Vincenzo Cerundolo: Cancer immunology
The development of therapeutic vaccines is more challenging. Current lines of research include the development of antibodies blocking inhibitory T cell signals, and the characterisation of adjuvants.
Q: What is the response of the immune system to cancer?
VC: Let me start by saying there is tremendous momentum in the field both of tumour immunology and cancer vaccines, and the last few years we are really observing and obtaining very exciting results in the clinic, mainly based on the knowledge derived from the last 20 or 30 years of basic research. The evidence that the immune system can recognise and attack tumour cells is very strong and compelling. This is mainly supported by results of experiments done in laboratory models and also by our ability to purify tumour-specific lymphocytes from a broad range of patients with different tumour types. The question is not whether the immune system can recognise cancer cells but why those tumour-specific lymphocytes are not capable of completing their jobs and eradicate and destroy tumour cells. It appears the answer to this question is mainly centred on the ability of tumour cells to evade or escape immune recognition mainly due to the unstable DNA or chromosomes of tumour cells, and on many mechanisms the tumour cells have to actively suppress and hamper the ability of the immune system to recognise cancer cells. This is the challenge that we're facing and this is in a sense what my laboratory is currently developing in terms of line of research.
Q: Can we harness T cells to fight cancer?
VC: Certainly. The field of tumour immunology is on a very solid, both conceptual and technical footing. We are benefiting from the basic knowledge derived from the last 30 years of research and we are applying those concepts to the clinic, to cancer patients right now.
Q: Can you give us an example?
VC: There are several strategies that are being developed in the field. These strategies range from the use of recombinant harmless viruses that encode tumour proteins that can be used to elicit tumour-specific immune responses. Other strategies are based on the injection of recombinant proteins - tumour proteins - together with adjuvants which are molecules that can enhance and boost the immune response. We are also purifying dendritic cells which are very powerful white blood cells, and pulse them with tumour fragments in order to elicit an immune response. Other groups are isolating, from patients, tumour-specific lymphocytes, expanding them in vitro, enhancing the affinity of their receptor - the receptor which is capable of recognising tumour cells - and then injecting them in vivo. But by far the most exciting development in the field is the use of antibodies which can block inhibiting signals in T cells, lowering the threshold of activation of T cells. In this way we can harness the immune system in order to recognise tumour cells more efficiently.
Q: What are the most important lines of research that have developed in the past 5 or 10 years?
VC: I think that by far, the most efficient cancer vaccine today is the vaccine against papilloma virus. As you know the injection of this vaccine has been shown to prevent, in a very large proportion of individuals, the incidence of cervical cancer. This family of vaccines is called prophylactic vaccines because they are designed to prevent the onset of cancer. The development of therapeutic vaccines is much more challenging. The difficulty here is that for therapeutic vaccines, vaccines for patients that have cancer, you need to expand a large number of tumour-specific lymphocytes. These lymphocytes need to home in to the tumour, and once they've reached the tumour they need to survive in a very nasty environment. They need to overcome all the immunosuppressive mechanisms that the tumour is switching on in order to supress the immune response. It is very challenging but in the last few years there has been a sea change in this field with the use of antibodies that can block inhibitory signals, antibodies such as ipilimumab (an anti CTLA-4). It has been shown that melanoma patients that receive these antibodies, 20% of these patients can have complete regression. Although there are side-effects, the initial results are extremely exciting because they pave the way towards strategies where these antibodies will be combined together with vaccination strategies that will specifically enhance tumour-specific T cells.
Q: Why does your line of research matter? Why should we put money into it?
VC: My research program is mainly focused on two complementary lines of research. One is the characterisation of adjuvants, small molecules that can harness and expand both the innate and the adaptive immune systems. By doing this we will enhance both antibody responses and T cell responses. In parallel, I am also dissecting several mechanisms that tumours use to suppress the immune response. The reason why it matters is because every year, just in the UK, 160,000 people die of cancer. This is the equivalent to the population of Oxford that every year dies of cancer so I think this is why it matters.
Q: How does your research fit into translational medicine within the department?
VC: Well it fits very well. Those adjuvants, those compounds that we are optimising and characterising in my lab will be used in cancer vaccines, in vaccination strategies in melanoma patients next year in a clinical trial that will be funded both by the Medical Research Council and the Ludwig Institute for Cancer Research. It is very much in line with the direction of travel of the department but also with the overall themes that are currently being developed within the Human Immunology Unit that focus on translating basic results into the clinic.