T cell therapy against cancer: A predictive diffuse-interface mathematical model informed by pre-clinical studies.

T cell therapy has become a new therapeutic opportunity against solid cancers. Predicting T cell behaviour and efficacy would help therapy optimization and clinical implementation. In this work, we model responsiveness of mouse prostate adenocarcinoma to T cell-based therapies. The mathematical model is based on a Cahn-Hilliard diffuse interface description of the tumour, coupled with Keller-Segel type equations describing immune components dynamics. The model is fed by pre-clinical magnetic resonance imaging data describing anatomical features of prostate adenocarcinoma developed in the context of the Transgenic Adenocarcinoma of the Mouse Prostate model. We perform computational simulations based on the finite element method to describe tumor growth dynamics in relation to local T cells concentrations. We report that when we include in the model the possibility to activate tumor-associated vessels and by that increase the number of T cells within the tumor mass, the model predicts higher therapeutic effects (tumor regression) shortly after therapy administration. The simulated results are found in agreement with reported experimental data. Thus, this diffuse-interface mathematical model well predicts T cell behavior in vivo and represents a proof-of-concept for the role such predictive strategies may play in optimization of immunotherapy against cancer.

In Vivo MR Imaging of Fibrin in a Neuroblastoma Tumor Model by Means of a Targeting Gd-Containing Peptide.

PURPOSE: A magnetic resonance imaging contrast agent based on a tetrameric Gd-DTPA-like system linked to a fibrin-targeting peptide (Gd-F) has been designed for in vivo tumor characterization. PROCEDURES: Gd-F was synthesized following Fmoc-SPPS strategy. Binding was measured using soluble fibrin DD(E) fragment and a dried fibrin assay. Contrast efficiency was tested on human and mouse clots and in vivo on Neuro2A tumor model. An anti-thrombotic drug was used to evaluate Gd-F sensitivity for changes in fibrin availability at the tumor site. RESULTS: The high relaxivity of Gd-F (42 mM(-1) s(-1), per molecule) yielded a strong signal enhancement in human and murine clots. High contrast was also measured in vivo in Neuro2A tumors, with a persistent enhancement in tumor rim and stroma. Upon treatment with an anti-thrombotic drug, the contrast uptake was significantly reduced in the tumor area confirming the specificity of the probe. CONCLUSIONS: Gd-F resulted to be an efficient probe for tumor delineation and for monitoring fibrin deposits during tumor progression and anti-thrombotic therapy.

Macrophages and liposomes in inflammatory disease: friends or foes?

Liposome-encapsulated corticosteroids have shown to exert strong beneficial effects in inflammatory diseases, such as arthritis and cancer. To extend the clinical applicability of these potent nanomedicines, the therapeutic effect of dexamethasone phosphate loaded long-circulating liposomes (LCL-DXP) was evaluated in animal models of multiple sclerosis (MS) and Crohn's disease (CD). In mice with experimental autoimmune encephalitis (EAE), a model for MS, treatment with LCL-DXP, but not free DXP, resulted in a decrease in disease activity when compared to PBS treated mice. In contrast, in mice with chronic DSS-induced colitis, a model for CD, treatment with LCL-DXP did not induce an improvement, but in fact worsened the fecal blood loss after treatment, indicating an aggravation of the disease. It is hypothesized that modulation of macrophage polarization towards a M2 phenotype underlies the efficacy of corticosteroid-based drug delivery systems, which is supported by the presented data. On the one hand, M1 polarized macrophages are part of the pathogenesis of MS; the modulation to M2-polarization by LCL-DXP is therefore beneficial. On the other hand, M1-polarized intestinal macrophages fulfill a protective and inflammation-suppressing role in intestinal homeostasis; changing their phenotype to M2 causes reduced protection to invading microorganisms, leading to a more severe intestinal inflammation. These findings therefore indicate that the interplay between the specific phenotype of macrophages and the specific inflammatory context of the inflammatory disease in question may be an important determining factor in the therapeutic applicability of liposomal corticosteroids in inflammatory disease.

Evaluation of adipose tissue distribution in obese fa/fa Zucker rats by in vivo MR imaging: effects of peroxisome proliferator-activated receptor agonists.

High-resolution MRI of obese (fa/fa) Zucker rats was investigated to characterize and assess in vivo adipose tissue distribution. Thirty animals were gavaged with a placebo, a PPARgamma activator (pioglitazone), or a dual PPARalphagamma activator (LM 4156). At day 15, T1-weighted images were acquired in vivo using a 2TMRI system with a high in-plane spatial resolution (254 microm). Fat volumes of selected territories were measured by image segmentation, and the retroperitoneal fat was weighed post-mortem. Body-weight gain was significant with pioglitazone (101.8+/-5.9 g, p<0.01 vs. placebo). The good quality of MR images allowed the delimitation and quantification of different fat territories. In response to pioglitazone, the retroperitoneal fat was more important compared to placebo (+23%, p<0.01) while subcutaneous fat was not different. No significant effects were observed with LM 4156. In vivo measurements of fat volumes were strongly correlated with ex vivo tissue weights (r=0.91). High-resolution MRI provides an in vivo measurement of adipose tissue distribution in obese Zucker rats. Specific fat depots of regions that were particularly involved in drug response were determined in vivo. Fat remodeling was observed with pioglitazone but not with a dual PPARalphagamma activator (LM 4156).

Contrast enhancement in atherosclerosis development in a mouse model: in vivo results at 2 Tesla.

To develop an MRI method for the evaluation of contrast enhancement in early atherosclerotic plaque development in the abdominal aorta of a mouse model. Male apoE-/- mice from three groups, respectively 4 (n = 6), 8 (n = 11) and 16 (n = 4) weeks were included. Axial T1 spin echo images of the abdominal aorta were obtained above and below the renal arteries (90 microm spatial resolution) before and over 1 h after the injection of a macromolecular contrast agent. Signal enhancement was measured in the vessel wall and compared to histological features. Maximal arterial wall signal enhancement was obtained from 16 to 32 min post injection. During this time, the signal-to-noise ratio increased by a factor up to 1.7 in 16 week mice and 2.7 and 2.4 in 8 and 4 weeks mice, respectively. The enhancement of the arterial wall appeared less pronounced in the oldest mice, 16 weeks old, exhibiting more advanced lesions. Using a macromolecular gadolinium agent, contrast uptake in atherogenesis varies with lesion stage and may be related to vessel-wall permeability. Dynamic contrast-enhanced MRI may be useful to evaluate the atherosclerotic plaque activity in mice.

Atherosclerotic plaques: classification and characterization with T2-weighted high-spatial-resolution MR imaging-- an in vitro study.

PURPOSE: To evaluate if T2-weighted high-spatial-resolution magnetic resonance (MR) imaging (117 microm per pixel) can help accurate classification of atherosclerotic plaques. MATERIALS AND METHODS: Thirty human arteries and 11 carotid endarterectomy specimens from 31 patients underwent T2-weighted MR imaging (2-T magnet; repetition time, 2,000 msec; echo time, 50 msec) at room temperature. After imaging, Bouin fixative was used to fix 26 arteries, and the other 15 arteries were fixed by means of freezing. Specimens were stained with hematoxylin-eosin and safranin or Sudan lipid stain. MR images and histologic slices were classified independently by two radiologists and a pathologist, respectively, on the basis of the American Heart Association classification. RESULTS: Results with MR imaging were the following: type I-II plaques, sensitivity of 67% and specificity of 100%; type IV-Va plaques, sensitivity of 74% and specificity of 85%; type Vb plaques, sensitivity of 90% and specificity of 100%; type Vc plaques, sensitivity of 80% and specificity of 90%. No type III plaque was diagnosed in the study. The overall kappa value was 0.68. CONCLUSION: High-spatial-resolution MR imaging with T2 weighting alone can help accurate classification of fibrocalcic plaques (type Vb), but it is subject to limitations for the classification and analysis of other types of atherosclerotic plaques.

Pulsed gradient analysis using a dedicated magnetometer.

In magnetic resonance imaging and spectroscopy, knowledge of the magnetic field gradient behavior is very important. This work describes a simple way to characterize the temporal and spatial dependence of the main magnetic field when a gradient is switched. Records are performed with a home-built magnetometer. This device is controlled by a personal computer for recording and processing the NMR signals from an array of small probes spatially distributed and switched by the magnetometer. We present results of measurements on a 2-T superconducting magnet. These results show the residual defects of an active shielded gradient coils system.