Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (>= 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-offlight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Result(s): We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICIinsensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusion(s): Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer.

Is mass rapid transit applicable for deep integration of freight-passenger transport? A multi-perspective analysis from urban China

Integrating goods movement into public/mass rapid transit (MRT) is an emerging initiative to improve urban freight transport services and sustainability. This paper explores new prospects to achieve extensive non-road city logistics based on a deep freight-on-rail-transit (FoRT) strategy. To begin, the strengths, weaknesses, opportunities, and threats (SWOT) of deep FoRT are analyzed in view of the development status quo of urban China. Next, a multi-criteria assessment model driven by real-world data and 11 quantified metrics is proposed to judge the suitability for developing the MRT-based integrated logistics system (MILS) in 16 Chinese cities. Finally, critical factors influencing MILS project adoption are explicated, and the possible supportive policies are discussed from aspects of planning, regulation, funding, marketization, and innovations. Results show that the alignment with national development goals, rich social-environmental benefits, and stakeholder interest are the primary drivers of deep FoRT strategy, whereas poor planning and decision-making, governance and management deficiencies, and high investment could be the main hurdles. Priority of MILS project adoption in the selected cities is divided into four tiers, where Shanghai, Beijing, and Shenzhen are recognized as the three best candidates. Strong and coordinated policies are needed to integrate the strategy into urban planning.

Kratom-induced Liver Failure and Death: A Case Report

Introduction: Kratom (mitragynine speciosa) is a tree native to Southeast Asia that has both opioid, stimulant, and other unknown properties. It is currently legal in the United States and used for therapeutic and recreational purposes. There is a dearth of literature on kratom’s effects on the body. At least half of reported kratom exposures resulted in a serious medical outcome, including death (1). In contrast, there are no controlled clinical trials on safety and efficacy of kratom as a treatment (2). Case: A 32-year-old Caucasian, currently unemployed, unmarried, mother of two children presented intubated to the MICU from an outside hospital with acute fulminant hepatic failure in the setting of significant kratom use. The patient also presented febrile with intracranial hemorrhage, cerebral edema, GI bleeding, acute renal failure, and diffuse intravascular coagulation. Psychiatry was consulted for potential liver transplant candidacy. Her previous history included six years of opioid use and transition to kratom 1-2 years prior to admission, with recent ingestion up to twenty-five times the patient’s usual amount (up to 125mg). Pertinent positive labs included elevated troponin (0.4), transaminitis ( >11,000), elevated PT/PTT (99/52), D-dimer ( >20), hematuria, pyuria, serum ferritin, prolonged QTc (514), and hypoglycemia. Pertinent negatives included unrevealing serum ethanol, phosphatidylethanol, viral hepatitis, HIV, COVID-19, EBV, CMV, other viral panels, acetaminophen level, toxicology screen, and EEG. Imaging revealed interstitial pulmonary edema and diffuse cerebral edema. Given lack of published information on kratom, the team emergently listed the patient for liver transplant despite significant concern for kratom use disorder. Over the course of three days, the patient’s mental status and labs continued to worsen, ultimately resulting in death. Interventions pursued included dialysis, mechanical ventilation, intracranial pressure monitoring with pressure optimization, anticonvulsant therapy, antibiotic therapy, N-acetylcysteine, and other routine MICU care. Due to relatively unremarkable health before ingestion, lack of other significant events, and severe rapid decline, multidisciplinary team consensus cause of death was due to kratom ingestion causing “acute liver failure with hepatic coma”. Discussion: This case report will go into further detail on kratom by analyzing kratom’s mechanism of action, therapeutic use, known side effects including addictive potential, effects on the liver including acute fulminant injury, and current laws and regulations surrounding kratom in the United States with relevance to public health. This is relevant to psychiatrists in the general consult, transplant, and addictions services. References: 1. Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011–2017. Clinical Toxicology. 2019 57:10,847-854. DOI:10.1080/15563650.2019.1569236 2. Prozialeck W. Update on the Pharmacology and Legal Status of Kratom. J of the AOA. 2016, 116, 802-809. DOI: https://doi.org/10.7556/jaoa.2016.156