What are the objectives for CART-meso immunotherapy?

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Published: 30 Apr 2015
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Dr Janos Tanyi - University of Pennsylvania, Philadelphia, USA

Dr Tanyi talks to ecancertv at AACR 2015 about how he has used mesothelin as a conjugate with the CART-cell and what the clinical objectives are for this treatment.

Read the news story for more.

The CAR T-cells is the patient autologous T lymphocyte that we build in a special receptor so they get specialised against one antigen.

There are different types of CAR T-cells and different types of transduction as we can build in the special receptor into the T-cells.

I work on especially called CART-meso T-cells and our work right now, what we do, we use a self-inactivating lentiviral vector to transfer the meso CAR inside of the autologous T lymphocytes of the patient.

Why did you choose mesothelin as an adjunct or a conjugate with the CAR T-cell?

Because mesothelin is not expressed in most of the normal human tissues but expressed in a small group of human malignancies and these are the malignant epithelial mesothelioma, the epithelial ovarian carcinoma and the pancreatic duct adenocarcinomas.

So the clinical objective would be what?

Would be what?

That the T-cells are identifying the mesothelin expression on the surface of these cancer cells and they attack these cancer cells and kill them.

So the T-cells are able to do the killing and you can help them to find the cancer?

Indeed, they are serial killers.

So a T-cell can kill 1,000-2,000 cancer cells if they are able to and we help them to identify who have to be killed.

You’ve been conducting a study then, what did you do?

I’m conducting the study with two other physicians together, Dr Andy Haas and Dr Gregory Beatty, so three of us together are focussing in this free group of cancers.

So after the patients enrolled the patients undergo an apheresis and we collect the T-lymphocytes. The T-lymphocytes are sent to a laboratory where they manufacture the CART-meso T-cells.

When the CART-meso T-cells are ready we infuse these CART-meso T-cells into the patients’ circulations and we follow the patients, evaluating the safety, the feasibility of the CART-meso T-cells and also the clinical efficacy.

How many patients have you treated with which sorts of cancers and what happened?

Today I represented the first cohort which is six patients, two patients with a recurrent pancreatic adenocarcinoma, both of them stage 4; two patients with epithelial ovarian carcinoma, stage 3c and one stage 4 and two malignant epithelial mesothelioma, stage 3 and stage 4.

It was exciting because after 28 days we saw that four patients developed stable disease from the six treated patients, so the disease stabilisation rate was 66% in the first cohort and this is just the start.

That is exciting because you took patients whose outlook was not very good.

These particular patients are heavily pre-treated and they usually already consumed all or most of the standard of care options.

To reach 66% disease stabilisation rate amongst those patients who had progressive disease, it’s a great success.

So why is it that your CART-meso cells are so good?

Why is it?

Because these are very specialised on these mesothelin molecules.

So when we transfer this meso-CART into the T-cells, the CART redirects the T-cells to identify the intact mesothelin molecule on the tumour cell surface.

After they identify, the CAR therapy takes advantage of the cytotoxic potential of the T-lymphocytes to identify and kill these tumour cells.

Is there a hope of quite an extended remission from disease?

I think it is.

This particular meso contains more sequences so it persists in the patient’s blood for about 3-4 weeks.

But we turn over to humanised sequences which will persist, I might say, indefinitely.

In that situation they will keep working in the patient’s circulation and in the tumour site.

So you inject the cure and it stays there, continuing to treat the patient?

We hope that we will find a cure one day.

What does this mean to doctors now, would you say? Obviously this is very early days for this therapy but what is it telling cancer doctors?

It will send a message that CAR therapy has a role in solid tumours and not just only in liquid tumours, in hematologic malignancies.

We know that CART is already very successful in hematologic malignancies as we see the success story of CART 19. But this is an exciting start for the treatment of solid tumours with CAR technology.

Now, you’ve got these CAR T-cells, they have to be made for each patient. Is that a weakness?

The technology is developing very quickly.

I don’t think it’s a weakness because individualised treatment is also the strength of these CAR T-cells but we need only an apheresis and the T-cell of the patients is easy to collect and, after the technology is already available, to very quickly generate these genetically engineered T-cells.

So, in a few words how would you sum this all up? What to remember from your findings so far?

We presented today that the CAR T-cell technology will have an effect on solid tumours, not just on liquid malignancies and hematologic malignancies.

This is an early start but I strongly believe that CAR technology and CAR treatment will win against solid tumours though.