Comparison of low vs. high dose radiation to reduce intratumoral pressure, creating an optimal time window for drug delivery

Abstract

Purpose/Objective(s): Intratumoral pressure creates a major barrier for delivery and retention of immuno-oncology drugs, such as checkpoint inhibitors. A strong pressure differential between the center region and outer region of the tumor produces a convection force that prevents the diffusion of therapeutic agents into the tumor. Radiation (XRT), a cornerstone of cancer treatment and immune system activator, is an attractive strategy to reduce intratumoral pressure prior to drug delivery. Here, we explored the effects of XRT on intratumoral pressure in a mouse model for lung cancer. Materials/Methods: 344SQ-parental lung adenocarcinoma tumors (0.5 × 106 cells) were subcutaneously implanted into the legs of 8- to 12-week-old 129Sv/Ev mice. When tumors reached 7-8 mm in diameter, they were irradiated locally with XRT (two fractions of 1 Gy, three fractions of 5 Gy, 8 Gy or 12 Gy, or one fraction of 20 Gy) from a Cesium source. The different fractions were scheduled such that all treatments were completed on Day 10 after tumor implantation. Intratumoral pressure was measured using a pressure transducer device at six different time points (Days 11, 13, 18, 22, 27, 33), following 24 hours after the last fraction of XRT. Results: Low dose radiation (two fractions of 1 Gy) and higher XRT doses (three fractions of 12 Gy, one fraction of 20 Gy) reduced intratumoral pressure levels between days 11 and 13 and 13 and 22, respectively, compared to control tumors that were not irradiated. An unpaired t-test was used to compare the mean pressure between study groups. On day 13, the mean intratumoral pressure for tumors irradiated with two fractions of 1 Gy was 69.6 mmHg versus 111.4 mmHg in controls (P = 0.06). On day 22, the mean intratumoral pressure for tumors irradiated with three fractions of 12 Gy was 64.2 mmHg versus 119.2 mmHg in controls (P = 0.01); tumors irradiated with one fraction of 20 Gy had mean pressures of 39.3 mmHg on day 22 (P = 0.001). Intermediate doses of XRT (three fractions of 5 Gy or 8 Gy) failed to reduce intratumoral pressure in the measurement period. Conclusion: XRT is widely being explored, pre-clinically and clinically, in combination with immuno-oncology agents due to synergistic effects of these therapies. Optimized XRT doses can help overcome the pressure barrier for successful intratumoral delivery of immuno-oncology agents. Further work will examine how the intratumoral pressure reduction improves retention of macromolecules injected directly into tumors.