Last Thursday morning I flew out to Stuttgart to attend the neuroblastoma symposium being held in the nearby town of Tübingen. I'd never attended a meeting or conference of this type before, so I was very keen to see if I found it useful, and whether I managed to understand at least part of what was being discussed. If so, might this be something that I could get involved in on a more regular basis? As one of the doctors there rightly pointed out to me knowledge is power.
Turns out the symposium was really useful and I understood enough of it (albeit not every mutated gene, deleted short arm chromosome, microRNA signature or laparoscopic surgical procedure) to find it informative without being completely mind-boggling.
The biggest eye-opener was the work that the Germans are doing - have been doing for years - trying to cure children with relapsed neuroblastoma. The UK has never had an systematic approach to trying to cure relapsed neuroblastoma. Until recently it never had any protocol whatsoever for treating them save for palliative chemotherapy.
The U.S. has a lot more drug trials, phase I and phase II clinical studies on which children with relapsed neuroblastoma are enrolled. However, many if not most of these are to see if a treatment is effective so that it might find it's way into upfront therapy, maybe initially for slow responders. They are not being developed and trialled purposefully to give children with relapsed neuroblastoma a second chance. Some of them do work well for a small subset of relapse children, but it's a matter by a combination of luck and judgement, of being in the right place at the right time with the right type of disease.
If a treatment works in a relapse setting and finds its way into upfront therapy you might not see it back in a relapse setting against for many many years. Just look at how 14.18 antibody therapy has evolved for evidence of that phenomenon.
The Germans, mainly in Tübingen itself, have been doing haploidentical transplants for many years. They've optimised the process to both maximize efficacy and minimize negative side-effects. They select the parent donor to try to get a KIR-ligand mismatch, a condition that lessens the likelihood of Natural Killer (NK) cells receiving inhibitory signals and being turned off. They prepare grafts by depleting T and B cells so that the chance or graft-versus-host disease (GvHD) is more remote. And they co-transfuse large numbers of NK cells at the time of transplant to try and maximize the anti-tumour effect. Early results were presented which were both impressive and encouraging. With the clear caveat that it would be many years before long-term survival outcomes could be established.
At the close of the symposium the Head of Paediatric Oncology at Universitätsklinikum Tübingen left the final word to a young medical researcher who had just started work in the labs there. Here was a young man who more than twenty years before had been diagnosed with neuroblastoma and treated by the very doctors that he now stood alongside. He had relapsed, and received a stem cell transplant. He had relapsed again, and became the first patient in Germany to be treated with monoclonal antibodies. He went on to have a complete response, and had been disease-free ever since. He was now stood before us as a long-term survivor of twice-relapsed neuroblastoma. It was a pretty amazing story. And one that told me that at as far as the German philosophy is concerned, there is always some hope.
As well as the work going on in Tübingen itself, it was also very interesting to hear more about what's going on in Greifswald, where Adam was treated. We spoke to Holger Lode and it was clear they are doing a lot of work around immunological therapies. It was also clear he is both convinced about, and committed to, this kind of approach. They are developing an anti-idiotype antibody with the idea that instead of infusing anti-GD2 antibodies, they could give anti-idiotype antibodies which would result in those same GD2 antibodies being produced by the immune system itself. The benefit being that these self-made antibodies would continue to work forever, a kind of permanent anti-GD2 therapy. They are also looking at novel drug combinations, such as the addition of fenretinide to complement and enhance the efficacy of ch14.18 antibody therapy.
I almost wished I was German. Almost. What was abundantly clear, unless there's a lot of very well kept secret work going on, is just how far behind the UK is where this stuff is concerned. For what reason(s) I just don't know.
So what has all this new found knowledge got to do with Adam? Well not a whole lot at this precise moment in time, but it could be at some stage. And I do think for other UK children facing relapse the strategy they've got in Germany with RIST, haploidentical transplantation, and antibody therapy might be a tough one to better right now. You've got to get to minimal disease prior to transplant, and ideally you need some stem cells bagged because of the possibility, however small, of the donor graft being rejected. The only other unknown is the long-term side effects of this type of transplantation in young children, which as yet nobody knows and won't for years to come. Then again, as far as relapsed neuroblastoma is concerned, long-term side-effects are not something the vast majority of parents ever need to worry about. It will be really something when the day comes that they do.
There is definitely a stigma around haploidentical transplantation. Parents are naturally afraid of it, myself included, and I suppose that's because it's an unknown. I've been told that if you asked parents whose children have been through it they would tell you it's nothing like as bad as autologous stem cell transplant that almost all neuroblastoma children go through as part of standard upfront therapy. The problem is that until the first child that we know goes through it, and the first parents share their experience, there will remain, rightly or wrongly, a fear of the unknown.
Most of us were nervous and unsure about antibody therapy, because of what we did know. But I think seeing many children go through it and come out the other side provides a certain reassurance that doesn't yet exist where haplo-transplant is concerned. We also remember how horrible putting our kids through stem cell transplant was the first time round, and thinking haplo must almost by definition be worse, creates a mental barrier that has to be overcome.
But having sat through what I did, and after hearing what I did, I think this might, just might, be something that is going to make a big difference to relapsed neuroblastoma in the months and years ahead …