TargomiRs show promise in phase I study of malignant mesothelioma

Prof Nico van Zandwijk - University of Sydney, Sydney, Australia

TargomiRs are targeted microRNA constructs and they are packaged in a mini-cell, in a nanocell, and those nanocells are covered with an EGFR antibody. So they are targeted to the tumour which is expressing EGFR and arriving there they are delivering their payload and these are the microRNA constructs.

Could you outline he MesomiR 1 study?

MesomiR 1 is the phase I study where we are defining the optimal dose, toxicity, optimal dose, of the targomiRs. Actually this abstract is pointing to the fact that already in the first six patients that we included in that phase I study there was activity of this medication in terms of response and disease stabilisation.

Could you comment on the speed and duration of the effect?

The duration of the response, the duration of the response in that patient that responded is remarkable, it’s now for more than 30 weeks on therapy and it is an almost complete response, it is a near complete response.

Could you give more information on the design and results of the study?

We are reporting on the first six patients, it is a classical 3-6 dose escalation cohort study. We did that because their earlier experience with the nanocells, and actually that is a technology that was invented by EnGeneIC, that is a biotech company in Sydney. Their early experience showed that there was dose limiting toxicity so we started in this study also with the classical approach of 3-6 patients in every cohort. While exploring that first dose that we had calculated on the basis of animal experiments we saw suddenly a response, a remarkable response, and also disease stabilisation in four of the six patients.

What about the tolerability and safety of this approach?

Tolerability is quite good, patients are tolerating the medication well. There is 80-90 minutes after the infusion of the targomiRs there is a period of shivering in most of the patients, sometimes rigor. That is of 20-30 minutes duration and then patients generally feel better. We did repeated quality of life measurements in them and the majority of patients, actually five out of six patients, reported to feel better, to be a bit more active and to have less complaints, general and local.

What’s the next step?

The next step is we are continuing with this dose escalation study and obviously the patients that are on therapy in this first cohort, they are eight weeks on therapy and then they were re-evaluated; they continue to be on therapy. So we are very curious what we will see in the next coming month.

What about the use in other tumour types?

There is also a potential for other tumour types, the study is also open for non-small cell lung cancer. A similar defect of microRNA 15/16 family has been noticed in non-small cell lung cancer and so far we have been unable to include non-small cell lung cancer patients because the amount of patients with mesothelioma presenting through their clinicians in Australia was amazing.

What is the role of microRNA expression in cancer?

MicroRNA, this family, the microRNA 15/16 family is more or less… you may describe it as a housekeeper and also as a tumour suppressor. If the levels are low then the normal housekeeping is disturbed and apoptosis is disturbed and proliferation is increased. When you add this microRNA in cell culture and also in experiment on animals, then the microRNA should be packaged in the mini-cells, then you see a slowing down of tumour growth or complete stop of tumour growth. It is a two-step approach, one is that you target the payload of the nanocells in the direction of the tumour and then it is expected that the mini-cells, that they are escaping the vasculature through the leaking parts of the tumour vasculature internalised in the tumour cells, and then get rid of their construct payload. Then they are able to restore normal apoptotic mechanisms and induce a slowdown of proliferation.

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WIN 2015

TargomiRs show promise in phase I study of malignant mesothelioma

Prof Nico van Zandwijk - University of Sydney, Sydney, Australia

TargomiRs are targeted microRNA constructs and they are packaged in a mini-cell, in a nanocell, and those nanocells are covered with an EGFR antibody. So they are targeted to the tumour which is expressing EGFR and arriving there they are delivering their payload and these are the microRNA constructs.

Could you outline he MesomiR 1 study?

MesomiR 1 is the phase I study where we are defining the optimal dose, toxicity, optimal dose, of the targomiRs. Actually this abstract is pointing to the fact that already in the first six patients that we included in that phase I study there was activity of this medication in terms of response and disease stabilisation.

Could you comment on the speed and duration of the effect?

The duration of the response, the duration of the response in that patient that responded is remarkable, it’s now for more than 30 weeks on therapy and it is an almost complete response, it is a near complete response.

Could you give more information on the design and results of the study?

We are reporting on the first six patients, it is a classical 3-6 dose escalation cohort study. We did that because their earlier experience with the nanocells, and actually that is a technology that was invented by EnGeneIC, that is a biotech company in Sydney. Their early experience showed that there was dose limiting toxicity so we started in this study also with the classical approach of 3-6 patients in every cohort. While exploring that first dose that we had calculated on the basis of animal experiments we saw suddenly a response, a remarkable response, and also disease stabilisation in four of the six patients.

What about the tolerability and safety of this approach?

Tolerability is quite good, patients are tolerating the medication well. There is 80-90 minutes after the infusion of the targomiRs there is a period of shivering in most of the patients, sometimes rigor. That is of 20-30 minutes duration and then patients generally feel better. We did repeated quality of life measurements in them and the majority of patients, actually five out of six patients, reported to feel better, to be a bit more active and to have less complaints, general and local.

What’s the next step?

The next step is we are continuing with this dose escalation study and obviously the patients that are on therapy in this first cohort, they are eight weeks on therapy and then they were re-evaluated; they continue to be on therapy. So we are very curious what we will see in the next coming month.

What about the use in other tumour types?

There is also a potential for other tumour types, the study is also open for non-small cell lung cancer. A similar defect of microRNA 15/16 family has been noticed in non-small cell lung cancer and so far we have been unable to include non-small cell lung cancer patients because the amount of patients with mesothelioma presenting through their clinicians in Australia was amazing.

What is the role of microRNA expression in cancer?

MicroRNA, this family, the microRNA 15/16 family is more or less… you may describe it as a housekeeper and also as a tumour suppressor. If the levels are low then the normal housekeeping is disturbed and apoptosis is disturbed and proliferation is increased. When you add this microRNA in cell culture and also in experiment on animals, then the microRNA should be packaged in the mini-cells, then you see a slowing down of tumour growth or complete stop of tumour growth. It is a two-step approach, one is that you target the payload of the nanocells in the direction of the tumour and then it is expected that the mini-cells, that they are escaping the vasculature through the leaking parts of the tumour vasculature internalised in the tumour cells, and then get rid of their construct payload. Then they are able to restore normal apoptotic mechanisms and induce a slowdown of proliferation.

What is the potential application of promise of this approach?

If this works and shows to be efficacious there are potential significant applications, not only mesothelioma but also non-small cell lung cancer and we have tested this approach also in other tumour models and there are several who respond in a similar way. So it is precision medicine but it is covering quite a broad area.

What is the take-home message?

A good thing is to realise that this is the result of an intensive co-operation between a research lab and a biotech company, EnGeneIC, Sydney-based. They have that nanocell technology which is, by the way, also inducing some sort of an immune mechanism because all the patients are reacting on the nanocells with some feverish symptoms. If you look into the blood there is lymphopenia, immediate lymphopenia and neutrophilia, so the innate immune mechanism is affected by the mini-cells. Then obviously the microRNA background that was invented in our institute and together we made this in quite a swift time from the lab to the clinic. Now this study is activated in three major academic hospitals in Sydney, in the Northern Cancer Institute, in Chris O'Brien Lifehouse and in Concord Hospital so it’s a wonderful co-operation.

If this works and shows to be efficacious there are potential significant applications, not only mesothelioma but also non-small cell lung cancer and we have tested this approach also in other tumour models and there are several who respond in a similar way. So it is precision medicine but it is covering quite a broad area.

What is the take-home message?

A good thing is to realise that this is the result of an intensive co-operation between a research lab and a biotech company, EnGeneIC, Sydney-based. They have that nanocell technology which is, by the way, also inducing some sort of an immune mechanism because all the patients are reacting on the nanocells with some feverish symptoms. If you look into the blood there is lymphopenia, immediate lymphopenia and neutrophilia, so the innate immune mechanism is affected by the mini-cells. Then obviously the microRNA background that was invented in our institute and together we made this in quite a swift time from the lab to the clinic. Now this study is activated in three major academic hospitals in Sydney, in the Northern Cancer Institute, in Chris O'Brien Lifehouse and in Concord Hospital so it’s a wonderful co-operation.