Potent Activity of an Anti-ICAM1 Antibody-Drug Conjugate against Multiple Myeloma.

PURPOSE: New therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC). EXPERIMENTAL DESIGN: Our anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state. RESULTS: The anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples. CONCLUSIONS: We propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.

Using gene expression to assess the status of fish from anthropogenically influenced estuarine wetlands.

The diverse mixture of contaminants frequently present in estuaries complicates their assessment by routine chemical or biological analyses. We investigated the use of gene expression to assess contaminant exposure and the condition of southern California estuarine fish. Liver gene expression, plasma estradiol concentrations, and gonad histopathology were used to study biological condition in longjaw mudsuckers (Gillichthys mirabilis). Metals, legacy organochlorine pesticides, PCBs, and contaminants of emerging concern were detected in sediments and whole fish. Overall gene expression patterns were characteristic to each of four sites investigated in this study. Differentially expressed genes belonged to several functional categories including xenobiotic metabolism, detoxification, disease, and stress responses. In general, plasma estradiol concentrations were similar among fish from all areas. Some fish gonads had pathologic changes (e.g., infection, inflammation) that could indicate weakened immune systems and chronic stress. The differential expression of some genes involved in stress responses correlated with the prevalence of histologic gonad lesions. This study indicates that gene expression is a promising tool for assessing the biological condition of fish exposed to environmental contaminants.

Race impacts outcome in stage III/IV squamous cell carcinomas of the head and neck after concurrent chemoradiation therapy.

BACKGROUND: The purpose of this study was to determine the impact of race on outcome in patients with stage III/IV squamous cell carcinoma of the head and neck (SCCHN) who have completed concurrent chemoradiotherapy. METHODS: The authors performed a retrospective analysis of 202 patients with stage III/IV SCCHN who were treated at the University of Maryland. Patients received daily radiation to a total dose of 70.2 Gray (Gy) (1.8 Gy/day), concurrently with weekly carboplatin (area under the curve [AUC] = 2) and paclitaxel (45 mg/m(2)) chemotherapy. RESULTS: There were 108 Caucasian (CA) and 94 African American (AA) patients. The median age was 56 years, and 81% were stage IV. The median follow-up was 33 months. The median overall survival (OS) and disease-free survival (DFS) were 33 months and 19 months, respectively. When analyzed by race, the median DFS was 33 months (CA) versus 12 months (AA) (P = .028). The median OS was 44 months (CA) versus 24 months (AA) (P = .071). The 3-year DFS for stage IV AA versus stage IV CA was 29% versus 50% (P = .031). The 3-year DFS for N2 disease in AA versus CA was 32% versus 51% (P = .046). The 3-year DFS for AA versus CA with oropharyngeal tumors was 30% versus 60% (P = .006). CONCLUSIONS: This analysis documents the inferior outcome for AA patients. They had inferior DFS and a trend toward worse OS. When stratified by several prognostic variables, the mediocre DFS in the AA patients remains. These data suggest that further investigation into the genetic characteristics of SCCHN in AA patients is warranted.