Evaluating immunotherapeutic outcomes in triple-negative breast cancer with a cholesterol radiotracer in mice.

Evaluating the response to immune checkpoint inhibitors (ICIs) remains an unmet challenge in triple-negative breast cancer (TNBC). The requirement for cholesterol in the activation and function of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged the PET radiotracer, eFNP-59. eFNP-59 is an analog of cholesterol that our group validated as an imaging biomarker for cholesterol uptake in preclinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing ICI-responsive and -nonresponsive tumors directly, uptake of fluorescent cholesterol and eFNP-59 increased in T cells from ICI-responsive tumors. We discovered that accumulation of cholesterol by T cells increased in ICI-responding tumors that received anti-PD-1 checkpoint immunotherapy. In patients with TNBC, tumors containing cycling T cells had features of cholesterol uptake and trafficking within those populations. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells allows detection of T cell activation and has potential to assess the success of ICI therapy.

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer.

Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged a novel positron emission tomography (PET) radiotracer, FNP-59. FNP-59 is an analog of cholesterol that our group has validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing immune checkpoint inhibitor (ICI)-responsive EO771 tumors to non-responsive AT-3 tumors, we found significantly higher uptake of a fluorescent cholesterol analog in T cells of the ICI-responsive tumors both in vitro and in vivo. Using the FNP-59 radiotracer, we discovered that accumulation of cholesterol by T cells increased further in ICI-responding tumors that received ant-PD-1 checkpoint immunotherapy. We verified these data by mining single cell sequencing data from patients with TNBC. Patients with tumors containing cycling T cells showed gene expression signatures of cholesterol uptake and trafficking. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells predict T cell activation and success of ICI therapy.

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Gallium-68: methodology and novel radiotracers for positron emission tomography (2012-2017).

Commercial 68Ge/68Ga generators provide a means to produce positron emission tomography agents on site without use of a cyclotron. This development has led to a rapid growth of academic literature and patents ongallium-68 (68Ga). As 68Ga positron emission tomography agents usually involve a targeting moiety attached to a metal chelator, the development lends itself to the investigation of theragnostic applications; the 68Ga-based diagnostic is utilized to determine if the biological target is present and, if so, a therapeutic isotope (e.g., 177Lu, 225Ac) can be complexed with the same scaffold to generate a corresponding radiotherapeutic. This review considers patents issued between 2012 and 2017 that contain a 68Ga-labeled molecule indexed by Chemical Abstract Services (a division of the American Chemical Society).

Fluorine-18 patents (2009-2015). Part 2: new radiochemistry.

Fluorine-18 ((18)F) is one of the most common positron-emitting radionuclides used in the synthesis of positron emission tomography radiotracers due to its ready availability, convenient half-life and outstanding imaging properties. In Part 1 of this review, we presented the first analysis of patents issued for novel radiotracers labeled with fluorine-18. In Part 2, we follow-up with a focus on patents issued for new radiochemistry methodology using fluorine-18 issued between January 2009 and December 2015.

Current imaging strategies in rheumatoid arthritis.

As remission has now become a realistic therapeutic goal in the clinical management of RA due to the introduction and widespread adoption of biologic agents, there is a greater need for earlier diagnoses and objective methods for evaluating disease activity and response to treatment. In this capacity, advanced imaging strategies are assuming an expansive clinical role, particularly as they take advantage of newer imaging technologies and the shift toward imaging at the molecular level. Molecular imaging utilizes target-specific probes to non-invasively visualize molecular, cellular, and physiological perturbations in response to the underlying pathology. Probes for nuclear and MR imaging have been and are being developed that react with discrete aspects of inflammatory and destructive pathways specific to RA. These probes in addition to new MR sequences and contrast agents have the potential to provide an earlier and more reliable assessment of clinical outcome, disease activity, severity, and location, and therapeutic response. Furthermore, these imaging strategies may enable a more fundamental understanding of critical pathophysiological processes and the advent of new molecular therapies. This review will discuss these advances in both nuclear medicine and MRI strategies for imaging RA with a particular emphasis on molecular imaging.