Cytotoxic T-lymphocyte associated protein 4

Solstis Oncology launched with a two hundred and twenty-five million dollar Series A, backed by investors including RA Capital, Canaan, and Forbion.

It plans to pair porostatart, a CTLA4 antibody, with pembrolizumab in a Phase 2 colon cancer study.

Canaan's rationale is to test immunotherapy before surgery in microsatellite stable colon cancer, a setting the investor describes as largely resistant to it.

The planned study focuses on Stage 2 and 3 disease, while the cancer can still be removed.

For the first time, that actually changed in 2010 with the phase three results from the first study using ipilimumab.

which is a CTLA-4 blocking antibody that was really developed first in melanoma.

That data was presented by Dr. Steve O'Day at the ASCO annual meeting in 2010 and showed for the first time that any intervention could improve overall survival in metastatic melanoma.

Just under a year later, the US FDA approved Ipilimumab for use in metastatic melanoma based upon that improvement in overall survival.

I think that As we develop more sensitive means for detecting minimal residual disease as time and technology march on, we probably will get a better sense of things in terms of complete eradication versus sort of a restoration of a state of immune surveillance against whatever the minimal residual disease is.

What we do know, though, is that the shape of the survival curves, as you alluded to, changes quite dramatically after about two to three years, where there is this plateauing effect.

And in Checkmate 67, which was the phase three randomized trial that looked at the combination of PD-1 blockade with nivolumab, CTLA-4 blockade with ipilimumab, alongside the monotherapies, we actually followed patients who enrolled on that trial for 10 years or longer.

So we were really able to observe this plateau, I would think, with much greater attention than we could using prior studies where the follow-up was shorter.

Additional in-transit metastases, which are metastases that basically are cutaneous deposits between the primary and the nearest sort of drainage lymph node, were allowed if the patient had less than three of them.

Patients had to be naive for anti-PD-1, anti-CTLA-4.

And they were stratified by BRAF status.

Now, what happened is they were randomized to standard of care where they had a total lymph node dissection after resection of the primary and then adjuvant therapy, which is standard of care.

T-cell INFORMA and the data that we have shown at EHA is showing strong single agent activity which position actually the compound in the first line setting as a single agent but also works nice in combination with Ketruda but going forward we'll develop it in the single agent setting.

Yeah, obviously like you've got your hands full with the cancers that you're focused on, but if you've essentially discovered a new checkpoint like you're talking about, you know, we've seen the wide breadth that PD-1 or even CTLA-4, like the applicability, like do you think that this could have wider applicability than just those cancers as well?

Absolutely.

As I said, already during the single agent dose escalation for 1808, we saw complete responses in ovarian cancer.

It was academic work.

And as I said, at least one small company, Mederex, decided to take the plunge with CTLA-4 and with PD-1 and PD-L1.

and got some spectacular results early on and everybody piled on.

It cost nothing.

Obviously, this, this study that, that Alfred and, and the Notch team have done is in monotherapy.

We need to understand the influence of combinations with CTLA-4, um, and PD-1 combos and whether that has an impact, whether that gives more priming and so would the time of day story get more important.

We need to understand the impact of, you know, what is the impact of the, the chemo IO.

Obviously, some of those studies have started looking into it.

Seastone Pharmaceuticals posted twenty twenty-six interim results today, and the lead asset did something people are going to quote badly.

CS2009 is a PD-1 VEGF CTLA-4 trispecific.

At thirty milligrams per kilogram in first-line non-small cell lung cancer with high PD-L1 expression, the company reported a one hundred percent objective response rate.

On patients, eleven of eleven is a hypothesis wearing a results clothes.

Twenty percent response in heavily pretreated metastatic colorectal cancer with a ninety-three point three percent disease control rate.

Colorectal is where PD-1 blockade goes to die.

If the CTLA-4 arm is doing real work, that's where it shows up first.

And they're taking it straight at the standard.

There's a lot of interest incorporating that in these types of treatment and looking at that in these types of trials.

We're looking at that in our ongoing trial, which is looking at a PD-1 CTLA-4 bispecific called Varustamig in the neoadjuvant setting.

That's a neoadjuvant immunotherapy trial that's ongoing.

We're looking at circulating tumor DNA in that trial.