AACR 2021 | First-in-human trial of intratumoral injection of SYNB1891

This is actually very exciting and interesting study. It is a very novel concept and obviously, SYNB1891 is technically a STING agonist, and you might say there are many STING agonists which are currently in the clinical development. But, I think this one is a type of compound, which really stands out because SYNB1891 is not just a SITNG agonist but, in fact it’s actually bacterium. It’s a probiotic E. coli Nissle, which is a probiotic, presumably harmless bacteria to a human, which is engineered to produce cyclic di-AMP, to simulate STING pathway. And, arguably because, I mean, obviously once the SYNB1891 is injected it stimulates distinct pathway, but arguably it might also actually stimulate some other pathway, innate pathways, which would be inherent to the fact that there is a present bacteria. So, presumably, it might also activate some other components of the innate immunities, such as TLR4 and similar, just because of the fact that there is actually bacterial chassis, which is present in the tumor microenvironment.

So, this one is actually the first-in-human study, which enrolls all solid cancers, including lymphomas and the drug is given intra-tumorally.

People might say it’s somewhat complicated approach, but it’s becoming relatively frequent for therapies using innate immunity and I think the logistics seems to be well worked out and it can be injected through superficial lesions but, I think it’s also important to know that we have tested injection of paremchymal lesions such as liver and so far it appears to be safe. The efficacy doesn’t seem to be compromised.

So, we do test SYNB1891 in 2 cohorts which are kind of open than some called kind of a bifurcation type of design, innovatory. Initially started with monotherapy and after clearing several doses, we allowed the dose escalation for combination, which includes atezolizumab as a PD-L1 antibody, as that immune checkpoint inhibitor backbone.

We have, to date, administered 59 intra-tumoral. It’s not actually to date, it’s to the date of analysis, 59 intra-tumoral doses and so far the experience has been positive.

We didn’t have any the dose limiting toxicities. We have seen, and I will talk about it in a minute, we have seen some symptoms that should be potentially associated with cytokine release syndrome. Which, however, are manageable and as of March 15, we have treated 22 patients in the, in the sites in the United States and monotherapy and combination therapy are both enrolling in the moment. We enrolled diverse tumor type population, which included cold tumors, as well as whole tumors or immune sensitive tumors, if you will, from melanomas to sarcoma, some other carcinomas, such as esophageal or colon, lung cancer. That would be small cell, small cell lung cancer and basal cell cancer and variety of other cancers.

I said that we’ve seen some cytokine release syndrome. So, I mean we’ve actually had 2 events, both results in one day. As far as the injection site reactions, not much, but we had one injection site reaction which was at erythema.

We obviously monitored, also, the presence of the bacteria in the blood and we don’t seem to be finding any. So, it looks like the, once you administer the medication, that there is not any leak into a systemic circulation.

What I’m presenting at the AACR are data on single-agent and it actually was quite exciting. So, we have 11 patients presented and it was actually quite exciting that even from the low dose levels. We actually, I’ve seen in some of them activate a better RECIST, which doesn’t necessarily include only the injected lesion because, so.

To our best patients are patients who have prolonged stable disease, with noticeable tumor shrinkage. One of them was a patient with vulvar melanoma, who had prior nivolumab, which is a PD1 antibody who actually attained stable disease, but minus 28% shrinkage per RECIST 1.1, which was actually very close to PR and that was maintained for prolonged period of time.

The patient ultimately started to lose response after more than 200 days and came off therapy after more than 250 days. The second patient had a little bit more modest shrinkage, but still about 20% reduction in tumor size is just single-agent bacteria. And, that was a patient with a small-cell lung cancer and that patient actually continues on therapy for close to 300 days at the moment.

This program also has quite a heavy translational component. I mean, at the moment we have relatively limited data which I was able to present at AACR and that actually includes the serum cytokines for the monotherapy cohorts that you do see increase in IL6 and other cytokines such as the TNFa, interferon gamma. Which seems to be the dose, for dose proportional, to some extent. Also, we have data on tumor cytokines and other immune, immune factors.

So, we do see up regulation interference to the stimulated genes and in the certain chemokines, as well as in certain T-cell mark, T-cell markers, such as granzyme A and the others.

We also present multiplexed immunofluorescent staining from the tumor biopsies for the presence of T-cells and the data are actually quite interesting because, we present 2 tumors which will be be considered to be immune sensitive or warm. If you will, which is vulvar melanoma and small-cell lung cancer and then side-by-side we present tumors, which are assumed to be cold, such as liposarcoma and chondrosarcoma and the change in the T-cell infiltration for both CD8 cells, as well as CD4 cells is actually distinctly different for these tumor population. We do see increase in bone tumors, such as vulvar melanoma and small cell lung cancer, but we see, we see nearly nothing for liposarcoma and chondrosarcoma.

We also actually look at the nanostring data for the expression of certain markers of interests which obviously includes interferon stimulated genes, cytokine, chemokine, some T-cell function factors. And, when we look at the vulvar melanoma who had shrinkage of minus 28%, I have to point out that this patient was treated on the lower dose level. I mean, we do see increase in STING pathway engagement reflected by increase in interference stimulated genes. You do see some upregulation, certain cytokines and chemokines, but relatively small changes in T-cell compartment. Ehen you look at a patient who was on the higher dose level, the patient with small-cell lung cancer who had about 12% reduction in that patient. We see actually a little bit more increase in pretty much all factors, including interferon stimulated genes, chemokines as well as the T-cell compartment. These are early data, but the compound seems to be safe. This side effect profile, which you would expect for this class of medication, but so far the AE’s such as mild forms of cytokine release syndrome or a injection site reaction appear to be manageable. We do see early evidence for target engagement and some early evidence for possible early signals of activity but, the study continues for both, for monotherapy and combination.