Biology subjects

Ong, I.

Publications and source records attributed to Ong, I..

4 recordsLinked to original sources

bioRxiv2026

Optimized dosing of spatially heterogeneous radiopharmaceutical therapy reprograms poorly immunogenic tumors to enhance response to immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are ineffective in patients with poorly immunogenic tumors due to exclusion or exhaustion of effector T cells in the tumor microenvironment (TME) and/or inadequate priming of tumor-specific T cells. Preclinical and clinical studies suggest that radiopharmaceutical therapy (RPT) may overcome such challenges, but an optimal approach to RPT dosing has not been clarified in combination with ICIs. Conventional RPT dosimetry emphasizes mean absorbed radiation doses in tumors and normal tissues, neglecting the spatial distribution of this dose in the TME. We hypothesize that RPT dose heterogeneity in tumors may be leveraged to initiate spatially restricted immuno-radiobiological effects in TME that potentiate antitumor immunity when injecting an activity that delivers high dose (V10%>20 Gy) while also preserving low dose regions (V90%<2.5 Gy) in the TME and not inducing systemic lymphopenia. In studies using lutetium-177 RPT in combination with ICIs, administered activities that met these dosimetric optimization metrics occurred at different mean tumor doses for different RPT agents and different models, yet each achieved therapeutic efficacy in poorly immunogenic murine tumors. Spatial transcriptomics at day 7 after RPT revealed heterogeneous distribution of tumor cell markers with distinct dose-response profiles and localization of dendritic cell (DC) migratory markers in regions of moderate/high dose response marker expression. Combination therapy sustained conventional type 1 DC (cDC1) activation in tumor draining lymph nodes and promoted systemic expansion of antigen-specific CD8 T cells, while serial biopsies revealed effector T cell recruitment and inflammatory cytokine expression in the TME. Optimized intratumoral dose heterogeneity may enable and predict response to ICIs when combined with RPT in tumors not responding adequately to ICIs alone.

cancer biology↗

bioRxiv2026

Low-dose radiopharmaceutical therapy enhances the efficacy of B7-H3 CAR T cells in murine metastatic neuroblastoma

Background: Chimeric antigen receptor (CAR) T cell therapy has had clinical success in hematologic malignancies, but limited efficacy is seen in solid tumors. In this study, we investigated whether systemic CAR T cell therapy could be enhanced in metastatic models of neuroblastoma when combined with radiopharmaceutical therapy (RPT). Methods: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cell phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD-Rag1nullIL2rgnull (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks. Results: In models of metastatic neuroblastoma, 177Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo. Pre-treatment of tumor cells with 177Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro. Co-culture of CAR T cells with irradiated tumors led to increases in PD-1+TIM3+LAG3+ T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy. Conclusions: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.

cancer biology↗

bioRxiv2026

Intratumoral dose heterogeneity promotes adaptive anti-tumor immunity and predicts clinical response to radiopharmaceutical therapy

Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering <2.5 Gy to >20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8+ T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.

cancer biology↗

bioRxiv2021

Systematic assessment of lipid profiles for the discovery of tissue contributors to the circulating lipid pool in cold exposure

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as acute stresses such as fasting and cold exposure. Advances in mass spectrometry based lipidomics have uncovered the complexity of the plasma lipidome which includes over 500 lipids that serve functional roles including energy substrate and signaling molecule. The plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge is establishing the tissues of origin and uptake for various plasma lipids, which is necessary to determine the lipid function. Using cold exposure as an acute stress, we performed global lipidomics on the plasma and nine tissues that may contribute to the circulating pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides were significantly changed with cold exposure. Through computational assessment, we identified the liver and brown adipose tissue (BAT) as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the BAT and kidney as regulators of the plasma ceramide pool. These studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have implications in understanding the function of plasma ACars and ceramides, which are elevated in metabolic diseases. SummaryThere are over 500 identified lipids in circulating plasma, many without known origin or function. Using untargeted lipidomics on plasma and nine other tissues of cold exposed mice, we identified novel regulation of circulating acylcarnitines through the kidney and intestine, and a multiorgan system that regulates plasma ceramides. Our findings offer new targets for the study and functional characterization of circulating lipids in acute cold exposure and a computational resource for other investigators to explore multi-tissue lipidome remodeling during cold exposure. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY HighlightsO_LIGlobal lipidomics atlas of 9 tissues and plasma demonstrate dynamic shift with cold exposure. C_LIO_LIAdaptive resource for the selection of extraction method, data processing, and data analysis of multi-tissue global lipidomics data. C_LIO_LIRegression analysis identified the liver, BAT, intestine, and kidney as regulators of the plasma acylcarnitine pool that are not apparent by lipid levels alone. C_LIO_LIAcute cold exposure increases plasma ceramide levels, with the BAT and kidney as major contributors C_LI

biochemistry↗