Preclinical Evaluation of Tumor Treating Fields Combined with Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR)

Abstract

Purpose/Objective(s)The PULSAR paradigm, treats patients using a few large dose “pulses,” delivered at least a week apart. These split treatments represent a radical break from conventional radiation treatments lasting six to nine weeks. The expectation is that therapy will be less toxic and will allow treatments to personalized based upon noted changes in tumor morphology, location and radiation response. Early pre-clinical experiments identified an optimal timing between radiation pulses with the use of immune checkpoint inhibitors (ICI). Other therapeutic combinations are being explored. Tumor Treating Fields (TTFields) is a novel noninvasive physical modality of cancer therapy that disrupts mitosis, causes replication stress, inhibits DNA damage repair, and sets up a conditional vulnerability to DNA damaging agents. This study combined the conditional vulnerabilities caused by TTFields exposure with a preclinical model of PULSAR to determine treatment efficacy for this combination.Materials/MethodsThe Inovivo system was used to generate Tumor Treating Fields across subcutaneously implanted tumors. Three distinct syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer). Tumor growth delay (TGD) was the endpoint determined.ResultsIn the three mice models tested in vitro, TTFields exposure alone modestly decreased tumor volume. A difference in tumor growth rate between the heat (sham) and TTFields group was not statistically significant. TTFields combined with 8 or 10 Gy radiation pulses, depending on tumor model radiosensitivity, produced a significant TGD effect on the MC38 mouse model after one round. The second round of TTFields and radiation treatment further delayed TGD, in a synergistic manner, confirming that TTFields induces a conditional vulnerability that is particularly suited to the PULSAR concept. The combination of TTFields, PULSAR and an ICI is being tested and will be reported.ConclusionThe addition of TTFields with a pre-clinical model of PULSAR resulted in synergistic delays in tumor growth compared to the PULSAR strategy alone when tested using three different subcutaneous tumor models. This combination is well suited for the addition of an ICI. The PULSAR paradigm, treats patients using a few large dose “pulses,” delivered at least a week apart. These split treatments represent a radical break from conventional radiation treatments lasting six to nine weeks. The expectation is that therapy will be less toxic and will allow treatments to personalized based upon noted changes in tumor morphology, location and radiation response. Early pre-clinical experiments identified an optimal timing between radiation pulses with the use of immune checkpoint inhibitors (ICI). Other therapeutic combinations are being explored. Tumor Treating Fields (TTFields) is a novel noninvasive physical modality of cancer therapy that disrupts mitosis, causes replication stress, inhibits DNA damage repair, and sets up a conditional vulnerability to DNA damaging agents. This study combined the conditional vulnerabilities caused by TTFields exposure with a preclinical model of PULSAR to determine treatment efficacy for this combination. The Inovivo system was used to generate Tumor Treating Fields across subcutaneously implanted tumors. Three distinct syngeneic mouse tumor models, LLC (Murine Lewis Lung Carcinoma), KPC63 (Pancreatic Cancer) and MC38 (Colon Cancer). Tumor growth delay (TGD) was the endpoint determined. In the three mice models tested in vitro, TTFields exposure alone modestly decreased tumor volume. A difference in tumor growth rate between the heat (sham) and TTFields group was not statistically significant. TTFields combined with 8 or 10 Gy radiation pulses, depending on tumor model radiosensitivity, produced a significant TGD effect on the MC38 mouse model after one round. The second round of TTFields and radiation treatment further delayed TGD, in a synergistic manner, confirming that TTFields induces a conditional vulnerability that is particularly suited to the PULSAR concept. The combination of TTFields, PULSAR and an ICI is being tested and will be reported. The addition of TTFields with a pre-clinical model of PULSAR resulted in synergistic delays in tumor growth compared to the PULSAR strategy alone when tested using three different subcutaneous tumor models. This combination is well suited for the addition of an ICI.