Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment.

Immune-Related Adverse Events Among COVID-19-Vaccinated Patients With Cancer Receiving Immune Checkpoint Blockade.

Background: Whether COVID-19 vaccination and the associated immune response increases susceptibility to immune-related adverse events (irAEs) among patients treated with immune checkpoint inhibition (ICI) remains unknown. Short-term follow-up can assess the safety of concurrent administration of the vaccine and ICI treatment.

Methods: We conducted an electronic health record analysis of a cohort of 408 patients with cancer receiving ICI therapy and who were vaccinated for COVID-19 between January 16 and March 27, 2021.

CD8 T cells contribute to survival in patients with COVID-19 and hematologic cancer.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses.

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center.

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance.

Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.

The production of melanin increases skin pigmentation and reduces the risk of skin cancer. Melanin production depends on the pH of melanosomes, which are more acidic in lighter-skinned than in darker-skinned people. We showed that inhibition of soluble adenylyl cyclase (sAC) controlled pigmentation by increasing the pH of melanosomes both in cells and in vivo.

The genetic landscape of programmed death ligand-1 (PD-L1) alterations in head and neck cancer.

Objectives: Nivolumab has recently been shown in the phase III clinical trial CheckMate-141 to have superior survival rates compared to the current standard of care chemotherapy for recurrent or metastatic platinum-resistant head and neck squamous cell carcinoma (HNSCC). Nivolumab targets the immune inhibitory receptor programmed cell death 1 (PD-1). Programmed cell death ligand 1 (PD-L1) genomics have been poorly characterized in the context of HNSCC, including expression levels of PD-L1 in individual tumors as well as related up or down-regulated genes that might function as co-targets.

Precision in donor selection: Identifying ideal stem-cell donors through their T cells.

HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers. Recent data suggest that we should rethink this paradigm. In "High Graft CD8+ Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning," we identified a group of stem-cell donors whose grafts contain an optimal composition of T-cells, leading to a dramatic decrease in disease relapse risk and an improvement in overall survival following allo-HSCT.

Generation of CD8+ T cell-mediated immunity against idiotype-negative lymphoma escapees.

We investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed.