Clinical Relevance of Intensive Laboratory Monitoring With Standard Venetoclax Ramp-Up for Chronic Lymphocytic Leukemia: A Real-World Experience.

Purpose: Venetoclax is the standard of care for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) but requires intensive monitoring for optimal safety. Clinical relevance of intensive monitoring in practice is unknown, especially for patients with low or intermediate risk for tumor lysis syndrome (TLS).

Patients And Methods: A retrospective review was conducted to determine clinical significance of monitoring for TLS during standard ramp-up for patients with CLL/SLL.

Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.

Background: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).

Methods: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.

Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.

Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America.

Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.

Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells.

The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda.

Inadequate T-cell control of Kaposi sarcoma-associated herpesvirus (KSHV) infection predisposes to development of Kaposi sarcoma (KS), but little is known about the T-cell response to KSHV. Postulating that KS tumors contain abundant KSHV-specific T-cells, we performed transcriptional profiling and T-cell receptor (TCR) repertoire analysis of tumor biopsies from 144 Ugandan adults with KS. We show that CD8 T-cells and M2-polarized macrophages dominate the tumor micro-environment (TME).

Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer.

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker.

Therapeutic targeting of tumor spheroids in a 3D microphysiological renal cell carcinoma-on-a-chip system.

Metastatic renal cell carcinoma (RCC) remains an incurable disease for most patients highlighting an urgent need for new treatments. However, the preclinical investigation of new therapies is limited by traditional two-dimensional (2D) cultures which do not recapitulate the properties of tumor cells within a collagen extracellular matrix (ECM), while human tumor xenografts are time-consuming, expensive and lack adaptive immune cells. We report a rapid and economical human microphysiological system ("RCC-on-a-chip") to investigate therapies targeting RCC spheroids in a 3D collagen ECM.

Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma.

The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure.

Concurrent pembrolizumab with AVD for untreated classic Hodgkin lymphoma.

Concurrent administration of pembrolizumab with chemotherapy in untreated classic Hodgkin lymphoma (CHL) has not been studied previously. To investigate this combination, we conducted a single-arm study of concurrent pembrolizumab with AVD (doxorubicin, vinblastine, and dacarbazine; APVD) for untreated CHL. We enrolled 30 patients and met the primary safety end point with no observed significant treatment delays in the first 2 cycles.

Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma.

5T4 (trophoblast glycoprotein encoded by TPBG ) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of 5T4 by emerging receptor-engineered cellular immunotherapies has been hampered by the lack of validated 5T4-specific reagents for immunohistochemistry (IHC). We tested 4 commercially available monoclonal antibodies (mAbs) for the detection of 5T4 in formalin-fixed, paraffin-embedded RCC and normal tissues.

Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas.

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules.

Integrated TCR repertoire analysis and single-cell transcriptomic profiling of tumor-infiltrating T cells in renal cell carcinoma identifies shared and tumor-restricted expanded clones with unique phenotypes.

Objective responses of metastatic renal cell carcinoma (RCC) associated with systemic immunotherapies suggest the potential for T-cell-mediated tumor clearance. Recent analyses associate clonally expanded T cells present in the tumor at diagnosis with responses to immune checkpoint inhibitors (ICIs). To identify and further characterize tumor-associated, clonally expanded T cells, we characterized the density, spatial distribution, T-cell receptor (TCR) repertoire, and transcriptome of tumor-infiltrating T cells from 14 renal tumors at the time of resection and compared them with T cells in peripheral blood and normal adjacent kidney.

A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda.

Objective: Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response.

Methods: Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated.

Serial Analysis of the T-Cell Receptor β-Chain Repertoire in People Living With HIV Reveals Incomplete Recovery After Long-Term Antiretroviral Therapy.

Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4 T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor β-chain () repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis.

Precision Medicine in Low- and Middle-Income Countries.

Most cancer cases occur in low- and middle-income countries (LMICs). The sophisticated technical and human infrastructure needed for optimal diagnosis, treatment, and monitoring of cancers is difficult enough in affluent countries; it is especially challenging in LMICs. In Western, educated, industrial, rich, democratic countries, there is a growing emphasis on and success with precision medicine, whereby targeted therapy is directed at cancers based on the specific genetic lesions in the cancer.

CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells.

T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells.

RNA helicase, DDX3X, is actively recruited to sites of DNA damage in live cells.

Recent studies have suggested that human RNA helicase, DDX3X, is important for DNA repair, but little is known about the nuclear activity of this protein. In vitro analysis of nuclear DDX3X interactions and localization with DNA damage pointed to a direct role for DDX3X in the DNA damage response. We aimed to investigate whether DDX3X plays a direct role in the DNA damage response in live cells.

Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma.

In renal-cell carcinoma (RCC), tumor-reactive T-cell responses can occur spontaneously or in response to systemic immunotherapy with cytokines and immune checkpoint inhibitors. Cancer vaccines and engineered T-cell therapies are designed to selectively augment tumor antigen-specific CD8 T-cell responses with the goal to elicit tumor regression and avoid toxicities associated with nonspecific immunotherapies. In this review, we provide an overview of the central role of T-cell immunity in the treatment of advanced RCC.