Merkel cell carcinoma (MCC) is rare and aggressive skin cancer with high risk of metastasis. Developments of PD-1/PD-L1 immunotherapy has significantly improved treatment outcomes of metastatic MCC. Unfortunately, only 50% of patients demonstrate long-term responses. Previous studies by our lab have demonstrated that infiltration of CD8+ T cells in MCC tumors correlates to long-term responses. However, the impact of other innate immune cells and lymphocytes remains unclear. I hypothesize that the spatial interaction of pro-inflammatory cells (primarily T and B cells) associate with better outcomes in the absence of suppressive macrophages that disrupt this immunological crosstalk. To investigate this, I have been using QuPath, a spatial analysis software, to examine the microenvironments of 75 MCC tumors. These tumors have been stained with 18-marker antibody panel to identify subsets of B, T, and innate immune cells. Using QuPath, I have been quantifying different immune cell populations, as well as investigating their spatial relationship to each other. Using this data, I have been working with a PhD student and Dr. Paul Nghiem, to correlate this immunological data to clinical outcomes. Our preliminary data demonstrates that high B-cell infiltration may correlate with better clinical outcomes. While this is promising, I plan to expand my studies, investigating the impact of other innate immune cells on immunotherapy outcomes. I will then work to validate my studies by investigating a different cohort of 35 MCC tumors taken from a recent immunotherapy clinical trial. By investigating the tumor microenvironment, my goal is to help identify which population of cells associate with better responses. This in turn may lead to a diagnostic assay that may help assess cancer aggressiveness, which physicians can use to tailor treatment course. In addition, this information can help guide future drug development, showcasing which cells are the most important to target and/or enhance.

Merkel cell carcinoma (MCC) is a rare and aggressive cancer of the skin with a mortality rate of ~30%. In the US, most MCC tumors arise from integration of the Merkel cell polyomavirus (MCPyV) DNA into a host chromosome, leading to expression of viral T-Antigen (T-Ag) oncoproteins that drive tumorigenesis. Though current treatment options have significantly improved MCC prognosis, new therapies are needed to address recurrent/resistant disease. While T-Ag-specific antibodies are usually detected in the blood of patients with virus-driven MCC, the role of these antibodies in tumor immunity remains unclear. Here, we analyzed blood samples from 100 MCC patients prior to definitive treatment, 51 of whom had high titers of antibodies recognizing the T-Ags. These 51 high titer samples were assessed for binding across two domains of the T-Ag. Suprisingly, we found that patients who had high titers of antibodies binding both regions of the T-Ag had worse MCC control than patients whose antibodies predominantly bound one region (median PFS 5.5 vs. 14.2 months, p=0.003). These data suggest that careful mapping of circulating antibody reactivity to different regions of T-Ag can serve as a biomarker to identify high-risk patients for which a more aggressive treatment regimen is needed. Future work is also focused on understanding the immune response resulting in differential response to T-Ag domains.

Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, shows approximately 60% response to immune-checkpoint inhibitors (ICIs) in immunocompetent patients. The efficacy of ICIs in immunosuppressed patients, who generally have poorer MCC prognoses, is less clear. This retrospective study assesses ICI outcomes in both immunocompetent and immunosuppressed MCC patients, and across various immunosuppression types. In this project, I determined the cohort of 183 patients with advanced MCC who were treated with first-line ICIs from a Seattle-based data registry. I collected the following data from analyzing patients’ medical records: treatment response, immunosuppressive status, disease-specific and overall survival. I coordinated with the statisticians for Kaplan-Meier analyses of the data, and am now working on the manuscript. The results show that initial response rates to ICIs were comparable between immunosuppressed (50%) and immunocompetent (61.5%) patients (p=0.17). After starting ICI treatment, immunosuppressed patients experienced a 65% increased rate of disease progression compared to immunocompetent patients (Hazard Ratio [HR]=1.65, p=0.04), with their median time to disease progression being 11.2 months, versus 32.9 months in the immunocompetent group. Outcomes also varied by immunosuppression subtype, with chronic lymphocytic leukemia patients having the lowest chance of response (20%, 2/10) and highest progression risk. In our cohort, immunotherapy often elicited an initial response in immunosuppressed MCC patients; however, the duration of this response was significantly shorter. Despite limited duration in immunosuppressed patients, ICIs still offer a high response rate for patients with advanced MCC, regardless of immunosuppression type. It is crucial to have a comprehensive prognosis discussion with patients before initiating treatment.

Stress-related physiological and social factors can have a direct impact on cancer biology and patient outcomes. Exposure to a stressor can lead to downstream activation of signaling pathways that can impact cancer-related processes. Compared to older and younger patients with cancer, adolescents and young adults (AYAs) have had less improvement in clinical outcomes and report high levels of psychosocial distress. The goal of this study is to examine the feasibility and acceptability of a multimethod triangulation protocol collecting stress biomarkers along with subjective patient reported outcomes among AYAs with cancer. Eligible participants are 12-24 years old within six months of initial cancer diagnosis and undergoing treatment at Seattle Children's Hospital. Once enrolled, participants wear a sensor measuring autonomic nervous system activity [quantified as heart rate variability (HRV)] while completing validated patient reported outcome (PRO) surveys assessing psychosocial symptoms and participating in a qualitative interview querying the same domains. Interviews are recorded using Microsoft Office Dictation services. I listen to the audio files and go over the transcribed document making corrections and highlighting key quotations. Additionally, at the time of a participant's planned clinical blood dram, 5mL of blood is collected to measure a social genomics stress biomarker called the conserved transcriptional response to adversity (CTRA). We expect to find greater than 70% feasibility and 80% acceptability in this study. Feasibility is defined as the percentage of participants who complete all (100%) study procedures; acceptability is defined as the percentage of participants who agree that similar patients could complete the study. Results from this pilot study will inform future longitudinal investigations and the development of targeted biopsychosocial interventions for AYAs with cancer. 

Androgen Deprivation Therapy (ADT) is the standard treatment for advanced prostate cancer (PCa), although it adversely affects muscle mass, physical function, and quality of life (QOL). It is unknown whether 1) these factors Pre-ADT can predict ADT-induced changes or 2) if non-White, non-Hispanic (NWNH) men experience greater adverse impact on these outcomes than White, non-Hispanic (WNH) men. I hypothesized that 1) greater muscle mass Pre-ADT would be protective against ADT-induced changes in muscle mass, physical function, and QOL and 2) NWNH men would experience worse changes in muscle mass, physical function, and QOL than WNH men. I assessed lean body mass (LBM) [dual energy x-ray absorptiometry], physical function [aerobic capacity (VO2Peak), hand grip strength (HGS), 6-minute walk test (6MWT), stair climb power (SCP)], and QOL [QLQ-C30 questionnaire] in PCa patients (n=59) from the Seattle VA before and 6 months after ADT. I used Pearson correlations to test associations between variables and independent t-tests to compare variables between WNH and NWNH men. Larger LBM (r=0.33, p=0.019, n=50), lower QLQ-C30 Function (r=0.31, p=0.03, n=50), and higher QLQ-C30 Fatigue (r=0.40, p=0.004, n=50) Pre-ADT were correlated with larger 6-month decreases in LBM. NWNH men (n=20) displayed significantly worse Pre-ADT HGS (p=0.038), 6MWT (p=0.037), and SCP (p=0.005) than WNH men (n=39). I anticipate that NWNH men will display worse 6-month changes in LBM, HGS, 6MWT, SCP, and QOL than WNH men in my ongoing analyses. Contrary to my hypothesis, larger LBM Pre-ADT was not protective against muscle loss. Consistent with reports that NWNH men experience greater tumor-related adverse impacts of PCa treatment, worse functional performance Pre-ADT may indicate physical function of these individuals is also disproportionately adversely impacted by ADT. By identifying predictors of adverse ADT outcomes, researchers can develop interventions aimed at preserving muscle mass, physical function, and QOL during ADT for high-risk populations. Additionally, reducing the disproportionate adverse effects of ADT on NWNH men will address disparities within PCa treatment, promoting personalized healthcare optimizing outcomes for all patients. 

Since approval by the FDA in 2019, BPaL/ BPaLM regimens are the favored treatment for multidrug-resistant tuberculosis (MDR-TB). Whereas traditional MDR-TB treatment generally includes an injectable and takes at least 18 months to complete, BPaL/ BPaLM regimens are all oral and typically take 26 weeks, suggesting potential for widespread implementation. Here, I aimed to elucidate patient demographic patterns and outcomes following treatment with BPaL/BPaLM to fill current gaps in knowledge. King County, Washington, with large populations of immigrants, refugees, and asylum seekers arriving from TB-endemic countries, sees high rates of TB incidence each year. Using medical data collected from active TB cases in King County, WA since 1993, I compiled demographics and outcomes (resolution of TB symptoms and treatment adherence) from patients receiving BPaL/BPaLM regimens. Of the 70 patients in our King County cohort, eight were given BPaL or BPaLM therapy to treat MDR-TB. At this time, five (63%) have completed therapy. Four (50%) are from Vietnam, two (25%) from China, one (13%) from Myanmar, and one (13%) is from the Russian Federation. Two (25%) are male; one (13%) was previously diagnosed with TB; and median age was 35 (range of 19-81). All eight had pulmonary disease and were HIV-negative. One patient was a household contact of another identified on contact tracing. Limitations of this analysis include a small BPaL/BPaLM cohort (n=8), and missing patient data. As more follow-up time accumulates, I can compare BPaL/BPaLM to the prior 18-month regimens using relapse rates and treatment completion. Based on my current analysis of King County MDR-TB cases, BPaL/BPaLM appears effective and well-tolerated—conducive to better TB outcomes than seen with prior MDR-TB regimens. Moreover, this study can provide data-driven insight to effectively treat MDR-TB patients from diverse populations across the US.