigen repertoire. So down the road you can imagine other formulations, other approaches to deliver these compounds systemically. Initially we’ll be delivering them to cutaneously accessible lesions, ultimately and very early we will be asking whether we can give the STING agonists into tumour bearing visceral organs, for example lung and liver and many others. The other interest we have in this pathway, actually, is that chronic expression of STING is implicated in a number of autoimmune diseases so the company has a very active programme in developing antagonists against the STING pathway.
We have essentially everything under a single umbrella, ways to activate the innate immune system with our STING agonists, with our recombinant listeria platform, we can broadly express tumour antigens that are relevant to any given indication. We have partnerships, for example, with Janssen in addition to our own programmes and then, of course, with the antibodies we can modulate those responses. We all know that immune checkpoint inhibitors are the foundation now of cancer immunotherapy but again what’s clear in many indications, that’s not significant or not sufficient as a single agent. So there’s an absolute requirement for modifying the tumour microenvironment in addition.