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BackgroundMedical Infrared Imaging (MII) is an investigative method that can be potentially used in emergency care to non-invasively detect thermal signatures associated with change in blood flow. We have developed a protocol for the use of MII in the Emergency Department (ED) and shown that it is feasible. To derive initial data for sample size calculations, we performed an exploratory study in patients with fever and sepsis.MethodsThe Leicester MII protocol was used to image the temperature patterns along the arm among three patient groups (control, fever and sepsis) of a total 56 patients. Anatomical markers were used to divide this gradient into upper arm, forearm, hand and finger regions. Variations in measurements within and between these regions were described.ResultsThe thermal gradient down the arm was successfully extracted in all patients. The distribution of values in each region of the arm was described in control, fever and sepsis patients. There was a significant gradient between upper arm and finger in controls (2.75, p < 0.0001), but no gradient in fever (p = 0.944) or sepsis (p = 0.710). This was reflected in the finger/arm difference, which was of -2.74°C (±3.50) in controls, -0.39C (±2.48) in fever, and -1.80°C (±3.09) in sepsis.ConclusionsThis study found different thermal gradients along the arm in control and febrile groups, and defined the degree of individual variation. It is likely that the difference between upper arm temperature and finger temperature (representing the temperature gradient down the arm) may be more useful than absolute measurements in future studies.

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Cancer cells display dysregulated amino acid synthesis underlying a key metabolic hallmark of tumorigenesis that may be exploited therapeutically via specific amino acid deprivation. In particular, we have identified that arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20), which hydrolyses exogenous arginine to citrulline and ammonia, is clinically active in argininosuccinate synthetase 1 (ASS1)-deficient non-small cell lung cancer (NSCLC) and enhances the activity of the antifolate pemetrexed. Moreover, prior studies have shown that ADI-PEG20 also induces tumoral PD-L1 expression and T cell infiltration and is additive with anti-PD-1/PD-L1 antibodies in melanoma and colorectal murine models. Here, we reverse translated ADI-PEG20 studies from patients with ASS1-deficient NSCLC, co-associating with KRAS mutations, to analyze the impact of arginine deprivation with PD1-based checkpoint immunotherapy using murine NSCLC cell line models. First, we showed the CMT64 cell line, which harbors the KRAS-G12V mutation and is resistant to anti-programmed death antibodies, was ASS1-negative and highly sensitive to ADI-PEG20 in vitro. Next, CMT64 tumor cells were implanted subcutaneously into the right flank of syngeneic immunocompetent C57BL/6 mice. Once tumors reached 80mm3 animals were randomly assigned to four groups and treated with vehicle control (PBS), ADI-PEG20 (12 mg/kg), anti-PD-1 antibodies (10 mg/kg) or the combination of ADI-PEG20 and PD-1 blockade. CMT64 tumors were refractory to PD-1 blockade while ADI-PEG20 monotherapy induced a modest tumor response, with a two-fold decrease in tumor growth compared to control (p=0.0058). In contrast, the combination of ADI-PEG20 and PD-1 blockade elicited robust anti-tumor activity with a five-fold reduction in CMT64 tumor volume compared to control (p=0.0003). Modulation of the tumor microenvironment was observed by fluorescence activated cell sorting. In particular, we noted that tumor-associated macrophages showed higher expression of MHCII upon ADI-PEG20 and anti-PD-1 therapy (p&lt;0.05). Lastly, mice treated with ADI-PEG20 and anti-PD-1 therapy, survived longer than either ADI-PEG20 or anti-PD-1 therapy alone or PBS. In summary, arginine deprivation with ADI-PEG20 and PD-1 blockade is synthetically lethal in aggressive murine NSCLC and warrants further clinical investigation. A new clinical trial evaluating ADI-PEG20 with atezolizumab in combination with pemetrexed and platinum is opening in 2020 in patients with aggressive ASS1-deficient and PD-1/PD-L1 refractory lung adenocarcinoma (ClinicalTrials.gov Identifier: NCT03498222). Citation Format: Iuliia Pavlyk, Julie Foster, Katie Dexter, Jane Sobasowski, John Bomalarski, Chiara Berlato, Frances Balkwill, Peter W Szlosarek. Pegylated arginine deiminase sensitizes ASS1-negative and KRAS mutant non-small cell lung cancer to PD-1 blockade immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2217.