Interstitial drug delivery to brain tumours

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Published: 4 Feb 2016
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Dr Henry Brem - Johns Hopkins University, Baltimore, USA

Dr Brem talks to ecancertv at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.

He discusses the use of interstitial drug delivery systems to target brain tumours.

Dr Brem highlights how the combination of chemotherapy wafer implants, radiation therapy and oral temozolomide have already helped increase the survival of patients with glioma substantially from 9 to 21 months.

The use of immunotherapies such as checkpoint inhibitors with local delivery of chemotherapy is potentially very promising.

Interstitial chemotherapy allows immediately after surgery or actually during surgery to start chemotherapy on what hopefully is a very small residual amount of tumour. If we can get 98% of the tumour out with surgery, and increasingly that’s the target of our surgical approaches, if we can do that safely then it immediately starts working on the remainder and then it’s followed by radiation therapy as well as Temodar systemic chemotherapy which is relatively well tolerated. Now, going forward, the question is should the Temodar be given in polymers as well, should we give that locally and we might reduce the 2% or so patients who have very serious side effects from Temodar, we might be able to eliminate that. We might also, and we certainly see that in the laboratory, we might get more effective treatment of that drug if it was given in log order higher concentrations and over a sustained period of time in the brain itself, during radiation therapy as well as afterwards. So I think there’s hope with that.

Some of the other things that we’re looking at, there’s a variety of new drugs that have not been shown to work before. For example Taxol is a very standard drug used for breast cancer, lung cancer, other cancers; it works in those cancers. It works beautifully in the laboratory against brain tumours. Every clinical trial has shown it to be a failure because it doesn’t cross the blood-brain barrier, you can’t get it in. Good drug, FDA approved, available readily, Taxol or Taxotere, but you can’t use it for brain tumour patients, adult or paediatric. We have shown that with polymers, and we’ve gone into clinical trials with that, into phase I trials, that with polymers you can deliver Taxol directly to the brain tumour and therefore you can take advantage of an existing drug, very powerful, that has no use clinically for brain tumour patients but may be very powerful to add either singly or in conjunction with other therapies. That would be one example, the platinum drugs would be another example. Newer drugs and newer glycolytic, things that affect glucose metabolism may be very powerful when given locally and to starve the tumour. We’ve looked at inhibitors of blood vessel proliferation, the antiangiogenesis, how do you use them both locally and systemically? All these are areas of study.

The most exciting area that I think right now is work with the immunotherapy and what the role of local chemotherapy is in combination with immunotherapy. So one of the most exciting areas now in oncology is harnessing the power of the immune system using checkpoint inhibitors and they allow the immune system to recognise the cancer cell and to destroy it. Some of the checkpoint inhibitors like PD-1 have been approved for melanoma, for small cell carcinomas and other cancers and are just beginning to be tried for brain tumours in clinical trials. Now we looked in the laboratory, and this is Michael Lim and colleagues at Hopkins and Drew Pardoll, and showed that in fact if you give the PD-1, which is a checkpoint inhibitor that’s now FDA approved, to animals you see a benefit and you see a memory, immunologic memory - if you re-challenge the survivors three months later they’ll reject the tumour. If you treat those animals with standard chemotherapy, either Carmustine or Temodar systemically, you don’t see much of an improvement and you lose that immunologic memory. On the other hand, if you use a local chemotherapy, either Gliadel, which is the Carmustine, or a polymer with Temodar, and the checkpoint inhibitor there’s a synergistic benefit initially, more of the animals survive the initial tumour and reject it and six months later they still have that immunologic memory. So that puts into question our whole paradigm of how we’re treating - if we’re going to use immunotherapy we may not want to use systemic chemotherapy that wipes out the immune system. In fact, to preserve the immune system but still get the benefits of chemotherapy we may very well want to combine local chemotherapy with checkpoint inhibitors and see if that combination is more effective at both wiping out the tumour and sustaining an immunologic memory. This is a hypothesis that’s based on animal work and experimental work but it is moving into a clinical trial now and we’ll have an answer if that is correct or not.

Are studies already being performed to test the combination of interstitial chemotherapy and immunotherapy?

We’re opening a clinical trial at Johns Hopkins combining local chemotherapy with Gliadel with the checkpoint inhibitors. That’s just going through the regulatory process now of getting approval for the trial but we have funding for the trial and approval from the hospital for the trial so I think that will open relatively soon. Then it takes about two years to do a trial like that and to analyse the data and we’ll know. And if it is correct it’s going to make us rethink how we’re giving chemotherapy in combination with immunotherapy. If it doesn’t work then we go back to the drawing board and that’s OK too because the only way we’re going to make progress is by trying new ideas.

Presumably that trial will be in adults. How will the results translate into the paediatric population?

We should be open-minded about whether it should be expanded, even initially, to children as well. Maybe that will be one of the outcomes of this workshop, that we have that discussion.

What are some of the challenges of taking data obtained in adults and relating that to children?

The basic biology of the tumours is the same, I do think that the context of the developing brain needs to be considered and the vulnerability of a child’s brain. On the other hand, when you’re dealing with fatal diseases the first objective is to destroy the tumour. If we can’t do that effectively then nothing else really matters anyway because the child unfortunately will succumb to that tumour. So if we have methods of more effectively treating the tumour we would be optimistic that that would lead to a better outcome. The other thing is these approaches, such as the immunotherapy and the more localised chemotherapy, make sense that they should be beneficial to children. There’s nothing in them that should be more toxic or more worrisome for children but that needs to be tested.

What is your take-home message?

The take-home message is that we’ve made progress and it’s real progress. We’ve seen a significant improvement in the median survival for the most untreatable malignant brain tumours and we’ve done it by an approach that goes from the laboratory to carefully designed clinical trials. We’re at such a different point in time now that we have a huge pipeline of great ideas that have been demonstrated in the laboratory to be very hopeful and now we have to select the best of those and continue to bring them into clinical trials. I can tell you that at Hopkins we have over fifteen brain tumour open clinical trials going on right now whereas we used to have one or two. Internationally there are many, many very exciting, very interesting and very new clinical trials being done in adults and children that if they’re successful will be very hopeful. But the only way we’ll find that success is if we push forward and enter patients into clinical trials and ask important questions. But we have reason to be optimistic based on the track record to date.