Synergistic expression of combined RT and dual-immune checkpoint blockade

Radiation therapy has become a staple of cancer treatment because it provides a method for producing lethal damage in cancer cells while sparing nearby healthy tissues. Only more recently has it been shown that radiation may also control the growth of satellite tumors–tumors far from the radiation target. This capacity of radiation to affect tumors indirectly is called the abscopal effect and appears to occur because radiation of a small target area stimulates an immune system response throughout the entire body. The demonstration that radiation therapy can augment the body’s natural immune defenses in this way, producing regression of non-irradiated tumors, has led to a radical rethinking of the therapeutic uses of radiation. Thus, contemporary treatment strategies in radiation oncology are based not only on the capacity of radiation to kill cells directly but rely also on remote immune-mediated effects to destroy cancers that have spread. One of the most promising of such strategies involves a combination of radiation therapy and drugs that stimulate the immune system (immunotherapy). In our laboratory, we have tested such a regimen in a mouse model of disseminated lung cancer and have shown that high-dose radiation therapy delivered to select tumors in combination with two immunotherapy agents can significantly inhibit the growth of satellite tumors. We would now like to extend our results with immunotherapy and high-dose radiation by developing a protocol that further exploits the ability of radiation to work in synergy with our natural immune responses. Several research groups have reported favorable results combining immunotherapy both with high-dose radiation and with low-dose radiation delivered to other secondary tumors. Preliminary evidence, however, suggests that low-dose radiation may actually do more to enhance natural immune defenses if it is given in the form of repeated very low dose pulses. The present study will thus employ an animal model of disseminated lung cancer to test a new radiation protocol with possibly enhanced immune effects. The results will determine if the therapeutic efficacy of immunotherapy in combination with high-dose and low-dose radiation can be improved by the use of low-dose radiation given to satellite tumors in the form of repeated very low-dose pulses.