Iron Oxide Nanoparticles Inhibit Tumor Progression and Suppress Lung Metastases in Mouse Models of Breast Cancer.

Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape, leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed the activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 receptor domain-containing adaptor-inducing IFN-ß (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent, induced significant antitumor effects, suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases supports a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anticancer immune (nano)adjuvant properties to generate a therapeutic benefit without requiring uptake by cancer cells.

Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses.

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

SREBP-dependent regulation of lipid homeostasis is required for progression and growth of pancreatic ductal adenocarcinoma.

Metabolic reprogramming is a necessary component of oncogenesis and cancer progression that solid tumors undergo when their growth outstrips local nutrient supply. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including brain, breast, colon, liver, and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using subcutaneous and orthotopic xenograft models, we showed that S CAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting the clinical importance of this pathway, the SREBP pathway is broadly required for cancer cell growth, SREBP target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets genes is associated with poor survival in PDAC patients. Collectively, these results demonstrate that SCAP and the SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo , identifying SCAP as a potential therapeutic target for PDAC. SIGNIFICANCE: Our findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.

Surgical and local control outcomes after sequential short-course radiation therapy and chemotherapy for rectal cancer.

Background: Total neoadjuvant therapy (TNT) is an accepted approach for the management of locally advanced rectal cancer (LARC) and is associated with a decreased risk of development of metastatic disease compared to standard neoadjuvant therapy. However, questions remain regarding surgical outcomes and local control in patients who proceed to surgery, particularly when radiation is given first in the neoadjuvant sequence. We report on our institution's experience with patients who underwent short-course radiation therapy, consolidation chemotherapy, and surgery. Methods: We retrospectively reviewed surgical specimen outcomes, postoperative complications, and local/pelvic control in a large cohort of patients with LARC who underwent neoadjuvant therapy incorporating upfront short-course radiation therapy followed by consolidation chemotherapy. Results: In our cohort of 83 patients who proceeded to surgery, a complete/near-complete mesorectal specimen was achieved in 90 % of patients. This outcome was not associated with the time interval from completion of radiation to surgery. Postoperative complications were acceptably low. Local control at two years was 93.4 % for all patients- 97.6 % for those with low-risk disease and 90.4 % for high-risk disease. Conclusion: Upfront short-course radiation therapy and consolidation chemotherapy is an effective treatment course. Extended interval from completion of short-course radiation therapy did not impact surgical specimen quality.

Spatial analysis of nanoparticle distribution in human breast xenografts reveals nanoparticles targeted to cancer cells localized with tumor-associated stromal cells.

The biological influence of physicochemical parameters of "targeted" nanoparticles on their delivery to cancer tumors remains poorly understood. A comparative analysis of nanoparticle distributions in tumors following systemic delivery across several models can provide valuable insights. Methods: Bionized nanoferrite nanoparticles (iron oxide core coated with starch), either conjugated with a targeted anti-HER2 antibody (BH), or unconjugated (BP), were intravenously injected into athymic nude or NOD-scid gamma (NSG) female mice bearing one of five human breast cancer tumor xenografts growing in a mammary fat pad. Tumors were harvested 24 hours after nanoparticle injection, fixed, mounted, and stained. We performed detailed histopathology analysis by comparing spatial distributions of nanoparticles (Prussian blue) with various stromal cells (CD31, SMA, F4/80, CD11c, etc.) and the target antigen-expressing (HER2) tumor cells. Results: Only BH nanoparticles were retained in tumors and generally concentrated in the tumor periphery, with nanoparticle content diminishing towards the tumor interior. Nanoparticle distribution correlated strongly with specific stromal cells within each tumor type, which varied among tumor types and between mouse strains. Weak or no correlation between nanoparticle distribution and HER2 positive cells, or CD31 cells was observed. Conclusion: Antibody-labeled nanoparticles were retained across all tumors, irrespective of presence of the "target" antigen. Though presence of antibody on nanoparticles correlated with retention, non-cancerous host stromal cells were responsible for their retention in the tumor microenvironment. This study highlights gaps in our understanding of the complex biological interplay between disease and host immune biology, and the need to account for the influence of underlying aberrant tumor biology as factors determining nanoparticle fate in vivo.

An International Study of Factors Affecting Variability of Dosimetry Calculations, Part 2: Overall Variabilities in Absorbed Dose.

Dosimetry for personalized radiopharmaceutical therapy has gained considerable attention. Many methods, tools, and workflows have been developed to estimate absorbed dose (AD). However, standardization is still required to reduce variability of AD estimates across centers. One effort for standardization is the Society of Nuclear Medicine and Molecular Imaging 177Lu Dosimetry Challenge, which comprised 5 tasks (T1-T5) designed to assess dose estimate variability associated with the imaging protocol (T1 vs. T2 vs. T3), segmentation (T1 vs. T4), time integration (T4 vs. T5), and dose calculation (T5) steps of the dosimetry workflow. The aim of this work was to assess the overall variability in AD calculations for the different tasks. Methods: Anonymized datasets consisting of serial planar and quantitative SPECT/CT scans, organ and lesion contours, and time-integrated activity maps of 2 patients treated with 177Lu-DOTATATE were made available globally for participants to perform dosimetry calculations and submit their results in standardized submission spreadsheets. The data were carefully curated for formal mistakes and methodologic errors. General descriptive statistics for ADs were calculated, and statistical analysis was performed to compare the results of different tasks. Variability in ADs was measured using the quartile coefficient of dispersion. Results: ADs to organs estimated from planar imaging protocols (T2) were lower by about 60% than those from pure SPECT/CT (T1), and the differences were statistically significant. Importantly, the average differences in dose estimates when at least 1 SPECT/CT acquisition was available (T1, T3, T4, T5) were within ±10%, and the differences with respect to T1 were not statistically significant for most organs and lesions. When serial SPECT/CT images were used, the quartile coefficients of dispersion of ADs for organs and lesions were on average less than 20% and 26%, respectively, for T1; 20% and 18%, respectively, for T4 (segmentations provided); and 10% and 5%, respectively, for T5 (segmentation and time-integrated activity images provided). Conclusion: Variability in ADs was reduced as segmentation and time-integration data were provided to participants. Our results suggest that SPECT/CT-based imaging protocols generate more consistent and less variable results than planar imaging methods. Effort at standardizing segmentation and fitting should be made, as this may substantially reduce variability in ADs.