Sophia Shalhout, PhD

Methods| Untreated patients with stage I or II HPV-associated OPSCC were prospectively enrolled in this cohort study. All patients underwent transoral robotic surgery and cervical lymphadenectomy followed by risk-adjusted adjuvant therapy. Blood was collected before treatment; on postoperative days (PODs) 1, 7, and 30; and every 3 to 6 months after treatment completion. Detailed enrollment criteria and ctHPVDNA detection by custom droplet digital polymerase chain reaction assays were previously described. 4Primary outcomes were 2-year OS and RFS, compared between patients with and without molecular RD (MRD) following treatment completion. MRD was defined as persistent elevation of ctHPVDNA at 2 consecutive time points, without clinical evidence of disease. Secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. Detectable MRD after …

ImportanceIn clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities.ObjectiveTo evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population.Design, Setting, and ParticipantsThis cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5).ExposuresCemiplimab or pembrolizumab.Main Outcomes and MeasuresPrimary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease …

Introduction: Efforts to overcome resistance to immune checkpoint inhibition (ICI) are paramount, and novel combination strategies are in development. Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment that has demonstrated immune modulatory effects. We hypothesized that cryoablation may prime the tumor microenvironment (TME) through direct modulation of the tumor, thereby generating an anti-tumor response in ICI refractory tumors. Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoint was safety and feasibility, with objective response rate (ORR) and disease control rate (DCR) in non-ablated lesions a key secondary endpoint. To better understand the …

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2–1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2–1.6; p-value < 0.0001). A …

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.

Objectives Tumor registries are a rich source of real-world data which can be used to test important hypotheses that inform clinical care. Exploratory data analysis at the level of individual subjects, when enhanced by interactive data visualizations, has the potential to provide novel insights and generate new hypothesis. Materials and Methods We created StoryboardR: an R package and Shiny application designed to visualize real-word data from tumor registries. Results StoryboardR facilitates the data visualization of real-word data from tumor registries captured in REDCap®. The output is an interactive timeline that allows for a visual interpretation of the relationship between potential prognostic and/or predictive biomarkers and outcomes. Conclusions StoryboardR is freely available under the Massachusetts Institute of Technology …

Solid organ transplantation is a life-saving procedure for patients with end-organ dysfunction or damage. While advances in both surgical technique, organ harvesting, and development of immune suppression have resulted in an increasing number of organ transplant procedures worldwide, many challenges remain such as the availability of appropriate donor allograft organs and the systemic sequelae of immune suppression. In 2021 there were an estimated 144,302 solid organ transplants performed worldwide (Figure 1)(Elflein 2023). Kidney continues to be the most commonly transplanted organ with liver and heart next in incidence. According to the United Network for Organ Sharing, there were over 42,000 solid organ transplants in the United States during 2022, an annual record number with nearly 117 transplant procedures every day. To avoid rejection, patients are placed on life-long immunosuppressive medications, which may vary depending on the organ being transplanted, the degree of HLA mismatch, and the timing of transplantation. A variety of drugs have been used alone and in combination (see Table 1).

Oncolytic viruses (OVs) are an emerging class of cancer therapeutics that offer the benefits of selective replication in tumour cells, delivery of multiple eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumour immunity, and a tolerable safety profile that largely does not overlap with that of other cancer therapeutics. To date, four OVs and one non-oncolytic virus have been approved for the treatment of cancer globally although talimogene laherparepvec (T-VEC) remains the only widely approved therapy. T-VEC is indicated for the treatment of patients with recurrent melanoma after initial surgery and was initially approved in 2015. An expanding body of data on the clinical experience of patients receiving T-VEC is now becoming available as are data from clinical trials of various other OVs in a range of other cancers. Despite increasing research interest, a better understanding of …

ResultsBesser et al.(2010) Phase II study, 20 evaluated patients, 50% objective clinical response (2 CR, 8 PR)

MethodsWe included adult patients who had received ICIs and were treated for suspected n-irAEs at Massachusetts General Hospital (MGH) between January 1, 2011, and December 31, 2020. In addition, the MGH Research Patient Data Registry (RPDR) identified other ICI-treated patients who had a neurology encounter and met specific criteria, either by electromyography (EMG), electroencephalogram (EEG), cerebrospinal fluid (CSF) nucleated cell count greater than 5, or abnormal creatine phosphokinase (CPK) levels. Chart review was performed to determine cancer type and the treatment and outcomes of toxicity. Neurologists specializing in autoimmune disorders of the central and peripheral nervous system reviewed all cases for inclusion.ResultsOf 70 total patients who developed n-irAEs, 16 (22.9%) had non-small cell lung cancer (NSCLC). Most patients were male (65.7%), ECOG 0-1 (80%) and …

e21514Background: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm with an increasing incidence rate and poor prognosis. The treatment landscape has changed dramatically over the last half decade, beginning with the 2017 approval of the anti-programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Accelerated approval for avelumab was based on data from the JAVELIN Merkel 200 study, which demonstrated an objective response rate (ORR) of 33% in previously treated subjects (≥2L). In the first-line (1L) clinical-trial setting, avelumab was associated with an ORR of 40% and a durable response rate (DRR) of 30%. There are limited data regarding the efficacy of avelumab in the real-world setting. Methods: We performed a Mass General Brigham (MGB) Institutional Review Board-approved retrospective study of patients with advanced MCC. Clinical data regarding the …

Immune checkpoint inhibitor therapy has revolutionized the management of skin cancer. 2–4 With over 50 FDA approvals, 5 immunotherapy has become the standard of care for the majority of advanced cutaneous neoplasms (Figure 1). 6–8 Furthermore, recent trials have demonstrated the activity of immune checkpoint inhibitor (ICI) therapy in the peri-operative setting for high-risk resectable disease. 9–16 Therefore, the cohort of skin cancer patients eligible for immunotherapy continues to expand.

Background Understanding the impact of surgical treatment on regionally metastatic cutaneous squamous cell carcinoma (cSCC). Methods Retrospective series of 145 patients undergoing parotidectomy and neck dissection for regionally metastatic cSCC to the parotid. Overall survival (OS), disease‐specific survival (DSS), and disease‐free survival (DFS) analyzed over 3 years. Multivariate analysis was completed using Cox proportional hazard models. Results OS was 74.5%, DSS was 85.5% and DFS was 64.8%. On multivariate analysis, immune status (HR = 3.225[OS], 5.119[DSS], 2.071[DFS]) and lymphovascular invasion (HR = 2.380[OS], 5.237[DSS], 2.595[DFS]) were predictive for OS, DSS, and DFS. Margin status (HR = 2.296[OS], 2.499[DSS]) and ≥18 resected nodes (HR = 0.242[OS], 0.255[DSS]) were predictive of OS and DSS, while adjuvant therapy was predictive of DSS (p = 0.018 …

Melanoma incidence has increased over the past few decades with age-adjusted rates for new melanoma of the skin rising 1.2% annually over 2010-2019 (NCI 2023). Currently, melanoma comprises 5.2% of all new cancer cases in the United States (NCI 2023). The 5-year relative survival rate for those diagnosed with melanoma between 2012-2018 based on Surveillance, Epidemiology, and End Results (SEER) staging is greater than 99% for those with localized disease, 71% for regional disease, and 32% for distant disease (NCI 2023).Melanomas are considered immunogenic, meaning antitumor immune responses are capable of killing tumor cells (Blankenstein et al. 2012; Huang and Zappasodi 2022). The immunogenicity of melanoma is thought to come from the high tumor antigen load comprised of cancer germline antigens, melanocyte differentiation antigens, overexpressed antigens, and neoantigens associated with the high mutational burden in melanomas due to UV radiation (Huang and Zappasodi 2022; Van Allen et al. 2015).

Objective To develop a clinical informatics pipeline designed to capture large-scale structured Electronic Health Record (EHR) data for a national patient registry. Materials and Methods The EHR-R-REDCap pipeline is implemented using R statistical software to remap and import structured EHR data into the Research Electronic Data Capture (REDCap)-based multi-institutional Merkel Cell Carcinoma (MCC) Patient Registry using an adaptable data dictionary. Results Clinical laboratory data were extracted from EPIC Clarity across several participating institutions. Laboratory values (Labs) were transformed, remapped, and imported into the MCC registry using the EHR labs abstraction (eLAB) pipeline. Forty-nine clinical tests encompassing 482 450 results were imported into the registry for 1109 enrolled MCC patients. Data-quality assessment revealed …

The Merkel Cell Carcinoma (MCC) Patient Registry is a national multi-institutional collaborative effort that will prospectively follow and record outcomes and events in MCC patients. MCC is the prototypical rare tumor, and this Registry will trail blaze new methodologies that will enable multiple investigators to examine real world outcome data in real time. Deliverables from the Registry include precise patient stratification into risk categories, identification of best practices, real-world data for drug development programs, revelations about optimal sequence and combinations therapies, uncovering low incidence toxicities, and the generation of novel testable hypotheses. Importantly, the Registry offers a way forward in the yet-unsolved dilemma of drug development for rare tumors, since the Registry's design will allow the creation of highly defined patient-level data that can be used as a robust comparator for single arm …

Background There has been a rapid proliferation of FDA-approved medications with labeled indications for skin cancer over the last decade, with particular growth over the last 5 years. Objective We aimed to evaluate the impact of an evolving U.S. regulatory framework on drug development programs to better understand current trends and regulatory considerations when adjudicating drug approvals for patients with skin cancer. Methods We reviewed publicly-available regulatory documents of all systemic medications with a labeled indication for skin cancer. Results We identified 130 FDA approvals that resulted in a unique indication, usage, formulation, or dosage change in skin cancer since 1949. Limitations Publicly available data from the mid-to-late 20th century is limited. Conclusions The therapeutic landscape in skin cancer has changed greatly since the first approval in 1949. In concert, regulatory medicine has also evolved over the last 70 years with the aim of ensuring safe and effective medicines for a diverse array of patients.

In this Perspectives on the Science piece, published in the Journal of Cutaneous Oncology, we reflect on the impact of the recently published article Neoadjuvant relatlimab and nivolumab in resectable melanoma.

Background and aims Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine carcinoma. Immune checkpoint inhibitors (ICIs) have emerged as the new standard of care in the treatment of advanced MCC, offering durable clinical benefit. Currently, two ICIs targeting the PD-1/PD-L1 axis-avelumab, an anti-PD-L1 agent, and pembrolizumab, an anti-PD-1 agent-are approved by the US Food and Drug Administration (FDA) for the treatment of advanced MCC. Despite these advances in effective treatment options, approximately 50% of patients with unresectable/locally advanced or metastatic MCC have primary or acquired resistance to ICIs. Effective second-line systemic therapy options are limited, and studies assessing potential salvage therapies are lacking. Methods We performed a multi-institutional, retrospective analysis designed to assess the objective clinical response to combination …

Merkel cell carcinoma (MCC) is a very rare but highly aggressive cutaneous neuroendocrine carcinoma and is associated with chronic exposure to ultraviolet light and the Merkel cell polyoma virus. The incidence rate of MCC is increasing and MCC is associated with high rates of recurrence and mortality. Immune checkpoint inhibitors (ICIs) offer durable responses and significant clinical benefit with 2 agents-avelumab (anti-PD-L1) and pembrolizumab (anti-PD-1)—currently approved by the US Food and Drug Administration for the treatment of advanced MCC. Despite the advances in systemic therapy options for MCC,~ 50% of patients with advanced MCC treated with ICI progress on therapy. There is a paucity of studies assessing second-line systemic therapy following primary/acquired resistance to ICIs. Current management in this setting remains a clinical challenge especially in trial ineligible patients. We …