Cancer immunotherapy has been a huge topic in recent years, and deservedly so. But there are some types of tumors that respond much better than others, which means that there are also some that hardly respond at all. A great deal of effort is going into trying to find ways to make these immunologically “cold” tumors respond to checkpoint inhibitors and other such drugs.
One way to do this is through external radiation therapy. For a decade or so now, there have been studies in both animal models and in human patients that show that combining local radiation and checkpoint inhibitors can lead to an effect noticeably greater than either one by itself. The mechanisms for this are complex and varied, but at least some of them, not mutually exclusive, are (1) upregulation of some “neoantigen” proteins in tumor cells as a response to radiation, whose expression then opens them up to recognition by T cells and (2) local release of cytokines and other immune-modulating signals in the tissue that’s been irradiated, which can suppress or reverse the immune-dampening effect of some tumor microenvironments.
This sort of treatment looks like it has the best chance of working against a localized tumor, though, since the tissues that don’t get irradiated don’t show the effects above. What if you could deliver radiation to all the tumor tissue simultaneously? You’re not going to be able to do that very feasibly with external beams, but dosing with radioactive drugs that accumulate more in tumor tissue could do the trick. That’s the subject of this new paper from a team at Wisconsin and Pittsburgh. They’re using NM600, which is a phosphocholine derivative with a metal-chelating group attached at the far end. It tends to accumulate in tumors over normal tissues, which is thought to be due to uptake into lipid rafts on the cell surface (tumor cells generally have larger amounts of alkylphosphocholines). NM600 has been decorated with a variety of radionuclides in the past – 86Y, 90Y, 177Lu, 225Ac, 64Cu, 89Zr and more, for both therapeutic and imaging applications. In this case, the authors used 86Y to do PET imaging to work out the dosing for 90Y, which is a beta-emitter.
In mouse models of various immunologically cold tumor lines, treatment with checkpoint inhibitors (anti-CTLA-4 antibodies or anti-PD-L1 antibodies, both raised against the mouse proteins), showed no response at all. Likewise, treatment with the radioactive NM600 compound showed no response, either. But combining the two led to over half the mice showing complete response along with tumor-specific T-cell memory. And in mice with multiple tumors, this combination was enhanced even more by simultaneously targeting a single tumor with external radiation as well – better effects than external beam plus antibodies or radionuclide therapy plus antibodies. Importantly, the total radiation dose is low compared to standard radiation therapy – it’s not enough to cause bone marrow suppression in the mice, as compared to tumor-killing levels.
The paper goes into a great deal of detail on the dosing and timing of these interventions, as well as cellular measures of the immunological effects. But the overall result seems clear: the radionuclide therapy alters the tumor microenvironment in ways that make the checkpoint antibodies far more effective. The tumor-killing effects are mediated by T cells, as expected. A limitation of the work is of course the xenograft mouse models, but that overall story looks to have a good chance to real-world examples, especially given the dramatic difference in the combined therapy groups. There are plenty of other experiments to be done (with other radionuclides, for example), but this looks like a strong candidate to start moving towards human trials.