Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer.

Target tissues include the active bone marrow, associated with radiogenic leukemia, and total shallow marrow, associated with radiogenic bone cancer. Monoenergetic electron emissions are considered over the energy range 1 keV to 10 MeV for the following sources: bone marrow (active and inactive), trabecular bone (surfaces and volumes), and cortical bone (surfaces and volumes). Specific absorbed fractions are computed according to the MIRD schema, and are given as skeletal-averaged values in the paper with site-specific values reported in both tabular and graphical format in an electronic annex. The distribution of cortical bone and spongiosa at the macroscopic dimensions of the phantom, as well as the distribution of trabecular bone and marrow tissues at the microscopic dimensions of the phantom, are imposed through detailed analyses of whole-body ex-vivo CT images (1 mm resolution) and spongiosa-specific ex-vivo microCT images (30 μm resolution), respectively, taken from a 40-year male cadaver. The method utilized in this work includes: (1) explicit accounting for changes in marrow self-dose with variations in marrow cellularity, (2) explicit accounting for electron escape from spongiosa, (3) explicit consideration of spongiosa cross-fire from cortical bone, and (4) explicit consideration of the ICRP’s change in the surrogate tissue region defining the location of the osteoprogenitor cells (from a 10-μm endosteal layer covering the trabecular and cortical surfaces, to a 50-μm shallow marrow layer covering trabecular and medullary cavity surfaces). Skeletal-averaged values of absorbed fraction in the present model are noted to be very compatible with those weighted by the skeletal tissue distributions found in the ICRP Publication 110 adult male and female voxel phantoms, but are in many cases incompatible with values used in current and widely implemented internal dosimetry software.

Stereotactic radiosurgery (SRS) is a procedure that delivers a single large radiation dose to a well-defined target. Here, we describe a frameless SRS technique suitable for intracranial targets in canines. Medical records of dogs diagnosed with a primary intracranial tumour by imaging or histopathology that underwent SRS were retrospectively reviewed. Frameless SRS was used successfully to treat tumours in 51 dogs with a variety of head sizes and shapes. Tumours diagnosed included 38 meningiomas, 4 pituitary tumours, 4 trigeminal nerve tumours, 3 gliomas, 1 histiocytic sarcoma and 1 choroid plexus tumour. Median survival time was 399 days for all tumours and for dogs with meningiomas; cause-specific survival was 493 days for both cohorts. Acute grade III central nervous system toxicity (altered mentation) occurred in two dogs. Frameless SRS resulted in survival times comparable to conventional radiation therapy, but with fewer acute adverse effects and only a single anaesthetic episode required for therapy.

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An important problem in internal dosimetry is the assessment of energy deposition by beta particles within trabecular regions of the skeleton. Recent dosimetry methods for trabecular bone are based on Monte Carlo particle transport simulations within three-dimensional (3D) images of real human bone samples. Nuclear magnetic resonance (NMR) microscopy is a 3D imaging technique of choice due to the large signal differential between bone tissue and the water-filled marrow cavities. Image voxel sizes currently used in NMR microscopy are between 50 microm and 100 microm, but the images are time consuming to acquire and can only be performed at present for in vitro samples. It is therefore important to evaluate what resolution is best suitable in order to properly characterize the trabecular microstructure, to adequately predict the tissue dosimetry, and to minimize imaging time. In this work, a mathematical model of trabecular bone, composed of a distribution of spherical marrow cavities, was constructed. The mathematical model was subsequently voxelized with different voxel sizes (16 microm to 1,000 microm) to simulate 3D NMR images. For each image, voxels are assigned to either bone or marrow according to their enclosed marrow fraction. Next, the images are coupled to the EGS4 electron transport code and absorbed fractions to bone and marrow are calculated for a marrow source of monoenergetic electrons. Radionuclide S values are also determined for the voxelized images with results compared to data calculated for the pure mathematical sample. The comparison shows that for higher energy electrons (>400 keV), good convergence of the results is seen even within images of poor resolution. Above 400 keV, a voxel resolution as large as 300 microm results in dosimetry errors below 5%. For low-energy electrons and high-resolution images, the self-dose to marrow is also determined to within 5% accuracy. Nevertheless, increased voxelization of the image overestimates the surface area of the bone-marrow interface leading to errors in the cross-dose to bone as high as 25% for some low-energy beta emitters.

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In this study, a comprehensive electron dosimetry model of newborn skeletal tissues is presented. The model is constructed using the University of Florida newborn hybrid phantom of Lee et al (2007 Phys. Med. Biol. 52 3309-33), the newborn skeletal tissue model of Pafundi et al (2009 Phys. Med. Biol. 54 4497-531) and the EGSnrc-based Paired Image Radiation Transport code of Shah et al (2005 J. Nucl. Med. 46 344-53). Target tissues include the active bone marrow (surrogate tissue for hematopoietic stem cells), shallow marrow (surrogate tissue for osteoprogenitor cells) and unossified cartilage (surrogate tissue for chondrocytes). Monoenergetic electron emissions are considered over the energy range 1 keV to 10 MeV for the following source tissues: active marrow, trabecular bone (surfaces and volumes), cortical bone (surfaces and volumes) and cartilage. Transport results are reported as specific absorbed fractions according to the MIRD schema and are given as skeletal-averaged values in the paper with bone-specific values reported in both tabular and graphic format as electronic annexes (supplementary data). The method utilized in this work uniquely includes (1) explicit accounting for the finite size and shape of newborn ossification centers (spongiosa regions), (2) explicit accounting for active and shallow marrow dose from electron emissions in cortical bone as well as sites of unossified cartilage, (3) proper accounting of the distribution of trabecular and cortical volumes and surfaces in the newborn skeleton when considering mineral bone sources and (4) explicit consideration of the marrow cellularity changes for active marrow self-irradiation as applicable to radionuclide therapy of diseased marrow in the newborn child.