Increased pyruvate-to-lactate conversion is a hallmark of HCC metabolism. In parallel, activation of pro-inflammatory immune cells triggers a metabolic switch towards anaerobic glycolysis. Hyperpolarized carbon-13 (13C) pyruvate MRI is a state-of-the-art non-invasive imaging method that offers real-time insights into tissue metabolism. Recent studies have demonstrated its promising potential in predicting responses to radiotherapy and immunotherapy in solid tumors, given the significance of pyruvate as a downstream metabolite in glycolysis. However, its application in assessing treatment response in hepatocellular carcinoma (HCC) patients remains unclear. The establishment of quantitative imaging biomarkers for predicting responses to radio-immunotherapy is an unmet need in the management of HCC patients.
While radiotherapy (RT) effectively controls localized tumors through the induction of unrepairable DNA double-stranded breaks (DSBs) and cell death, its therapeutic efficacy on distal, non-irradiated tumor cells is limited, with out-of-field recurrence being a common pattern of failure in HCC patients treated with high-dose irradiation. Atezolizumab (anti-programmed death-ligand 1; anti-PD-L1) in conjunction with bevacizumab (anti-vascular endothelial growth factor; anti-VEGF) has recently emerged as the standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC). Despite an objective response rate (ORR) of only 27%, the majority of patients succumb to HCC progression and liver failure. Our preclinical study (Hsieh et al., Science Immunology 2022) uncovered that RT, when combined with PD-L1/PD-1 blockade, induces immunogenic cell death and tumor antigen cross-presentation in antigen-presenting cells, enhancing systemic antitumor T cell responses in murine tumor models. Recent retrospective cohorts suggest that RT targeting all hepatic tumors combined with PD-L1/programmed death-1 (PD-1) blockade is associated with an improved ORR and median progression-free survival (PFS) in patients with unresectable HCC, demonstrating a favorable safety profile. The synergistic antitumor effects of this combination therapy with RT, atezolizumab, and bevacizumab have led to its increasing adoption in routine clinical practice.
This phase II non-randomized trial aims to prospectively investigate the predictive value of hyperpolarized 13C-MRI, along with comprehensive metabolomics and radiomics analyses, for immune response assessment including tumor control outcomes and toxicity in patients with HCC undergoing radiotherapy, atezolizumab, and bevacizumab.
Histologically or cytologically proven diagnosis of HCC.
Typical arterial enhancement and delayed washout on multiphasic CT or MRI.
Age ≥18 years at the time of signing informed consent document.
ECOG performance status 0-1.
Prior invasive malignancy unless disease free for a minimum of 2 years
Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields
Prior selective internal radiotherapy/hepatic arterial yttrium therapy, at any time
Untreated active hepatitis B or hepatitis C
Single group
Hyperpolarized 13C pyruvate MRI
Diagnostic testThe subject enrolled in this trial will receive DNP-MRI scanning for two times through hyperpolarized \[1-13C\]pyruvate injection (\~250 mM, 0.43 mL/Kg) before and 2-5 weeks after radiotherapy.
Dynamic Nuclear Polarization (DNP)
Dynamic Nuclear Polarization (DNP) conversion flux (pyruvate-to-lactate conversion rate \[Kpl\] and area under the curve \[AUC\]) before radiotherapy combined with atezolizumab and bevacizumab
Dynamic Nuclear Polarization (DNP)
Dynamic Nuclear Polarization (DNP) conversion flux (pyruvate-to-lactate conversion rate \[Kpl\] and area under the curve \[AUC\]) 2-5 weeks after radiotherapy combined with atezolizumab and bevacizumab
Progression free survival (PFS) by RECIST1.1
PFS is defined as the time from signing the informed consent to the first occurrence of disease progression or death from any cause (whichever occurs first) according to RECIST1.1
Local control (LC) by RECIST1.1
LC is defined as the time from signing the informed consent to the first occurrence of disease progression in the irradiated field according to RECIST1.1
Time to progression (TTP) by RECIST1.1
TTP is defined as the time from signing the informed consent to the first occurrence of disease progression according to RECIST1.1
Overall Response Rate (ORR) by RECIST1.1
ORR is defined as a complete or partial response according to RECIST1.1
Change in myeloid-derived suppressor cell (MDSC) level in peripheral blood
We will measure the level of Lin- HLA-DR- CD11b+ MDSCs in peripheral blood using flow cytometry before and 2-5 weeks after radiotherapy.
Click on the lead sponsor to view all of their trials.
