What this new paper (from the Levy group at Stanford) is doing is injecting tumors with CpG, for starters. That sets off the local CD4 T cell population, and the authors can then see these cells start to express OX40 on their surfaces. This only happens after the addition of exogenous CpG; it doesn’t take place in the normal tumor environment. If you take tumor-infiltrating T cells out in vitro and expose them to CpG, nothing happens on the OX40 front, and nothing happens even inside the tumor if you deplete macrophages and dendritic cells. So it’s these “sentinel cells” that are picking up the presence of CpG and communicating it to the T cells, apparently through IL-12, interferon-gamma, and TNF-alpha or some combination of those (determined through a whole set of other experiments.
So the next step was to do the CpG injection and follow it up with an OX40 agonist to set off those newly expressed receptors. There’s an antibody that binds to OX40 as an agonist, fortunately, and the effects were dramatic. In implanted tumor models in mice, injecting CpG alone showed strong effects at the site of tumor injection, but only there, not at distal tumors. Injecting the OX40 agonist antibody alone showed some effect at all tumor sites, but not enough to be useful. But the combination of the two showed complete regression of both the injected and noninjected tumors. The local CpG injection site went down first, followed after a few days by the distal tumors, consistent with the time it takes to raise a response in both cases.