Adoptive cell therapy for solid tumours

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Published: 18 Oct 2017
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Dr Sophie Papa - Guy's Hospital, London, UK

Dr Papa speaks with ecancer at the ACP immunotherapy workshop about genetically modified immune cells as a treatment choice for solid tumours.

She highlights the successes of using tumour-infiltrating lymphocyte to treat a small subset of melanoma patients, and how engineered CAR T cells are 'heating up' tumours which had previously been non-immunogenic.

By comparison to haematological malignancies, Dr Papa considers the challenges in treating solid tumours with systemic therapies,

Cell therapy just means using our own immune system, cells from our own immune system that we can isolate and then potentially expand and give back to a patient as a therapy. We’ve been doing that, using leucocyte infusions in haematological cancers, for many, many years. Similarly for a number of decades small groups have been using tumour infiltrating lymphocytes extracted from deposits of cancer, particularly melanoma, which they then expand ex vivo, so outside the patient, grow up and give back. What’s always been tantalising about that therapeutic approach is that in selected patients it works extremely well. Back before we had checkpoint inhibitor therapy to treat melanoma the disease had a median survival of nine months and was frequently rapidly very, very fatal. There was a subset of patients that you could treat with TIL therapy who would have this long-term survival that we see with checkpoint inhibitors.

So the rationale for using cells, T-cells from the immune system, to treat cancer has been long established but we live in a new era now where we have functional, extremely, in some circumstances, efficacious immune therapy drugs that work by taking the brake off T-cells and allowing them to attack the cancer within the body without having to manipulate the cells outside of the body. Which raises the question why would we need to go down the route of doing that kind of thing, the complicated scientific approaches, the manufacturing approaches, and expensive, to cell therapy.

But the reality is that for all the patients in melanoma who get fantastic benefit from checkpoint inhibitor therapy there are still many who do very poorly. Then outside of melanoma the benefit of these drugs, the group that’s benefitting is much, much smaller. Then we have a huge amount to learn about why that is but a very simple way of looking at it is this idea that some tumours are immunologically cold and others are immunologically hot. Work now is directed around trying to take a cold tumour and make it into a hot tumour – take a tumour that’s not responding to the immune system, for whatever reason, and enable it to be targeted. One possible way to do that is to use T-cells as a tool for delivering aggressive cytotoxicity in a patient. We are trying to approach that by taking blood from patients, isolating T-cells, genetically modifying them with a virus that puts a synthetic protein in called a chimeric antigen receptor that is designed to target a particular weakness in the cancer that you’ve chosen, and then you grow those cells up in the lab and then put them back into the patient. That sounds very simple but it’s not that straightforward and there are lots of possible ways that you can trip up along the way but that’s the general principle of adoptive cell therapy with genetically modified cells.

How has progress been so far?

Within the field, and we are very much led by haematology and I don’t need to be the one to say that targeting CD19 in particular subsets of B-cell malignancies in haematological cancer represents a huge breakthrough with CAR T-cell therapies. There is now one CAR T-cell therapy that is in the clinic in the US, it was FDA approved about a month and a half ago for treating young patients with relapsed refractory acute lymphoblastic leukaemia. What we see in those patients, and this is a patient population that has a universally dreadful prognosis of weeks to months, and if they can get the CAR T-cell product in in time then they are salvaging upward of 60-80% of those patients. How durable those remissions are going to be we don’t know yet because this data is still quite new but for children with ALL that’s a huge step forward which is why that therapy has been approved by the FDA at the cost of $475,000 per patient.

That leads the way and then there is much more progress coming down the line behind that in haematological cancers. Other companies that are involved in bringing CAR T-cell therapies into different haematological indications, we’re anticipating more approvals in the US over the coming year and then in Europe after that.

So there has been and there continues to be a huge amount of success in using this kind of technology to treat haematological cancers, taking that into solid tumours is much harder. There are a number of obstacles to success in solid tumours, one is finding the right target because it’s very difficult to find a target on a cancer cell that is not found on a normal cell in a solid tumour. If you get a very vigorous attack from your T-cells against that target and that can also attack normal tissue then that’s potentially going to be very difficult to manage. So we’re having to be very cautious about the way we roll this kind of approach out in solid tumours.

And other challenges around homing, around toxicity, around comorbidities within the patient population etc. make solid tumours a more difficult area to take this therapy forward but there are successes. So notable successes in recent years have been the team down at Baylor in the US who are successfully targeting HER2 which is a receptor that’s found on a number of different epithelial cancers. They’re targeting HER2 in sarcomas and they’re starting to see responses without unmanageable toxicity which is very, very exciting. Also a group, also in the US, who are using an IL-13 receptor alpha targeting CAR in glioma, which is a dreadful brain tumour which is universally fatal. They are starting to show some data from patients of efficacy in that tumour so that’s very exciting as well.

So what were the key points to take away from your talk?

The main thrust of my talk was to try and convince the audience. I was speaking to an audience of trainee medical oncologists and some medical oncology consultants, and we’re going through a period of transition in oncology where we’re moving from cytotoxic and targeted therapy technicians into also immune therapy technicians. So we are training up a community in the future who are going to understand immunology a lot better I hope. My main aim today was to bring cell therapy just into their consciousness and I hope I’ve done that.