Abstract A024: Preclinical quantification of sources of solid tumor resistance onset: Hypoxia and immune exhaustion
Authors: Howard J Halpern, Ralph J Weichselbaum, Boris Epel
Journal: Cancer Research (2025)

Abstract Immune Checkpoints (ICs) are saturable systems that fatigue at when sufficiently high levels of tumor antigen is generated by cytotoxic antitumor therapy. Immune Checkpoint Inhibitor (ICI) therapy increases therapy outcome from both systemic chemotherapy and localized ionizing radiation (IR). Preclinical murine cancers in syngeneic immune competent mice duplicates the immune response toof human tumors as well asand the onset of IF. IF was quantified with the mouse ortholog of the human chemokine CXCL10 responding to IR. Tumor hypoxia has long been known to induce resistance to radiation cytotoxicity. More recently, primarily in preclinical models, hypoxia was found to enhance IFimmune fatigue. Clinical 10% dose boosts of dose to hypoxic areas defined by 18Fluoromisonidazole retention failed to reach significance. Our first mammalian determination of the oxygen enhancement ratio (OER) in murine FSa fibrosarcomas show 26% higher boosts are needed. This technique can be used to explore the IR dose modification of both hypoxia and ICI. Quantification is a basic approach to clarify the onset of fatigue. IR is the best quantified cytotoxic dose physically delivered to tumors in medicine. Local tumor control probability (LTCP) is a specific outcome. A classical model of tumor control is a logistic function of IR dose, D is LTCP(D)=1/[1+exp(-k(D-D0))]. D0 is the IR dose at which only one clonogen remains. k is the rate of approach to D0. We model the immune response as a linear reduction of D0 with clonogen reduction with IR dose D whichthat generates antigens, which at a dose DF , fatigues at rate kF. D0 reduction approaching DF is modeled D0= D0(1-D/D0)/[1+exp(-kF(DF -D))] Methods: We developed Electron paramagnetic resonance (EPR) oxygen imaging (EPROI) operating at high MRI frequency (250 MHz) has been developed to provide a means by which to generate near absolute pO2 images of mammalian tumors using injectable non-toxic paramagnetic OX071 spin probe. Comparing localized stereotactic fiberoptic Oxylite phosphorescence quenching pO2 local measurements with the EPR images demonstrated excellent quantitative pO2 measurement agreement voxel by voxel between EPROI and the Oxylite fiber tip. 9.4 T MRI T2 weighted images defined pO2 registered tumor margins. Conformal opposed field radiation was delivered to FSa fibrosarcomas using tungsten loaded PLA plastic apertures mounted in an XRAD225Cx isocentric radiator. BioXcell (Lebanon, NH), anti PDL-1 antibodies at two doses 150µg or 200µg /mouse/dose are given ip on the day of IR at the D0=TCD50, 4 doses total, twice a week, ip injection after which the mice will beare followed 90 days for control. IF is quantified with the mouse ortholog of the human chemokine CXCL10. Data Presented: Using the XRAD225Cx as a 2 field conformal opposed field radiator, we have derived the first in vivo oxygen enhancement ratio. We will estimate the modification of the D0 from the BioXcell anti PDL-1 treatment for both hypoxic and well oxygenated tumor using Kaplan-Meier survival assays. Citation Format: Howard J Halpern, Ralph J Weichselbaum, Boris Epel. Preclinical quantification of sources of solid tumor resistance onset: Hypoxia and immune exhaustion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A024.