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Background: CF33-hNIS-anti-PD-L1 is a novel chimeric orthopoxvirus shown to have anti-cancer activity in triple negative breast cancer (TNBC) xenografts. For clinical tracking of the oncolytic virus (OV), human sodium iodide symporter (hNIS) transgene was inserted into the virus. hNIS gene expression allows cells to take up iodine and be visible by non-invasive imaging techniques. Animal studies showed that tumor cells infected with CF33-hNIS-anti-PD-L1 express functional hNIS and are visible by single-photon emission computed tomography (SPECT) or positron emission tomography (PET). The current report describes imaging results from an ongoing first-in-human trial. Methods: This is a phase I, single center, single arm clinical trial evaluating the safety and tolerability of CF33-hNIS-anti-PD-L1 intratumoral (IT) injections in patients with metastatic TNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies; ECOG 0-2; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated IT injections. Eligible patients receive CF33-hNIS-anti-PD-L1 IT at 1 of 8 assigned dose levels (from 1 × 105 PFU to 3 x 108 PFU) on Days 1 and 15 of each 28-day cycle for a total of 3 cycles of treatment. The primary objective is to evaluate the safety and tolerability of CF33-hNIS-anti-PD-L1. Secondary objectives are to determine optimal biological dose, recommended phase II dose, and response rates. Exploratory objectives include assessing feasibility of non-invasive hNIS imaging as a method of tracking viral infection and replication. SPECT whole body imaging was performed at Cycle 1 Day 8 (C1D8). Results: From October 2021 to October 2022, 8 patients were enrolled in this ongoing study and received at least 1 dose of CF33-hNIS-anti-PD-L1 injection at one of the first 3 dose levels (1 x 105, 3 x 105, or 1 x 106 PFU). All 8 patients underwent SPECT imaging at C1D8 with 6/8 patients (75%) having uptake at the site of injection on the SPECT imaging study. Four of 4 patients (100%) with injection sites at metastatic subcutaneous nodules, intramuscular masses, or axillary lymph nodes and 2/4 patients (50%) with injection sites at matted dermal metastatic lesions had uptake on SPECT. Conclusion: SPECT imaging successfully showed enhancement at the injected lesions in 75% of patients treated with CF33-hNIS-anti-PD-L1, even at current low doses, suggesting local viral replication and hNIS expression. Further analysis will evaluate the correlation of SPECT imaging results with pathologic immune cell infiltrate, viral staining, and tumor response. This is the first known report of hNIS-based imaging to track oncolytic poxvirus replication in humans and gives promise that this technology may be used for noninvasive tracking of systemically administered OV and other therapies. Citation Format: Jamie Green Rand, Dave Yamauchi, Shyambabu Chaurasiya, Jianying Zhang, Raju Pillai, Colt Egelston, Jonathan Kessler, Badri Modi, Leslie Chong, Amanda Seiz, Giovanni Selvaggi, Nick Ede, Mireya Murga, Norma Martinez, Wichanee Borisuthirattana, Hans Meisen, Susan Yost, James Waisman, Daphne Stewart, Joanne Mortimer, Yuman Fong, Yuan Yuan. hNIS imaging data from a first-in-human trial of the oncolytic virus CF33-hNIS-antiPD-L1 in patients with triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6788.

Background: Despite recent FDA approvals of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of metastatic triple negative breast cancer (mTNBC), the overall survival benefit of these therapies remains modest. Oncolytic virotherapy (OV) utilizes genetically modified viruses to infect and kill cancer cells while sparing healthy cells. CF33-hNIS-anti-PD-L1 (CHECKvacc) is a novel chimeric orthopoxvirus with robust anti-cancer activity in TNBC xenografts. Cells infected with CHECKvacc were shown to express functional human sodium-iodide symporter (hNIS) and anti-PD-L1 proteins. hNIS gene transfer allows tracking of virus by 99mTc single-photon emission computed tomography (SPECT). Our preliminary animal studies demonstrated that tumor cells infected with CHECKvacc successfully secrete functional hNIS and anti-PD-L1. CHECKvacc administered by intratumoral injection appears safe and is generally well-tolerated. CHECKvacc detects and effectively kills TNBC at doses several magnitudes lower than other OVs in xenograft models. Methods: This study is a first-in-human phase I, single center, single arm clinical trial evaluating the safety and tolerability of CHECKvacc intratumoral injection in patients with mTNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated intratumoral injections. Eligible patients receive CHECKvacc intratumorally at one of 8 assigned dose levels (1 × 105 PFU, 3 × 105 PFU, 1 × 106 PFU, 3× 106 PFU, 1 × 107 PFU, 3 × 107 PFU, 1 × 108 PFU, 3 x 108 PFU) on Days 1 and 15 of each 28-day cycle for a total of 3 cycles of treatment. The primary objective is to evaluate the safety and tolerability of CHECKvacc by CTCAE v5.0. Secondary objectives are to determine optimal biological dose, recommended phase II dose (RP2D), and response rate by RECIST1.1. The first 3 subjects of dose level 1 were enrolled sequentially for safety monitoring. Once the initial 3 subjects were treated sequentially, the study followed the Phase I Queue 3+3 (IQ 3+3) design which expands a dose level up to 8 subjects after a single DLT has been observed. Enrollment to the final RP2D may be expanded to include up to 12 patients for efficacy assessment. The estimated targeted accrual is 33 patients (minimum) to 78 patients (maximum). Correlative aims include assessing viral kinetics, viral plaque assay, 99mTc SPECT imaging for virus tracking, peripheral blood and tumor tissue for antiviral immune activation, and tumor microenvironment changes in association with response to therapy. Results: From October 2021 to June 2022, 6 patients were enrolled and received at least 1 dose of CHECKvacc injection at dose level 1 (1 x 10^5 pfu) and 2 (3 x 10^5 pfu). The intratumoral CHECKVacc injections were well tolerated. No DLTs were observed. No treatment emergent AEs (TEAEs) have been reported for the 6 patients so far. 99mTc SPECT imaging for virus tracking is on-going. Baseline and on treatment tumor biopsies were submitted for spatial immune profiling. Peripheral blood at baseline, on treatment and EOT were subjected for flow cytometry analysis. Conclusion: CF33hNIS-antiPD-L1 administered by intratumoral injection in patients with mTNBC is safe and well tolerated at the dose levels tested. Clinical trial information: NCT05081492 Citation Format: Yuan Yuan, Jamie G. Rand, Jianying Zhang, Jonathan Kessler, Badri Modi, Raju Pillai, Colt A. Egelston, Shyambabu Chaurasiya, Mireya Murga, Aileen Tang, Norma Martinez, Hans Meisen, Dave Yamauchi, Susan E. Yost, Leslie Chong, Amanda Seiz, Bonnie Nixon, Nick Ede, James Waisman, Daphne Stewart, Mina S. Sedrak, Yuman Fong. Phase I study of intratumoral administration of CF33-hNIS-antiPD-L1 (CHECKvacc) in patients with metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-03-01.

Despite the changing paradigms of melanoma treatment in recent years, there remains a relative paucity of data regarding subungual melanoma in the literature. From 2002–2018, 25 patients with subungual melanoma were surgically treated at our facility. A retrospective chart review was conducted to collect relevant demographic, clinical, pathologic, and outcomes data. The median age at diagnosis was 69 years. Most patients (60%) were male, and the melanoma lesion was most often located on the foot (68%). Acral-lentiginous was the most common histologic subtype (59%), and the median Breslow thickness was 3.4 mm. Fifteen patients (63%) underwent a sentinel lymph node biopsy as part of their surgical resection, and four of these patients (27%) had metastatic disease in the lymph nodes. In total, 10 patients underwent lymph node dissection of the involved basin. The median follow up was 21 months in this patient population. Age, gender, tumor location, ulceration, and lesion histology were not significantly associated with recurrence free survival (RFS). Increasing Breslow thickness was found to be significantly associated with shorter RFS (HR: 1.07, CI: 1.03–1.55). In total, 13 patients developed a disease recurrence, and RFS rates were 66% at 1 year and 40% at 3 years. Additionally, 91 and 37% of patients were alive at one year and three years, respectively. Subungual melanomas are rare lesions that often have a more advanced stage at diagnosis, which contributes to the poor prognosis of these cutaneous malignancies.

OBJECTIVES Delays from surgery to adjuvant radiation therapy (aRT) are associated with poorer prognosis in multiple neoplasms. Presently, no data exist for Merkel cell carcinoma (MCC). The authors sought to assess the time interval from surgery to aRT and effect on outcomes in MCC. MATERIALS AND METHODS The National Cancer Database was queried for histologically confirmed nonmetastatic MCC status post resection and aRT diagnosed between 2004 and 2015 who received aRT within 24 weeks of surgery. Kaplan-Meier analysis assessed univariate overall survival (OS); multivariable Cox proportional hazards modeling assessed multivariate OS; χ and logistic regression assessed differences in baseline characteristics and predictors of delayed aRT. RESULTS Of 5952 patients meeting criteria, 13% commenced aRT within 4 weeks, 48% between 4 and 7 weeks, 23% between 8 and 11 weeks, 11% between 12 and 15 weeks, and 6% between 16 and 24 weeks. There were no differences in OS on the basis of the surgery-aRT interval (P=0.99). Predictors of worse OS on the multivariate analysis included advanced age, greater comorbidities, male sex, lower regional income, earlier year of diagnosis, more advanced tumor and nodal staging, positive margins, head and neck location, and treatment at community facilities (P

e13070 Background: Despite recent FDA approval of immune checkpoint inhibitor pembrolizumab and drug-antibody conjugate in the treatment of metastatic triple negative breast cancer (mTNBC), the overall survival benefit of these therapies remains modest. Oncolytic virotherapy (OV) utilizes genetically modified viruses to infect and kill cancer cells while sparing healthy cells. CF33-hNIS-anti-PD-L1 (CHECKvacc) is a novel chimeric orthopoxvirus with robust anti-cancer activity in TNBC xenografts. Cells infected with CHECKvacc were shown to express functional human sodium-iodide symporter (hNIS) and anti-PD-L1 proteins. hNIS gene transfer allows tracking of virus by 99mTc single-photon emission computed tomography (SPECT). Our preliminary animal studies demonstrated that tumor cells infected with CHECKvacc successfully secrete functional hNIS and anti-PD-L1. CHECKvacc is safe and well-tolerated, and detects and effectively kills TNBC at doses several magnitudes lower than other OVs in xenograft models. Methods: This study is a first-in-human (FIH) phase I, single center, single arm clinical trial evaluating the safety and tolerability of CHECKvacc intratumoral injection in patients with mTNBC. Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on at least 2 prior chemotherapies including immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease; and at least one tumor amenable to repeated intratumoral injections. Eligible patients receive CHECKvacc intratumorally at one of 8 assigned dose levels (1 × 105 PFU, 3 × 105 PFU, 1 × 106 PFU, 3× 106 PFU, 1 × 107 PFU, 3 × 107 PFU, 1 × 108 PFU, 3 x 108 PFU) on Days 1 and 15 of each 28-day cycle for a total of 3 cycles of treatment. Primary objectives are to evaluate the safety and tolerability of CHECKvacc (DLTs and other toxicities by CTCAE v5.0). Secondary objectives are to determine optimal biological dose (OBD), recommended phase II dose (RP2D), and response rate by RECIST1.1. Results: The first 3 subjects of dose level 1 will be enrolled sequentially for safety monitoring. Once the initial 3 subjects are treated sequentially, the study will follow the Phase I Queue 3+3 (IQ 3+3) design which expands a dose level up to 8 subjects after a single DLT has been observed. Enrollment to the final RP2D may be expanded to include up to 12 patients for efficacy assessment. The estimated targeted accrual is 33 patients (minimum) to 78 patients (maximum). Correlative aims include assessing viral kinetics, viral plaque assay, 99mTc SPECT imaging for virus tracking, peripheral blood and tumor tissue for antiviral immune activation, and tumor microenvironment changes in association with response to therapy. Conclusions: This FIH trial of CF33-hNIS-antiPD-L1 intratumoral injection in patients with mTNBC is currently underway. Clinical trial information: NCT05081492.

In locally advanced basal cell carcinoma (BCC) patients who are not surgical candidates and where radiation therapy (RT) alone would offer lower control rates, the combination of vismodegib and RT delivered concurrently may potentially improve outcomes compared to single modality treatment. The current study presents a case of very advanced, multifocal BCC who received concurrent vismodegib and RT. The patient initially came in with four large primary areas of disease including the left preauriculum, right shoulder, chest wall and right lateral ankle. All sites achieved a clinical complete response, with a pathologic complete response at the right shoulder. The ankle lesion did not require RT and continues to have a clinical complete response. The findings from our case report support several other cases with similar efficacy when vismodegib and RT are combined.

Background Hematopoietic cell transplantation (HCT) is a curative option for a growing number of patients with hematologic diseases and malignancies. However, HCT-related factors, such as total body irradiation used for conditioning, graft-versus-host disease, and prolonged exposure to immunosuppressive therapy, result in very high risk for melanoma and non-melanoma skin cancer (NMSC). In fact, skin cancer is the most common subsequent neoplasm in HCT survivors, tending to develop at a time when survivors’ follow-up care has largely transitioned to the primary care setting. The goal of this study is to increase skin cancer screening rates among HCT survivors through patient-directed activation alone or in combination with physician-directed activation. The proposed intervention will identify facilitators of and barriers to risk-based screening in this population and help reduce the burden of cancer-related morbidity after HCT. Methods/design 720 HCT survivors will be enrolled in this 12-month randomized controlled trial. This study uses a comparative effectiveness design comparing (1) patient activation and education (PAE, N = 360) including text messaging and print materials to encourage and motivate skin examinations; (2) PAE plus primary care physician activation (PAE + Phys, N = 360) adding print materials for the physician on the HCT survivors’ increased risk of skin cancer and importance of conducting a full-body skin exam. Patients on the PAE + Phys arm will be further randomized 1:1 to the teledermoscopy (PAE + Phys+TD) adding physician receipt of a portable dermatoscope to upload images of suspect lesions for review by the study dermatologist and an online course with descriptions of dermoscopic images for skin cancers. Discussion When completed, this study will provide much-needed information regarding strategies to improve skin cancer detection in other high-risk (e.g. radiation-exposed) cancer survivor populations, and to facilitate screening and management of other late effects (e.g. cardiovascular, endocrine) in HCT survivors. Trial registration ClinicalTrials.gov, NCT04358276. Registered 24 April 2020.

Introduction: Ruxolitinib is an oral selective JAK1/JAK2 inhibitor, initially approved by the FDA for the treatment of intermediate-2 or high-risk myelofibrosis and patients with polycythemia vera ...

Background BRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers. Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility. However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity. Case presentation Here we present the case of a 49-year-old female who presented with an asymptomatic dome-shaped pink papule on the dorsal foot which was found on biopsy to be deficient in the BAP1 tumor suppressor. While the patient’s family history did not suggest the presence of a familial cancer syndrome, germline genetic testing was performed and was negative. The patient underwent surgical excision of this sporadically appearing “BAPoma” by Mohs surgery. Conclusions Given the relatively banal clinical appearance of these dome-shaped neoplasms, sporadic BAPomas may often be overlooked by clinicians and dermatologists. In addition to providing a representative case, here we also provide a synopsis of the current understanding of these neoplasms, both in terms of the histopathological features, as well as the molecular mechanisms underlying BAP1 function and its ability to prevent tumorigenesis.

Background Many factors influence anxiety and satisfaction of patients undergoing Mohs micrographic surgery (MMS). Objective We sought to determine the effect of a preoperative educational telephone call on anxiety and satisfaction for patients undergoing same-day office consultation and MMS. Methods Patients with skin cancer (N = 104) scheduled for same-day office consultation and MMS were randomly assigned to receive or not to receive an educational telephone call during the week before surgery. All patients rated their anxiety levels immediately before and after the same-day office consultation and MMS by completing the State-Trait Anxiety Inventory and an anxiety visual analog scale. Patients also rated satisfaction immediately after MMS by completing the Visit-Specific Patient Satisfaction Questionnaire. Results Patients undergoing same-day office consultation and MMS reported similar levels of increased anxiety and high satisfaction, regardless of whether they received a preoperative educational telephone call. Limitations Lack of control for patients' prior surgery or self-education is a limitation. Conclusion Preoperative educational telephone calls did not relieve anxiety or improve satisfaction for patients undergoing same-day office consultation and MMS. Preoperative education and counseling has uncertain benefits to anxiety and satisfaction of patients undergoing MMS.

Chronic graft-versus-host disease (cGVHD) is a late-occurring inflammatory condition post- allogeneic hematopoietic cell transplantation (HCT), which involves multiple distinct interactions among alloreactive dysregulated T and B cells. Prior studies have shown that autoantibodies to platelet-derived growth factor receptor (PDGFR) induce tyrosine phosphorylation and accumulation of Reactive Oxygen Species (ROS), causing expression of collagen type-1 gene through the Ha-Ras-Erk1/2–ROS signaling pathway. We hypothesize that antioxidant markers of inflammation (8-OHdG, total antioxidant levels, CXCL4 and pH2Ax) will be elevated in patients with scleroderma cGVHD compared to patients who do not develop cGVHD or have non-scleroderma cGVHD. Patients (n=36) were consented on an IRB-approved protocol for a cross-sectional single time point biospecimen collection. Patients with established cGVHD (n=29) or ≥2 years post-HCT without clinical manifestations of cGVHD (n=7) were included. Patients with cGVHD were divided into Scleroderma cGVHD (n=14) and Non-scleroderma cGVHD (n=15). Median age was 49 (range: 21-69) and 56 years (range: 18-72) for patients with scleroderma (group 1) and without scleroderma or no GVHD (group 2), respectively. Median prior lines of therapy was 3.2 (range: 2-5) for patients in group 1. All patients is group 1 and 77% of patients in group 2 received PBCSs as the graft source. Transplant was from a matched unrelated (group 1: 75%, group 2: 73%) or a matched sibling donor (group 1: 25%, group 2: 23%). Tacrolimus/sirolimus was the most commonly used GVHD prophylactic regimen in both groups (group 1: 83% and group 2: 64%). Peripheral blood samples were drawn at a single time point post-HCT, and serum samples were used for ELISA assays for levels of total antioxidants, 8-OHdG, and CXCL4. Flow cytometric analysis was performed to investigate percentage of Tregs and pH2AX+ cells. There were no differences in the total antioxidant levels, CXCL4 and Tregs between groups 1 and 2. Using a cutoff threshold of 10 ng/ml of 8-OHdG, 11 patients (78%) in group 1 and 9 patients (40.9%) in groups 2 had elevated levels of 8-OHdG (p=0.029, Fisher's exact). Percentage of pH2AX expressing cells was lower in group 2. At the cutoff threshold of 37%, only one patient (7%) in group 1 and 13 patients (59%) in group 2 had more than 37% pH2AX-expressing CD45+ cells in their peripheral blood (p=0.002, Fisher's exact). In conclusion, our pilot cross-sectional study showed that scleroderma cGVHD is associated with increased ROS levels (8-OHdG) without elevation of pH2AX cells in peripheral blood T cells. Our results indicate that ROS elevation in scleroderma patients may be a stress response to inflammatory milieu and is independent of DNA damage. Our data justify further prospective cohort studies to define the role of ROS markers in scleroderma cGVHD and to develop novel strategies to treat/prevent cGVHD.

BackgroundCemiplimab, a high-affinity, potent human immunoglobulin G4 monoclonal antibody to programmed cell death-1 demonstrated antitumor activity in a Phase 1 advanced cutaneous squamous cell carcinoma (CSCC) expansion cohort (NCT02383212) and the pivotal Phase 2 study (NCT02760498). Here we report the primary analysis of fixed dose cemiplimab 350 mg intravenously every 3 weeks (Q3W) (Group 3) and provide a longer-term update after the primary analysis of weight-based cemiplimab 3 mg/kg intravenously every 2 weeks (Q2W) (Group 1) among metastatic CSCC (mCSCC) patients in the pivotal study (NCT02760498).MethodsThe primary objective for each group was objective response rate (ORR) per independent central review (ICR). Secondary endpoints included ORR by investigator review (INV), duration of response (DOR) per ICR and INV, and safety and tolerability.ResultsFor Group 3 (n=56) and Group 1 (n=59), median follow-up was 8.1 (range, 0.6 to 14.1) and 16.5 (range, 1.1 to 26.6) months, respectively. ORR per ICR was 41.1% (95% CI, 28.1% to 55.0%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 45.2% (95% CI, 35.9% to 54.8%) in both groups combined. Per ICR, Kaplan–Meier estimate for DOR at 8 months was 95.0% (95% CI, 69.5% to 99. 3%) in responding patients in Group 3, and at 12 months was 88.9% (95% CI, 69.3% to 96.3%) in responding patients in Group 1. Per INV, ORR was 51.8% (95% CI, 38.0% to 65.3%) in Group 3, 49.2% (95% CI, 35.9% to 62.5%) in Group 1, and 50.4% (95% CI, 41.0% to 59.9%) in both groups combined. Overall, the most common adverse events regardless of attribution were fatigue (27.0%) and diarrhea (23.5%).ConclusionIn patients with mCSCC, cemiplimab 350 mg intravenously Q3W produced substantial antitumor activity with durable response and an acceptable safety profile. Follow-up data of cemiplimab 3 mg/kg intravenously Q2W demonstrate ongoing durability of responses.Trial registration numberClinicaltrials.gov, NCT02760498. Registered May 3, 2016, https://clinicaltrials.gov/ct2/show/NCT02760498

Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval, .388 to .673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost.

Background No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma. Methods We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review. Results In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval [CI], 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event. Conclusions Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).

9519Background: CSCC is rivaled only by basal cell carcinoma as the most common cancer in the US. There is no standard of care for patients with mCSCC; hence there is a significant unmet need in th...

Chronic GVHD remains as the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are the first line of therapy, but outcomes are poor in steroid refractory (SR) patients. Previous reports show that in SR patients, IL-2 therapy results in partial response (PR) associated with increase in regulatory T cells (Tregs). ECP has been used for cGVHD with skin response rates of 40-100%. Based on non-overlapping toxicities and, we prospectively studied a combination of low dose IL-2 + ECP to treat SR-cGVHD. Patients with SR-cGVHD, were treated with low dose IL-2 (1 × 106 U/m2, daily) + ECP for 12 weeks. IL-2 was provided by Prometheus Laboratories. ECP was administered 2 times/week for 4 weeks followed by 2 treatments every 2 weeks for the next 8 weeks. The NIH consensus criteria was used to assess cGVHD severity. PBMC and plasma samples were banked at baseline and on 3-week intervals to assess regulatory T cell (Tregs) and reactive oxygen species (ROS). Of the 12 consented patients, 9 completed the study (2 were not treated due to rapid disease progression before enrollment and 1 died from sepsis at week 11). All enrolled patients (n=10) had scleroderma as the predominant cGVHD manifestation. Median age was 45.6 years (range: 23-66). Median prior lines of therapy were 4.2(range 3-6), 5 patients had prior exposure to ruxolitinib and 4 were on ECP at the enrollment. Donors were fully matched unrelated (n=8), matched sibling (n=1) or mismatched unrelated (n=1). Conditioning regimen was myeloablative (n=5) or reduced intensity (n=4). GVHD prophylaxis was tacrolimus/Sirolimus (tac/sir) (n=6), tac/methotrexate (MTX) (n=2), or Tac/sir/MTX (n=1). Of the 10 enrolled patients, 9 responded to IL-2 + ECP combination (all classified as PR). A 37% dose reduction in steroid dose was noted among 7 patients. The remaining 3 patients were on stable steroid dose at end of study. Only 1 patient had progressive cGVHD in form of scleroderma. ECP+IL-2 therapy was well tolerated with no drug related serious adverse events (SAE). Grade 3-4 AEs included grade 3 metabolic and nutrition (n=8), grade 3 anemia (n=3), and grade 4 atrial flutter (n=1). Infectious complications were noted in 3 patients (one grade 4 [sepsis]). There was a robust increase in Tregs from the baseline mean of 0.755% (range 0.08-1.88) to end of treatment 6.999% (range 0.78-17.13) [p=0.02] Fig 1. Increment in Tregs was seen in patients who were on ECP therapy prior to enrollment (n=4) and in one patient who progressed while on therapy. No correlation was found between the treatment response and ROS levels. In conclusion, the combination of ECP +IL-2 is well tolerated in patients with SR-cGVHD with no apparent increase in infectious complications or other toxicities. Clinical response correlates with a robust increase in Tregs, but no correlation was found with ROS levels.

Introduction: Hematopoietic cell transplantation (HCT)-related factors, such as total body irradiation (TBI) used for conditioning, graft-versus-host disease (GvHD), and prolonged exposure to calcineurin-inhibitors, can result in high risk for subsequent skin cancers in long-term survivors. Previous studies examining skin cancers after HCT have largely focused on patients transplanted in earlier eras ( Methods: 2338 consecutive patients who underwent a first HCT between 2005 and 2014 at City of Hope (COH) and survived ≥1 year, were included in the study. Patients with a history of skin cancer prior to HCT were excluded from the cohort. All skin cancers were validated using pathology reports, and physician notes (20%) whenever the former was not available. Skin cancers included SCC, BCC, melanoma, atypical fibroxanthoma, and merkel cell carcinoma. Patients were followed from HCT to death, second HCT, last known alive date, or December 31, 2018, whichever occurred first. Cumulative incidence of skin cancer was estimated taking into consideration competing risk of death. Fine-Gray sub-distributional hazard regression was used to calculate hazard ratio (HR) estimates, adjusted for relevant covariates. Results: Median age at HCT was 51.8y (range: 0.7-78.7); 57.6% were male; 56.5% were non-Hispanic white (NHW); 4.4% had a history of Pre-HCT cancer (antecedent to primary diagnosis); 47.7% underwent allogeneic HCT; 22.0% received myeloablative TBI (≥1200 cGy)-based conditioning. Among survivors of allogeneic HCT, 57.2% developed ≥moderate chronic GvHD (84% involving the skin); the most common immunosuppressive agents used for the management of ≥moderate chronic GvHD were tacrolimus (84.6%), followed by sirolimus (76.5%), and cyclosporine (28.4%). Burden of skin cancer over time: 179 survivors developed a total of 450 skin cancers after HCT; median time from HCT to first skin cancer was 2.8 years (range: 0.2-13.6). SCC was the most common subtype (59.1%), followed by BCC (31.3%), melanoma (5.1%), and other (4.4%); 43.4% of patients with SCC had invasive or high grade disease at presentation. The cumulative incidence of de novo skin cancer after HCT was 8.3% at 5 years, and 14.8% at 10 years (figure). Eighty-nine patients with skin cancer had a second skin cancer at a median of 0.5 years (range: 0.2 to 7.2) from the first; 55.1% were of a different histology. The cumulative incidence of a second skin cancer was 41.9% at 5-years (figure). Risk factors: Multivariate analysis revealed male sex (HR=1.7, p=0.0008), NHW race/ethnicity (HR=9.0, p Conclusions: This study confirms the higher risk of skin cancer by sex, race/ethnicity, and age at HCT, and highlights the greater than two-fold risk of skin cancer among allogeneic HCT survivors compared to autologous patients, a finding that is not entirely explained by GvHD and its treatment. Further, we identified a previously unreported association between pre-HCT (non-skin) cancer and post-HCT cancer risk, and describe the very high burden of multiple histologically distinct skin cancers over time. Taken together, these data set form the basis for implementation of updated risk-based screening and prevention practices in survivors at highest risk of skin cancer after HCT. Disclosures Abdulla: Johnson & Johnson: Research Funding; Elorac: Research Funding; Trillium: Research Funding; Stemline: Research Funding; MiRagen: Research Funding; Bionz: Research Funding; Mallinckrodt: Research Funding; Mallinckrodt: Consultancy; Mallinckrodt: Speakers Bureau. Nakamura:Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: support for an academic seminar in a university in Japan; Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan.

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

Post-vaccinial non-viral folliculitis has been recognized in the past decade as a new adverse cutaneous reaction to smallpox vaccination. Contrary to more serious smallpox vaccine reactions, post-vaccinial non-viral folliculitis has a benign course and resolves spontaneously within approximately 7 days. We describe additional histopathologic findings associated with post-vaccinial non-viral folliculitis, which has only been described once previously. New findings include the presence of a neutrophilic or lymphohistiocytic infiltrate that is concentrated around the hair follicles. We compare our findings to the follicular nature of varicella and herpes zoster infections, generating the hypothesis of deposition of vaccinia protein within folliculosebaceous units as a potential pathophysiologic mechanism behind post-vaccinial non-viral folliculitis.

Peripheral edema with painful erythema is an increasingly recognized but poorly understood cutaneous adverse reaction to the antifolate agent pemetrexed. It is frequently misdiagnosed as cellulitis, and when it occurs, it is often dose-limiting. The authors report the case of a patient with preexisting lower extremity edema who developed extensive painful, bilateral erythema 5 days after administration of pemetrexed. An eosinophil-rich dermal inflammatory infiltrate was noted histologically. The authors review previously reported cases of pemetrexed-induced pseudocellulitis and discuss possible pathophysiology.

The Dark Side of Langerhans Cells Several immune cell populations reside in the skin and are thought to provide a protective barrier against infections and to act as sentinels against malignant transformation. However, studies in mice that lack Langerhans cells, a subset of dendritic cells, have suggested that these cells may actually promote tumorigenesis. Using a mouse model of squamous cell carcinoma, Modi et al. (p. 104 ) now reveal how Langerhans cells may promote the transformation of skin epithelial cells. In response to the carcinogen 7,12-dimethylbenz[α]anthracene (DMBA), Langerhans cells increased their expression of the cytochrome P-450 enzyme CYP1B1, which can metabolize DMBA to the mutagenic DMBA- trans -3,4-diol. Thus, besides their functions in regulating the adaptive immune response, Langerhans cells may participate in the metabolism of environmental carcinogens.

Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model that, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional magnetic resonance imaging (fMRI) that electrically stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, whereas frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged on by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures.

The cutaneous T-cell lymphomas have been shown to be associated with dysregulation of effector T-cell activity, making them an attractive target for immune activating therapies. Interferons and extracorporeal photopheresis-based therapeutic approaches have been shown to induce clinical responses of significant duration in selected patients. Similarly, activity has been demonstrated with cytokine-based therapies, including interleukin-2, interleukin-12, and the toll-like receptor agonists. Retinoids and histone deacetylase inhibitors, widely used therapies in early stage CTCL, have been shown to modulate immune effector mechanisms. For most patients with CTCL, the goals of therapy are to exploit immunotherapeutic approaches for as long as possible and to keep immune function intact.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sezary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.

A man with a history of chronic renal insufficiency (baseline creatinine level, 2.8mg/dL) presented for evaluation of a painful forehead erythematous eruption and associated headache. (To convert creatinine to micromoles per liter, multiply by 88.4.) Three days prior to symptom onset he underwent a contrast-enhanced computed tomographic (CT) scan to evaluate abdominal pain. On the central forehead was a tender 5-cm reddish brown plaque composed of numerous coalescing vesicles and hemorrhagic pustules with intermixed serous and hemorrhagic crust. Similar vesicles and pustules were present on the nasal bridge and tip, the bilateral conchal bowls, and on the scalp (Figure, A). Two days later, the patient developed several 0.5to 1.0-cm purpuric macules and hemorrhagic vesicles on the bilateral hands and nail beds. Initial blood tests revealed a white blood cell count of 6400 cells (range, 4000 to 11 000/μL; to convert to ×109/L, multiply by 0.001). The patient denied any new medications, any known contacts with or exposures to individuals who were ill, and any history of skin disease. A punch biopsy of the forehead plaque was performed (Figure, B and C). What is your diagnosis?