At AACR 2023 we presented the first in human results for a quite novel molecule called E-602 which is a first in human bi-sialidase approach to try to treat cancer.
In the GLIMMER-01 study we evaluated E-602 as a bi-sialidase approach for cancer immunotherapy. It’s important to take a step back and describe what is this field, because it’s relatively new. So, siglecs are a large family of sialoglycan-sensing ITIM-containing checkpoint receptors. We sometimes call them glycoimmune checkpoints. There are 14 different siglecs but nine of them have a similar ITIM domain to the PD-1 receptor. When we look at the downstream signalling from there we actually see very similar to that which is already known to drive immune responses in cancer. These sialoglycans which bind the siglec receptors have been known to be associated with bad outcomes in cancer for many decades but it wasn’t until very recently with the work of Dr Carolyn Bertozzi, who won the Nobel Prize last year for chemistry, that we were actually able to find a mechanistic association between these siglecs and bad outcomes.
Siglecs bind to sialic acid residues which are covering immune cells and the tumour cells in the tumour microenvironment and there’s quite a degree of redundancy. This was the rationale for development of the bi-sialidase approach, essentially to try to reduce the amount of sialic acid exposed on the cancer cell surface and around the T-cells in hopes that that might trigger anti-tumour immunity.
What was the study design?
The GLIMMER-01 study was the dose escalation portion investigating the bi-sialidase E-602. In the clinical trial we dose escalated this first in human molecule from 1mg/kg up through 30mg/kg. We managed the side effect profile, which was actually quite easy to manage, there were very few grade 3 and 4 events. There were no dose limiting toxicities and we saw pharmacodynamic effects that suggested that we were having the kind of immune responses that we were looking for.
What were the results?
In our dose escalation study we demonstrated the safety of E-602 up to 30mg/kg with a manageable safety profile that was mostly characterised by infusion reactions at the higher doses. We were able to mitigate these without major issue, however. The drug is given on a weekly basis and essentially what we were able to show in this study was that the drug is safe. We look forward to the subsequent study looking at monotherapy activity in defined cohorts of patients, specifically in melanoma and non-small cell lung cancer. Subsequent to that, there will be a combination dosing regimen with anti-PD-1.
Very importantly, we were able to show dose proportional pharmacokinetic properties to E-602 and in the peripheral blood we were able to demonstrate on-target desialation of immune cells that led to activation in the CD8 as well as CD4 and NK cell compartments as well as elaboration of peripheral blood cytokines that were consistent with the kind of immune response that we see with other immune checkpoint inhibitor approaches, so IP-10, TNF-α and MIP-1β all went up, notably, with the rise, consistent with that that we see in the treatment naïve setting for nivolumab plus ipilimumab in melanoma.
Overall, a safety profile that was advantageous and peripheral blood immune monitoring that suggested potential activity when moved in the right population of patients.
How do you think these results can impact future research and treatment?
This study is obviously a phase I safety finding study for this novel molecule. So this study is quite important because this is the first time in human beings with cancer that we have attempted desialation as a therapeutic approach in cancer. So we showed that that is safe to administer and in this population of heavily pre-treated patients we were able to show peripheral blood activation of immune cells that was consistent with what was seen in the preclinical models.
All of that is very exciting, given this new class of agent, so surely then to try to look at what kind of activity can we see in a population of patients who are more likely to benefit from immuno-oncology approaches i.e., melanoma and non-small cell lung cancer. So this is really a new area of biology and cancer research and it’s very exciting to see that on our first pass we are getting the early signs suggestive that we’re impacting the science and biology in a way that might be meaningful for subsequent clinical trials.