Abstract Body

PULSAR is an adaptation of SAbR that is less toxic at the same total dose, facilitates tumor adaptation (and personalization of therapy) and interacts with immune oncology more effectively. PULSAR abandons fractionated radiation for near marginless targeting of tumors using “pulses” of radiation, which are effectively stand-alone treatments, at doses high enough to afford months of durable control with the intervals between pulses long enough to discern tumor response. Tumor response can be shape, position, volume; but can also be via interrogation of immune signaling, mutational profile, or radiomics, as examples. Indeed, PULSAR is an approach that is highly amenable to hypo- oligo-fractionated radiotherapy combined with more sophisticated imaging technologies such as MRI and PET. PULSAR may prompt a “vaccine” effect where the host initiates an adaptive immune response. Clinical trials and preclinical experiments are underway to validate this concept. Initial experiments in immunocompetent mouse tumor models were designed to determine the optimal spacing between pulses and whether PULSAR could elicit an immune response. Using MC38 tumors the optimal time between 8 Gy radiation pulses was determined to be 7-10 days. Furthermore, the timing of the use of the immune checkpoint inhibitor (ICI) anti-PDL1 was most effective when given prior to the second pulse of radiation. Moreover, in immunologically cold Lewis Lung Carcinoma tumors the combination of PULSAR with ICI was highly effective compared to either therapy alone suggesting that PULSAR could elicit an immune response in a cold tumor. Tumor Treating Fields (TTFields), which makes cells more susceptible to radiation, was tested in MC38 tumors as a way to take advantage of the time between pulses. Synergistic reductions in tumor growth delay were seen after each round of TTFields and radiation and when an ICI was added to the combination. These studies, and ongoing clinical trials, suggest that the PULSAR approach is a paradigm shift in radiation oncology that will combine local therapy with systemic therapy to facilitate the personalization of cancer therapy.