Drew A. Torigian

CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

CD40 immunotherapy shows efficacy in treating pancreatic cancer in mice and humans by eliciting antitumor immunity. Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.

Mesothelin-Specific Chimeric Antigen Receptor mRNA-Engineered T Cells Induce Antitumor Activity in Solid Malignancies

Beatty, Haas, and colleagues report antitumor activity in two patients treated with autologous T cells transfected with mRNA encoding a chimeric antigen receptor that recognizes mesothelin and contains the CD3-ζ and 4-1BB costimulatory domains (CARTmeso). The short-lived CARTmeso cells induced novel antiself antibodies and a broadly directed epitope spreading. Off-target toxicity due to the expression of target antigens in normal tissue represents a major obstacle to the use of chimeric antigen receptor (CAR)-engineered T cells for treatment of solid malignancies. To circumvent this issue, we established a clinical platform for engineering T cells with transient CAR expression by using in vitro transcribed mRNA encoding a CAR that includes both the CD3-ζ and 4-1BB costimulatory domains. We present two case reports from ongoing trials indicating that adoptive transfer of mRNA CAR T cells that target mesothelin (CARTmeso cells) is feasible and safe without overt evidence of off-tumor on-target toxicity against normal tissues. CARTmeso cells persisted transiently within the peripheral blood after intravenous administration and migrated to primary and metastatic tumor sites. Clinical and laboratory evidence of antitumor activity was shown in both patients, and the CARTmeso cells elicited an antitumor immune response revealed by the development of novel antiself antibodies. These data show the potential of using mRNA-engineered T cells to evaluate, in a controlled manner, potential off-tumor on-target toxicities and show that short-lived CAR T cells can induce epitope spreading and mediate antitumor activity in patients with advanced cancer. Thus, these findings support the development of mRNA CAR-based strategies for carcinoma and other solid tumors. Cancer Immunol Res; 2(2); 112–20. ©2013 AACR.

Positron Emission Tomography as a Diagnostic Tool in Infection: Present Role and Future Possibilities

The past decade has witnessed the emergence of yet another promising application of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in the detection and management of patients with infection and inflammatory disorders. This phenomenon is quite evident when the peer-reviewed scientific literature is searched for on this topic. Among these scientific communications, the 6 conditions in which FDG-PET has demonstrated its greatest utility include (1) chronic osteomyelitis, (2) complicated lower-limb prostheses, (3) complicated diabetic foot, (4) fever of unknown origin, (5) acquired immunodeficiency syndrome (ie, AIDS), and (6) vascular graft infection and fistula. On the basis of published literature, orthopedic infections, particularly those related to implanted prostheses and osteomyelitis (including that occurring in the setting of a complicated diabetic foot), can be detected successfully by the use of FDG-PET and, therefore, this modality has great promise for becoming the study of choice in these complex settings. Increasingly, this technique is being used to detect infection in soft tissues, including those representing the sources of fever of unknown origin. The ability of FDG-PET to diagnose vascular graft infection and fistula, even when the anatomical imaging modalities are inconclusive, is of considerable interest to practitioners of vascular surgery. Combined PET/computed tomography (CT) imaging has the potential to determine the sites of infection or inflammation with high precision. The data on the role of PET/CT imaging in the assessment of infection and inflammation is sparse, but this combined modality approach may prove to be the study of choice in foreseeable future for precise localization of involved sites. However, the role of PET/CT may be limited in the presence of metallic artifacts (such as those caused by prostheses) adjacent to the sites of infection.

Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

PET/MR Imaging : Technical Aspects and Potential Clinical Applications

UNLABELLED Instruments that combine positron emission tomography (PET) and magnetic resonance (MR) imaging have recently been assembled for use in humans, and may have diagnostic performance superior to that of PET/computed tomography (CT) for particular clinical and research applications. MR imaging has major strengths compared with CT, including superior soft-tissue contrast resolution, multiplanar image acquisition, and functional imaging capability through specialized techniques such as diffusion-tensor imaging, diffusion-weighted (DW) imaging, functional MR imaging, MR elastography, MR spectroscopy, perfusion-weighted imaging, MR imaging with very short echo times, and the availability of some targeted MR imaging contrast agents. Furthermore, the lack of ionizing radiation from MR imaging is highly appealing, particularly when pediatric, young adult, or pregnant patients are to be imaged, and the safety profile of MR imaging contrast agents compares very favorably with iodinated CT contrast agents. MR imaging also can be used to guide PET image reconstruction, partial volume correction, and motion compensation for more accurate disease quantification and can improve anatomic localization of sites of radiotracer uptake, improve diagnostic performance, and provide for comprehensive regional and global structural, functional, and molecular assessment of various clinical disorders. In this review, we discuss the historical development, software-based registration, instrumentation and design, quantification issues, potential clinical applications, potential clinical roles of image segmentation and global disease assessment, and challenges related to PET/MR imaging. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121038/-/DC1.

Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]-Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT): A Pilot Study

OBJECTIVE To evaluate the feasibility of using [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) to detect and quantify systemic inflammation in patients with psoriasis. DESIGN Case series with a nested case-control study. SETTING Referral dermatology and preventive cardiology practices. PARTICIPANTS Six patients with psoriasis affecting more than 10% of their body surface area and 4 controls age and sex matched to 4 of the patients with psoriasis for a nested case-control study. MAIN OUTCOME MEASURES The FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean standardized uptake value, a measure of FDG tracer uptake by macrophages and other inflammatory cells. RESULTS FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints was observed in a patient with psoriatic arthritis as well as in 1 patient with no history of joint disease or joint symptoms. In a nested case-control study, FDG-PET/CT imaging demonstrated increased vascular inflammation in multiple segments of the aorta compared with controls. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate analysis (mean β = 0.33; P < .001). Patients with psoriasis further demonstrated increased hepatic inflammation after adjusting for cardiovascular risk factors (β = 0.18; P < .001), but the association was no longer significant when adjusted for alcohol intake (β = -0.25; P = .07). CONCLUSION FDG-PET/CT is a sensitive tool for identifying inflammation and can be used to identify clinically observed inflammation in the skin and subclinical inflammation in the blood vessels, joints, and liver of patients with psoriasis.

Role of Modern Imaging Techniques for Diagnosis of Infection in the Era of 18F-Fluorodeoxyglucose Positron Emission Tomography

SUMMARY During the past several years, it has become quite evident that positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) imaging can play a major role in the management of patients with suspected infection. Particularly, several groups have demonstrated that this powerful imaging methodology is very effective in the evaluation of osteomyelitis, infected prostheses, fever of unknown origin, and AIDS. In view of its extraordinary sensitivity in detecting disease activity and the ability to quantitate the degree of FDG uptake, PET might prove to be an appropriate modality for monitoring disease activity and evaluating response to therapy. FDG-PET has many advantages over existing imaging techniques for the diagnosis of infectious diseases. These include feasibility of securing diagnostic results within 1.5 to 2 h, excellent spatial resolution, and accurate anatomical localization of sites of abnormality. The availability of PET/computed tomography as a practical tool has further enhanced the role of metabolic imaging in many settings. In the future, this modality is very likely to be employed on a routine basis for detecting, characterizing, and monitoring patients with suspected and proven infection.

Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer

Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 109 autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8+ lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes.

Diagnostic Performance of FDG-PET, MRI, and Plain Film Radiography (PFR) for the Diagnosis of Osteomyelitis in the Diabetic Foot

BackgroundThe early and accurate diagnosis of osteomyelitis in the diabetic foot is essential to provide appropriate treatment and obviate long-term complications of the disease. The currently employed non-invasive imaging modalities such as plain film radiography (PFR) lack the sensitivity to accurately exclude osteomyelitis, while magnetic resonance imaging (MRI) is limited by its low specificity and contraindications in certain patients. Therefore, accurate non-invasive detection of osteomyelitis in the diabetic foot remains a challenge. [18F]-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) has been proven useful in other settings to detect infection. In this ongoing prospective study, we assessed the diagnostic performance of FDG-PET to diagnose osteomyelitis in the diabetic foot and compared it with that of MRI and PFR.MethodsPatients who met the prespecified criteria for complicated diabetic foot underwent FDG-PET, MRI, and PFR of the feet. Each imaging study was then interpreted in a blinded fashion for presence of osteomyelitis or other abnormalities. The gold standard for diagnosis in each patient was based on surgical, microbiological, and clinical follow-up results.ResultsOne hundred ten consecutive patients have been enrolled to date into this prospective project. FDG-PET correctly diagnosed osteomyelitis in 21 of 26 patients and correctly excluded it in 74 of 80, with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 81%, 93%, 78%, 94%, and 90%, respectively. MRI correctly diagnosed osteomyelitis in 20 of 22 and correctly excluded it in 56 of 72, with sensitivity, specificity, PPV, NPV, and accuracy of 91%, 78%, 56%, 97%, and 81%, respectively. PFR correctly diagnosed osteomyelitis in 15 of 24 and correctly excluded it in 65 of 75, with sensitivity, specificity, PPV, NPV, and accuracy of 63%, 87%, 60%, 88%, and 81%, respectively.ConclusionFDG-PET is a highly specific imaging modality for the diagnosis of osteomyelitis in diabetic foot and, therefore, should be considered to be a useful complimentary imaging modality with MRI. In the setting where MRI is contraindicated, the high sensitivity and specificity of FDG-PET justifies its use after a negative or inconclusive PFR to aid an accurate diagnosis.

Diagnosis of Pneumonia With an Electronic Nose: Correlation of Vapor Signature With Chest Computed Tomography Scan Findings

Objectives/Hypothesis: The electronic nose is a sensor of volatile molecules that is useful in the analysis of expired gases. The device is well suited to testing the breath of patients receiving mechanical ventilation and is a potential diagnostic adjunct that can aid in the detection of patients with ventilator‐associated pneumonia.