Radiation and immunology – a new therapeutic partnership
Dr Ralph Weichselbaum - University of Chicago, Chicago, USA
Radiation therapy is primarily a local treatment modality so we treat localised tumours, for example, of the head and neck, prostate, brain tumours. Frequently we’re unsuccessful and so, of course, we want to make this better. The paradigm to date is to use chemotherapy with radiotherapy to make local control better but this is has only been marginally successful and achieved at very high toxicity expense. Also what defeats us, in addition to local treatment, is the fact that tumours metastasise, that they spread away from the primary site. So what we’re hoping to do is to combine radiotherapy and immunotherapy not only to improve local control but to affect the treatment of systemic disease, that is to affect the treatment of metastasis.
What is some of the work you have been doing and the main findings?
What we have found is that when radiation is given in high doses it liberates danger signals that alerts the immune system; it stimulates cytokines such as interferon, tumour necrosis factor alpha, which also not only alert the immune system but seem to improve the antigen presenting cells which present antigens to T-cells and activate T-cells and in general promote T-cell priming which is the general activation of T-cells to go and then kill tumour cells. What we’ve found is that by the use of the so-called checkpoint inhibitors, these anti-CTLA4, which suppresses the priming phase of T-cells, or anti-PD1, which suppresses the effector phase of T-cells, by combining these molecules with radiation we can not only improve the local control of tumours but we can set up the systemic immune response that under some circumstances can eliminate tumours outside the primary site.
What results have been seen when combining checkpoint inhibitors with radiation?
It looks as if we set up to change the local tumour microenvironment so that we get infiltration of T-cells. There is some cross-reactivity between T-cells and the local tumour microenvironment, at least under … tumours outside of the irradiated seal, this is known as the abscopal effect, or an effect away from the primary tumour. What we’ve found is that what goes on in the primary or the irradiated tumour not only stimulates T-cells but it eliminates or decreases cells called myeloid derived suppressor cells. These are complex cells and their natural function is to promote wound healing and suppress the immune response. In tumours these cells seem to dampen down T-cells and it seems by combining anti-PDL1, which is the ligand for PD1, and radiation we can not only take the brakes off the T-cells to kill the tumour cells but encourage the T-cells to secrete a cytokine tumour necrosis factor alpha which kills the myeloid derived suppressor cells in the tumour microenvironment locally and it seems as if also outside of the local irradiated tumour, although this is under investigation now.
These are pre-clinical, although others have done studies. There’s a paper in The New England Journal of Medicine using ipilimumab or anti-CTLA4 and radiation where the colleagues of Jed Wolchok and Mike Postow from Memorial Sloan Kettering show irradiation of a local tumour or of a tumour in the chest caused regression of tumours outside of the irradiated site in a patient who was not responding to ipilimumab. This is quite interesting because the patient went into remission for years, was controlled everywhere but the irradiated field. So my colleagues in immunology just think, ‘Well, we can give any old radiation to wake up the immune system,’ but my suspicion is that we need to give curative doses of radiation within the field, that it’s more that we should not throw out the cytoreductive properties of radiation in favour of the immunogenic properties of radiation.
What about the practicalities or toxicities of combining radiotherapy and immunotherapy?
So far, because it’s been fairly limited in confined volumes there hasn’t been much toxicity. In my presentation I’ll talk about anti-PD1 antibodies in lung cancer which have been a remarkable change. My suspicion is that this will be brought up front with radiation therapy from resectable lung cancer. Under these circumstances I think we might see pulmonary toxicity since the acute effects of radiation and the acute effects of PD1 or anti-PD1 are both inflammatory and this can cause problems and we’ll have to find a way around this.
How do you foresee radiotherapy and immunotherapy being used to treat patients in the future?
In the long run I actually think radiotherapy and immunotherapy will supplant surgery and chemotherapy, or not completely supplant it. But when we find out how to integrate radiotherapy and immunotherapy we’ll be able to suppress microscopic disease outside the field and cure large primary tumours within the field. In this metastatic setting I think it’s going to be more complicated in the context of how many tumours can we irradiate. My colleague, Samuel Hellman, and I have put forward a hypothesis called oligometastasis, that is some patients only have a few metastases that can be cured with radiation alone. It may be with newer methods of image guidance for radiation we can treat quite a lot of metastatic tumours and this will go a long way towards curing metastatic disease. This is likely to be more complicated and involve targeted agents and chemotherapy and so forth.
