The abscopal effect
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Radiation therapy is received by about 60% of all cancer patients as part of their treatment. Many of its effects are well known, including those local to the treated tumor as well as systemic effects, such as fatigue and weight loss. However, a more rare, clinically significant phenomenon may also occur: the abscopal effect. This effect results in the shrinking or control of tumors that did not receive any direct radiation treatment. Possible mechanisms of the abscopal effect have been proposed and tested in preclinical settings, the foremost of which posits that the immune system mediates this phenomenon. Such claims are supported by data on the elimination of any abscopal effect in mice that lack T-cells, as well an increase in tumor control with the additional use of immunomodulatory agents such as anti-CTLA4, anti–PD-L1, Flt3-L, and ECI301. All of the aforementioned therapies improve the likelihood of producing an abscopal effect when combined with radiation. Despite the clinical reports of a radiation-only induced abscopal response, no research publications have been able to induce a radiation-only abscopal effect. Therefore, the hypothesis we wanted to test was that local radiation—alone—to a single tumor improves the likelihood of systemic tumor regression. To begin, we sought a murine cell line which was highly immunogenic. This property improves the immune system’s initial probability of systemic antitumor control, and therefore also improves the feasibility of demonstrating radiation’s immunogenic effects. One such highly immunogenic cell line is CT26. To this end, tumors were initiated, one on each leg, by the subcutaneous injection of 500,000 CT26 cells, and allowed to reach 30-100 mm 3 before receiving 6Gy to a single side. Our results support the hypothesis, by demonstrating that a small, basal level of spontaneous, untreated tumor regression is amplified after irradiating another tumor in the same organism. These results have also provided us with ample opportunity to further characterize this radiation-only model. This includes two rechallenge experiments on previously cured mice, which together demonstrate the immune system’s memory for antigen specific cell kill is independent of CD8+ T-cells. We have simultaneously included photoacoustic imaging (PAI) data prior to irradiation. This non-invasive technique has added valuable insight into how higher oxygenation of a tumor predicts better response to radiation—of the treated tumor, but not the abscopal tumor. Finally, we are underway with additional experiments that manipulate the fundamental model we have constructed. First and foremost are, like the aforementioned, immunomodulatory, since the immune system is intricately entangled with the abscopal effect. Our lab looks forward to understanding the mechanisms mediating these abscopal responses, so that they may one day be applied to improve cure rates of cancer patients. Finally, we are interested in applying our successful demonstrations of photoacoustic imaging to the clinic, where healthcare could benefit from predictive assessment of how well a tumor will respond to RT.