Beating cancer from within: why we’re investing in a platform for immunotherapy
Cancer immunology and immunotherapy have become the hot topic in cancer research, and now the excitement is spreading as patients and the public begin to see the results in the clinic. As the field gears up to tackle the next challenges, Cancer Research UK is investing to create the platform for immunotherapy to benefit more patients.
“I’ve been interested in immunotherapy since the ‘90s,” says Professor Christian Ottensmeier. “It has been fantastic to see how the field has grown and the dramatic effects we’re now getting. In melanoma especially it’s amazing. Patients who three years ago would have died are now surviving. In my own clinical practice I stopped using chemotherapy as the mainstay of melanoma treatment, it’s now an exception rather than the rule, and that shift has come very quickly.
“One particular patient brought it into sharp focus for me; a lady with melanoma who had a huge mass in her lung, progressing after chemotherapy, and another on her shoulder which really affected her mobility and independence. She said to me ‘I can’t play with grandchildren anymore. I don’t mind the dying bit, but I hate this not being able to do anything.’ We had access to anti-CTLA4 so we tried it and she started getting better, we could then operate, and five years on she’s still playing with the grandchildren.”
After many decades in the pipeline, the excitement that cancer immunologists like Ottensmeier feel for the potential of immunotherapy is finally spilling over, and in 2015 it looks set to capture the public imagination. With promising trial results such as T-VEC and the nivolumab/ipilimumab immune checkpoint inhibitor combination leading news agendas in recent weeks, immunotherapy is hitting the mainstream.
Response, resistance and toxicity
“But they’ve been far from consistent outcomes. Different cancers are responding variably, but even within cancer types there is massive variation between patients in response to treatment, in the side-effects they experience — which with some therapies can be substantial and sometimes fatal — and in the development of resistance. Still only a relatively small fraction of patients are seeing the benefit. Solving that is crucial to discovering better therapies, and of course in finding the right treatment for each patient. It’s going to be a huge challenge to untangle that variation, but it creates some really exciting opportunities.”
Bringing immunologists into cancer research is important, says Ottensmeier, but what really gets him excited is the potential discoveries at the intersection of immunology and tumour biology. “A mechanistic understanding of what determines outcomes is what we really need to work towards. We have to find out what’s going on inside the tumour. Not the immune cells in the blood, not what’s happening on the chest X-rays, not the circulating DNA, useful tools though they might be. It’s working out what’s happening inside the tumour which will deliver the breakthroughs. For example, we’re beginning to learn the importance of tumour cells’ ability to horde glucose and scavenge amino acids. That can starve T-cells. So we can’t just focus on the immune system, we have to make the immune system work inside the tumour.”
At Cancer Research UK we are working to ensure that our funding of cancer immunology and immunotherapy research and development is set up to capitalise on the promise that the field offers. Through new funding schemes launched this year, we have made it a priority to bring immunologists working in other disease areas into cancer research and to establish immunotherapy research programmes. Our biotherapeutic drug discovery capacity is also boosted by our partnership with MedImmune — which will provide industry assistance to CRUK researchers looking for opportunities to translate their research. And through our Centres Network Accelerator Awards we are establishing a major platform for immunotherapy research.
In 2015 we awarded the first of our Centre Network Accelerator Awards. These are five-year funding pots designed to build capacity across the CRUK Centre network, and to facilitate collaboration between Centres with complementary expertise. One of the first Accelerator Awards to be funded will focus on immunology and immunotherapy research.
“The award will allow us to implement comprehensive immune monitoring of patients who are being treated with immunotherapies,” says Professor Henning Walczak, who led the bid out of UCL. “We’re looking for the mechanisms and markers of response, resistance and toxicity. The award primarily pays for the infrastructure — the cytometry, immunohistochemistry, genomics, proteomics and bioinformatics — and the collection of that data.”
“What we’re creating here is a toolbox for the whole cancer immunology and immunotherapy community to use. The CRUK community should look at this platform and think about what it can do for their projects. If you’re interested in interfering with toxicities, for example, tap into this and it could really accelerate your research.”
The Award brings together a network of immunologists, cancer biologists and cancer immunotherapists across Centres and Institutes in London, and will also help the next generation to develop careers in the field.
“We have world experts on T cells, B cells, dendritic cells and endothelial cells on board, and we’re turning their focus to the tumour, and they’re already making extraordinary discoveries. It provides a great opportunity for the next generation of clinician scientists and basic scientists to become literate in cancer immunology and immunotherapy, going from the lab to the clinic and back. It has been an incredible experience for me to work together with such fantastic people on this application — people like Adrian Hayday, Sergio Quezada, Charlie Swanton, Karl Peggs, Kairbaan Hodivala-Dilke, James Larkin, Julian Downward and the many others who contribute to this network. Everyone has been so keen to get this off the ground.”
“I’ve been working on tumour immunology for 20 years, so I sensed for a long time that if we were ever going to see cures in what is known as incurable cancer, it would come from the immune system,” says Walczak. “I always thought it was the future, but now it’s here, and it’s just fantastic to see.”
Dr Sergio Quezada is a Cancer Research UK Career Development Fellow based at University College London. Here he explains the story behind his focus on immunotherapy, and describes his current efforts to understand how the regulatory and effector functions of CD4+ T cells are influenced by the tumour microenvironment and other signals.
“My research focus is mechanistic, understanding what regulates immunity to cancer and why therapies work and why they fail. This approach generates a body of evidence that can inform development of the next generation of drugs. Regulation of immunity in the context of cancer is complex: the immune system does not respond well to the presence of cancer and cancer can overcome potential threats posed by the immune system. Hence, molecules that specifically regulates the patient’s immune system could represent a therapeutic target.
My basic research programme aims to unravel mechanisms controlling the opposing functions of CD4+ T cells with respect to tumourigenesis. These cells are key orchestrators of immunity but they are also potent tumour-killing machines in their own right. Therefore, the main question that we are trying to address is can the direct effects of CD4+ T cells be switched on or boosted therapeutically?
We’re using transplantable and autochthonous mouse models to identify and target pathways that restrict CD4+ and CD8+ T cell function. Transplantable models generate rapid and reproducible results in vivo but the tumours in these mice arise from a cell line meaning that the cancer initiation stages are not modelled. So we also use autochthonous models, such as an inducible system of melanoma, because the tumours that grow spontaneously in these mice carry the same mutations as human cancers, allowing us to evaluate physiologically relevant immune responses.
We hope that finding ways to modulate the tumour microenvironment, the activation state of CD4+ and CD8+ T cells, or their tumour-infiltrating capacity could tip the balance in favour of tumour eradication in a clinical setting. For example, as the tumour microenvironment influences the activity of antibodies conceived in the lab to modulate immune function, using antibody engineering approaches that take such effects into account might make them work better. Also, understanding how T cell functions are controlled might help improve the efficacy of cellular vaccination and adoptive T cell transfer techniques.
I first became aware of the power of immunotherapy during my PhD on autoimmunity and transplant rejection, and decided to postdoc in this area. Working at Memorial Sloan Kettering with James Allison, who conceived the concept of immunological checkpoints, and helped in the development of the CTLA-4 inhibitor ipilimumab, I had the opportunity to interact with Lloyd Old, one of the founding fathers of modern cancer immunotherapy. Old’s setup at Memorial Sloan Kettering Cancer Centre brought basic scientists and clinicians together in a fast-paced environment that fostered strong collaborative research, enabling us to propose and test hypotheses generated through the study of both mouse and human tumours. That’s an approach I have tried to emulate with my own independent research here at the UCL Cancer Institute, bridging a gap between basic and clinical research in cancer immunology. Our work is currently split about 70% basic and 30% clinical, thanks to colleagues at the Royal Marsden and University College London Hospital who provide access to a range of human cancer samples both before and after treatment.
On the clinical side, and in collaboration with the Swanton lab, my team is mapping evolution of the immune response to lung cancer from diagnosis to relapse as part of the TRACERx study. Most importantly we want to understand how T cells recognise non small cell lung cancer cells and how to enhance immune reactivity against this cancer. I am also involved in protocol development and study design for trials that will examine immune checkpoints in renal cancer and melanoma.
Receiving a Career Development Fellowship was the best thing that could have happened for my career in immunotherapy. Without it, I would probably never have moved to the UK. The scheme is equivalent to a high-level start-up package in the USA as it offers funding to both deliver what you have originally proposed and the freedom to extend the scope. Because it lasts for 6 years, you have enough time to do quality work. Cancer Research UK is in it for the long haul, supporting researchers as they progress from junior group leader to a more senior level.”