Predicting response to immunotherapy with hyperpolarized 13C MRI

Summary Many cancers are treated with immunotherapy, sometimes leading to durable remissions and, in rare cases, cures. However, individual responses are variable, and few biomarkers are clinically validated to predict response. Current methods to detect on-treatment response are also not ideal. Evaluation of therapeutic efficacy, including response evaluation criteria in solid tumors (RECIST) and immune-response related criteria (irRC), is based on computed tomography (CT) and magnetic resonance imaging (MRI). However, these criteria often prove insufficient in the immunotherapy setting due to pseudoprogression caused by immune infiltration into the tumor, resulting in apparent tumor enlargement despite death of cancer cells. Another problem is the long period between initiation of therapy and assessment (typically at least 3 months). Detecting resistance earlier is critical because patients at advanced stages of cancer may have only months to live and toxicity can be severe. If resistance to a toxic and ineffective therapy could be detected quickly, the patient could transition to an alternate therapy. For many reasons, the emerging technology of hyperpolarized (HP) 13C MRI may be particularly suited to overcoming current deficiencies in monitoring immunotherapy. HP 13C MRI is a safe, quantitative and nonradioactive approach that enables real-time monitoring of metabolism. Hyperpolarization techniques enrich the 13C signal-to-noise ratio >104-fold, making metabolic imaging of molecules by MRI feasible. Clinical studies have shown that a rapid (<2 minutes) HP 13C MRI measurement of conversion of infused HP [1-13C]pyruvate to [1-13C]lactate, a measure of glycolysis, can provide information about tumor aggressiveness and detect response to therapy since glycolysis often decreases when cells stop growing or die. Recently, [1-13C]pyruvate co-polarized with 13C-urea received investigational new drug (IND) approval from the Food and Drug Administration (FDA) for studies in humans. Unlike HP [1-13C]pyruvate, HP 13C-urea is a metabolically inactive, predominantly extracellular agent whose MR signal is not affected by metabolic conversions but instead reflects blood flow, tissue perfusion, and probe distribution volume. This dual HP-pyruvate/urea agent uniquely permits simultaneous evaluation of metabolism and perfusion that can reveal the enhanced metabolism and reduced perfusion associated with poor response to systemic therapy and early relapse or disease progression of cancer. Another HP agent, [1,4-13C2]fumarate, offers the opportunity to detect cell death. Few preclinical or clinical studies have investigated immunotherapy and HP 13C MRI. The proposed project will use syngeneic mice bearing matched bladder cancers sensitive and resistant to immunotherapy to test whether changes in glycolysis, perfusion and/or cell death as measured by HP [1-13C]pyruvate/13C-urea and [1,4-13C2]fumarate MRI can detect response to immunotherapy earlier and more accurately than current standard of care imaging modalities. Project Number: 1R21CA303193-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Renuka Sriram | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $421,685 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 ISB-M (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371476