3rd Immunotherapy of Cancer Conference (ITOC3)
T cells expressing two additional receptors (TETARs) for the use in a multiple- hit immunotherapy
Dr Gerold Schuler - Universitätsklinikum, Erlangen, Germany
This is something we have started a few years ago when we developed methods to electroporate RNA into cells. We were at that time primarily, and still are, interested in dendritic cells but we also used that to introduce T-cell receptors or CAR T-cell receptors into T-cells by using RNA transfection. At that time people were laughing at us because everybody stated why should you use RNA transfection because it strengthens so the T-cell receptor or CAR T-cell receptor is present on the T-cell only for a limited period of time, when you can refer to or rely on a viral transfection. But our argument at that time was already that there might be safety problems and actually that turned out to be true. So if you put in T-cell receptors it may happen, or even CAR T-cell receptors, it may happen that you get toxicity and that has happened in clinical trials already. Then you have the problem that you don’t get rid of the living and replicating virally transfected T-cells. So our idea was if you have many candidate T-cell receptors or CAR T-cell receptors to screen, let’s do that by usng RNA transfection.
That was the idea and later on then we came up with the idea and possibility to put in two T-cell receptors, for example, as we have done now, a conventional T-cell receptor and a CAR T-cell receptor, to test whether this is possible. It was possible and we also could put the RNA into gamma delta T-cells which has a big advantage because there there is no danger that there is a mis-sparing of T-cell receptor chains. So no danger of auto-immunity.
What results have you seen so far?
So far these are only in vitro studies. What we saw was that by performing such a double hit you get much better killing of the tumour cells, as expected. We are planning clinical trials with these transfected T-cells.
Are there any limits to the receptors that could be added to the T-cells?
In theory there are no limits, of course what you have to do in the long run if this in principle turns out to be very useful, that you work on mutating the RNA and modifying it so that you get the stabilised version. So that’s possible and we’ve already done that in other cases so that the RNA then stays in the cell for days and even longer.
Does the transience of the RNA transfection present a problem?
Right now, with the unmodified RNA, that’s for several days so for a clinical trial that’s enough. So the transiency is something that’s good for testing because if you are confronted with toxicity the toxicity will wane so you don’t have any problems. Even if you want to get clinical results you just give another shot of the T-cells every few days. That’s no problem because you can grow up tonnes of those autologous T-cells and transfect them so you freeze them down and give just serial shots. So that’s certainly not a problem. You would then, of course, also combine, maybe, with checkpoint blockade so you destroy the tumour etc. etc. So we would not go for T-cells or CAR T-cells that see antigens that seem undangerous so we, of course, would go right now for the so-called mcsB antigen that has not been exploited and people refrain from that because mcsB is also expressed on normal cells to some extent. So at low levels probably that doesn’t produce any toxicity but the nice thing is that mcsB is expressed on melanomas, on neuroblastomas and on the tumour vasculature of virtually all tumours. So if it works it’s really something to go for.
Would alternating or additional receptors beyond two be possible?
I think then also from a production point of view, we have a lot of experience in GMP production, you would rather come up with different batches of T-cells because there is a limitation to optimising things. But if you put in eight RNAs the relative quantities etc., you have to test that out, that’s too complicated. So you would deliver and administer different batches and each batch has two receptors. The idea to put in two receptors is to hit also tumour cell clones that have lost one or the other antigen; that’s the idea.
What is next in the pipeline?
We are pursuing this adoptive T-cell therapy programme and our main programme we have been pursuing for a long time and we started that together with Ralph Steinman is the dendritic cell vaccination. Vaccination and cancer vaccines in general have not been so fashionable in the past few years but now, as checkpoint blockade has become available, and it turned out that you don’t get success in all cases, all types of tumours and even if a tumour is responsive not in all patients, it’s getting more interesting again. So we are interested in melanoma, cutaneous melanoma, and also uveal melanoma.
Uveal melanoma is notoriously resistant to checkpoint blockade antibodies, as far as they are available right now. So you rarely get responses to anti-CTLA4 antibodies or anti-PD1 antibodies or even the combination of those. So what we have started is adjuvant vaccination, that’s a phase III trial actually, and the reasoning for that is there is no therapy available, no effective therapy available, to treat metastasis as soon as they have occurred in uveal melanoma. There is also no therapy yet available to prevent the metastasis, so no adjuvant therapy. So we have designed a trial where after destruction or removal of the tumour, the primary tumour in the eye, if it classifies as high risk, which is indicated by a loss of one chromosome 3, we then prepare a vaccine out of the tumour RNA which is put into dendritic cells and people get vaccinated in a randomised fashion. So half of the patients do not receive the vaccine, the other half gets the vaccine.
