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The causes of death in COVID-19 patients with cardiac injury are uncertain.We conducted a case-control study and reviewed the electronic medical record of 109 deceased COVID-19 patients with cardiac injury on admission and 32 deceased COVID-19 patients without cardiac injury at two hospitals in Rhode Island.Among the 109 deceased COVID-19 patients who had cardiac injury on admission, 79 patients (72.5%) died of hypoxic respiratory failure, 21 patients (19.2%) of multi-organ failure and septic shock, 6 patients (5.5%) of cardiac arrhythmia, 3 patients (2.8%) of severe kidney failure as the immediate causes of death. We observed a similar pattern of distribution when compared to deceased patients without cardiac injury on admission (n=32).The main causes of death of COVID-19 patients with cardiac injury were non-cardiac, mostly hypoxic respiratory failure. Cardiac-related arrhythmia only accounted for a small proportion of cases.

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4–31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.

Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA

Melanoma has been a long-standing focal point for immunotherapy development. In this review, we explore the evolution of melanoma treatments with particular attention to the history and recent advances in melanoma immunotherapy. We also discuss novel combinations of these modalities and their potential to offer novel therapeutic options for patients with advanced melanoma.

Highlights • COVID-19 can cause a hyperinflammatory state akin to cytokine release syndrome (CRS). • Our report shows the efficacy and safety of using anti-IL-6/IL-6-R therapy in 31 patients. • Treatment at the onset of severe CRS may be the ideal window for intervention. • Long term effects of these agents are currently lacking., The SARS-CoV-2 virus responsible for the COVID-19 pandemic can result in severe or fatal disease in a subset of infected patients. While the pathogenesis of severe COVID-19 disease has yet to be fully elucidated, an overexuberant and harmful immune response to the SARS-CoV-2 virus may be a pivotal aspect of critical illness in this patient population. The inflammatory cytokine, IL-6, has been found to be consistently elevated in severely ill COVID-19 patients, prompting speculation that IL-6 is an important driver of the pathologic process. The inappropriately elevated levels of inflammatory cytokines in COVID-19 patients is similar to cytokine release syndrome (CRS) observed in cell therapy patients. We sought to describe outcomes in a series of severely ill patients with COVID-19 CRS following treatment with anti-IL-6/IL-6-Receptor (anti-IL-6/IL-6-R) therapy, including tocilizumab or siltuximab. At our academic community medical center, we formed a multi-disciplinary committee for selecting severely ill COVID-19 patients for therapy with anti-IL-6 or IL-6-R agents. Key selection criteria included evidence of hyperinflammation, most notably elevated levels of C-reactive protein (CRP) and ferritin, and an increasing oxygen requirement. By the data cutoff point, we treated 31 patients with anti-IL-6/IL-6-R agents including 12 who had already been intubated. Overall, 27 (87%) patients are alive and 24 (77%) have been discharged from the hospital. Clinical responses to anti-IL-6/IL-6-R therapy were accompanied by significant decreases in temperature, oxygen requirement, CRP, IL-6, and IL-10 levels. Based on these data, we believe anti-IL-6/IL-6-R therapy can be effective in managing early CRS related to COVID-19 disease. Further study of anti-IL-6/IL-6-R therapy alone and in combination with other classes of therapeutics is warranted and trials are underway.

Background There has been a significant improvement in survival of advanced malignancies with the advent of checkpoint inhibitors. These newer treatment modalities come with a wide spectrum of unique side effects, termed immune related adverse events (irAE), ranging from mild skin rash to severe colitis. Included in that spectrum is the rare side effect of autoimmune diabetes mellitus. Despite a few case reports illustrating the incidence of autoimmune diabetes associated with immunotherapy, there has not been much mentioned about exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading to de novo diagnosis of type 2 diabetes mellitus. Case presentation We report the case of a 42 year old man with metastatic melanoma and no prior history of diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in the absence of prior personal or family history. Autoimmune or type 1 diabetes mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65 (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2) antibody. Conclusions This case report highlights the importance of recognizing rare but serious adverse events related to immunotherapy and incorporation of appropriate tools for early identification and management in national cancer treatment guidelines.

Background: Cholangiocarcinoma (CCA) includes cancers arising from the intrahepatic and extrahepatic bile ducts. The etiology and pathogenesis of CCA remain poorly understood. This is the first study investigating both incidence patterns of CCA from 1973 through 2012 and demographic, clinical, and treatment variables affecting survival of patients with CCA. Patients and Methods: Using the SEER database, age-adjusted incidence rates were evaluated from 1973-2012 using SEER*Stat software. A retrospective cohort of 26,994 patients diagnosed with CCA from 1973-2008 was identified for survival analysis. Cox proportional hazards models were used to perform multivariate survival analysis. Results: Overall incidence of CCA increased by 65% from 1973-2012. Extrahepatic CCA (ECC) remained more common than intrahepatic CCA (ICC), whereas the incidence rates for ICC increased by 350% compared with a 20% increase seen with ECC. Men belonging to non-African American and non-Caucasian ethnicities had the highest incidence rates of CCA. This trend persisted throughout the study period, although African Americans and Caucasians saw 50% and 59% increases in incidence rates, respectively, compared with a 9% increase among other races. Median overall survival (OS) was 8 months in patients with ECC compared with 4 months in those with ICC. Our survival analysis found Hispanic women to have the best 5-year survival outcome (P

Purpose Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. Patients and Methods A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m2 every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). Results The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. Conclusion Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m2 once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.

OBJECTIVES: There are no effective treatment options for patients with unresectable CEA+ liver metastases (LM) from gastrointestinal adenocarcinoma refractory to conventional systemic therapy. In the previous Hepatic Immunotherapy for Metastases (HITM) phase I study we demonstrated the safety and biologic activity of anti-CEA CAR-T cell hepatic artery infusions (HAI). HITM-SIR was a single arm phase Ib trial testing anti-CEA CAR-T HAI followed by selective internal radiation therapy (SIRT) in patients with refractory CEA+ LM. METHODOLOGY: We enrolled 8 patients with unresectable, chemotherapy refractory CEA+ LM and 6/8 completed the study. Two patients were withdrawn for disease progression prior to CAR-T infusion and biliary obstruction due to centrally located disease. Limited extrahepatic disease (EHD) was permitted. Subjects received 3 HAI of anti-CEA CAR-T cells (1e10 cells per dose) along with low dose continuous IL-2 infusions (50,000 IU/kg/day). SIRT was administered in standard fashion 2 weeks following the 3rd CAR-T HAI. Primary objective was to establish safety of the CAR-T/SIRT combination. Secondary objectives included response assessed by modified RECIST (mRECIST), immune-related response criteria (irRC), and tumor marker kinetics. RESULTS: The mean age for enrolled subjects was 54.6 years (39-61) with 3 women and 5 men. Histologies (completed patients): 2 colon, 2 rectal, and 2 pancreas. This heavily pre-treated, advanced disease group of patients received an average of 2.3 lines of prior chemotherapy, 3/6 had >10 LM, and the average largest LM size was 7.3 cm. The average transduction efficiency as measured by CAR expression was 60.4%, with 90.9% viability, and an average production time for >3e10 cells of 13.8 days. There were no grade (G) 4/5 events related to the CAR-T, SIRT, or combination. Toxicities included G 1/2 liver function test elevations (n=5/6), fever (n=5/6), hypereosinophilia (n=2/6), and edema (n=2/6). G3 toxicities included colitis (n=2/6), fever (n=2/6), and edema (n=2/6). One patient experienced a hypertensive crisis during a single CAR-T infusion but tolerated 2 infusions without incident. All colitis episodes resolved with IL-2 dose reductions. Post-SIRT serum CEA decreases were noted in 2/6 patients (-40% and -71%) with CA19-9 decreases in 2/5 detectable patients (-31% and -32%). When considering all on-study time points, 5/6 patients had CEA responses (mean decrease 59.7%) and 4/5 patients expressing CA 19-9 decreases (mean 59.6%). At completion of the study, 3/6 patients had stable disease (SD) in the liver by mRECIST and irRC, and 3/6 SD overall by irRC. Target liver lesion decreases in size among patients with SD ranged from 6-28%. Regression of extrahepatic tumors or abscopal effects were noted in 2/6 at lung and bone sites. One patient remains without evidence of viable liver disease at 10.8 months follow-up. The median overall survival time for all patients is 6.9 months (range 3.8-10.8+). CONCLUSIONS: Following this phase Ib trial, the recommended phase 2 dose for anti-CEA CAR-T HITM infusions is 1010 cells with or without SIRT. The favorable safety profile and evidence of biologic activity indicate that CAR-T HITM infusions should be further studied in a phase 2 trial. Clinical trial information: NCT02416466. Citation Format: Steven C. Katz, Ethan Prince, Marissa Cunetta, Prajna Guha, Ashley Moody, Vincent Armenio, Li J. Wang, N. Joseph Espat, Richard P. Junghans. HITM-SIR: Phase Ib trial of CAR-T hepatic artery infusions and selective internal radiation therapy for liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT109. doi:10.1158/1538-7445.AM2017-CT109

e15620 Background: Cholangiocarcinomas are invasive carcinomas of uncommon diagnosis and often diagnosed at an advanced and metastatic stage. To this date, there is limited clinical data to support a standard chemotherapy regimen. Single agent systemic chemotherapy such as 5FU or gemcitabine achieves ORR of about 25% while combination regimens including 5-FU, adriamycin, mitomycin or 5-FU and cisplatin has OS of less than a year. Methods: We conducted a single institution retrospective analysis of survival, response and toxicity in patients with advanced or metastatic hepatobiliary carcinoma who had been treated with fluoropyrimidine, irinotecan, and oxaliplatin combination therapy from October 2008 to May 2015. Primary endpoint was PFS measured as the date of first treatment until evidence of clinical progression and/or death. Secondary endpoint was toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE) for non hematologic and hematologic toxicity. Patients were age greater or equal to 18, histologically confirmed, locally advanced unresectable or metastatic adenocarcinoma of the biliary tract (intrahepatic or extrahepatic cholangiocarcinoma), treatment naive or one prior chemotherapy, ECOG performance status of 0-2. Results: Twenty-five patients were eligible for analysis. A total of six patients (24%) received FOLFIRINOX either as first line therapy or as a second line therapy after progression on gemcitabine based regimen. The median PFS was 5 months (151 days). The median OS was about 14.5 months (436 days). Frequency of hematologic toxicity was more common than non-hematologic toxicity. Thrombocytopenia (67%) and nausea (67%) were the most common adverse event. No treatment related death was recorded. All patients discontinued therapy due to disease progression. Conclusions: In this single institution retrospective outcome analysis, FOLFIRINOX was shown to have activity in maintaining disease control as either a first or second line therapy in advanced cholangiocarcinoma. Hematologic and non-hematologic side effects were frequent but manageable without significant treatment delay or discontinuation. There was no treatment related deaths.

We perform large-eddy simulations of turbulent convection in a cubic cell for Rayleigh numbers, Ra, between ${10}^{6}$ and ${10}^{10}$ and the molecular Prandtl number, $\text{Pr}=0.7$. The simulations were carried out using a second-order-accurate finite-difference method in which subgrid-scale fluxes of momentum and heat were both parametrized using a Lagrangian and dynamic Smagorinsky model. The scaling of the root-mean-square fluctuations of density (temperature) and velocity measured in the cell center are in excellent agreement with the scaling measured in the laboratory experiments of Daya and Ecke [Phys. Rev. Lett. 87, 184501 (2001)] and differ substantially from that observed in cylindrical cells. We also observe the time-averaged spatial distributions of the local heat flux and density fluctuations, and find that they are strongly inhomogeneous in the horizontal midplane, with the largest density gradients occurring at the corners at the midheight, where hot and cold plumes mix in the form of strong counter-rotating eddies.

e15583Background: Gallbladder cancer (GBC) is a rare tumor that often presents at an advanced stage and is associated with a poor prognosis. Little is known about the incidence patterns and factors...

5047 Background: NKTR-102, a topoisomerase-I inhibitor-polymer conjugate with markedly reduced peak concentrations and a continuous concentration profile, demonstrated broad antitumor activity per RECIST in a phase I study. The original phase 2 study in platinum-resistant/refractory ovarian cancer showed a 21% confirmed objective response rate (ORR) (RECIST; Vergote, ASCO 2010). Methods: 71 pts with platinum resistant/refractory ovarian cancer (PROC) were originally randomized to NKTR-102 IV at a dose of 145 mg/m2 q14d vs. q21d. In addition to being resistant/refractory to platinum, 33 pts in this analysis (16/q14d; 17/q21d) had also progressed on prior PLD. 6 of these 33 pts were platinum-refractory (progression within 28 days of last platinum dose). Eligible pts had ECOG PS 0-1, adequate renal, hepatic, and marrow function. The primary endpoint was ORR per RECIST; secondary endpoints included PFS, OS and safety. Results: For the 33 PROC pts pre-treated with PLD, median age was 59; ECOG PS 0/1 was 46%/54...