Combined VLA-4–targeted radionuclide therapy and immunotherapy in a mouse model of melanoma

Very late antigen-4 (VLA-4; also known as integrin a4ß1) is expressed at high levels in aggressive and metastatic melanoma tumors and may provide an ideal target for imaging and targeted radionuclide therapy (TRT).177Lu-DOTA-PEG4-LLP2A (177Lu-LLP2A) is a TRT that shows high affinity for VLA-4 and high uptake in B16F10 mouse melanoma tumors in vivo. Here, we report efficacy studies of177Lu-LLP2A, alone and combined with immune checkpoint inhibitors (ICIs) (anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies), in B16F10 tumor–bearing mice. Methods: Tumor cells (1 · 106) were implanted subcutaneously in C57BL/6 mice. After 8–10 d, the mice were randomized into 8 groups.177Lu-LLP2A was injected intravenously on day 8 or 9 (single dose), and ICI antibodies were administered intraperitoneally in 3 doses. Tumor growth was monitored over time via calipers. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining for apoptosis was performed on fixed tumors. In a separate study, Cy3-LLP2A or Cy3–scrambled LLP2A was injected in tumor-bearing mice, and tumors were collected 4 h after injection and then analyzed by flow cytometry and immunofluorescence microscopy using different immune cell markers. Results: TRT alone showed efficacy comparable to the dual-ICI anti-PD-1 1 anti-CTLA-4 or anti-PD-L1 1 anti-CTLA-4, whereas TRT 1 ICIs significantly enhanced survival. TUNEL staining showed that the highest levels of apoptosis were in the TRT 1 ICI groups. In addition to targeting tumor cells, TRT also bound immune cells in the tumor microenvironment. Flow cytometry data showed that the tumors consisted of about 77% tumor cells and fibroblasts (CD45-negative/ CD49d-positive) and about 23% immune cells (CD45-positive/ CD49d-positive) and that immune cells expressed higher levels of VLA-4. Cy3-LLP2A and CD49d colocalized with macrophages (CD68), T cells (CD8, CD4), and B cells (CD19). Immunohistochemical analysis identified a significant colocalization of Cy3-LLP2A and CD68. Conclusion: Combination treatment with TRT 1 ICIs targets both tumor cells and immune cells and has potential as a therapeutic agent in patients with metastatic melanoma

Gamma-ray production cross sections from neutron interactions with iron.

The initial purpose of this experiment was to provide a consistent data base of neutron-induced gamma-ray production cross sections over a large energy range for use in estimating elemental composition of the martian surface by observing gamma rays produced by cosmic ray interactions on the planet's surface [Bo02]. However, these data should be useful for other projects such as oil-well logging, accelerator transmutation of nuclear waste, shielding calculations, gamma-ray heating for nuclear reactors and verification of nuclear model calculations and databases. The goal of the measurements was to collect data on the strongest gamma rays from many samples of interest. Because of the available beam time this meant that many of the measurcments were rather short. Despite the short running time the large samples used and the good beam intensity resulted in very satisfactory results. The samples, chosen mainly as common constituents of rock and soil and measured in the same few week period, include: B&, BN, C, Al, Mg, Si, S, Cay Ti, Cr, Mn, and Fe. Be was also used as a neutron scatterer that only produces one gamma ray (478 keV from 7Li) with appreciable intensity. Thus Be can serve as a measure of neutron-induced backgrounds. In this first paper we present results for Fe

Impact of partial volume correction on the regional correspondence between in vivo [C-11]PiB PET and postmortem measures of Aβ load

The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p < 0.01, suggesting that PVC is of minimal importance in understanding the relationship between Aβ PET and neuropathologically assessed Aβ. Thus, the utility of PVC in Aβ PET imaging should continue to be examined on an application-specific basis. Keywords: Partial volume correction, Amyloid imaging, PiB, PE