Association Between Early on-Treatment Weight Loss With Enfortumab Vedotin Plus Pembrolizumab and Survival in Advanced Urothelial Carcinoma.

Background: Combination therapy with enfortumab vedotin plus pembrolizumab (EV+P) is now the preferred first-line (1L) therapy for advanced urothelial carcinoma (aUC), but prognostic indicators for patients on 1L EV+P have not yet been described.

Patients And Methods: We conducted a retrospective cohort study of patients receiving 1L EV+P for aUC. We analyzed deidentified electronic health record data from the Flatiron Health database to identify adults with aUC who initiated EV+P between April 3, 2023 and December 31, 2024.

Assessment of synergistic vs. independent drug activity for enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma.

Background: The combination of enfortumab vedotin (EV) and pembrolizumab (EV+P) was recently approved as a first-line (1L) therapy for patients with advanced urothelial cancer (aUC). Preclinical studies have suggested that these 2 drugs synergize with one another to drive anti-tumor responses. However, it remains unknown whether EV and pembrolizumab demonstrate synergistic activity in a clinical setting.

Cas12a-knock-in mice for multiplexed genome editing, disease modelling and immune-cell engineering.

The pleiotropic effects of human disease and the complex nature of gene-interaction networks require knock-in mice allowing for multiplexed gene perturbations. Here we describe a series of knock-in mice with a C57BL/6 background and with the conditional or constitutive expression of LbCas12a or of high-fidelity enhanced AsCas12a, which were inserted at the Rosa26 locus. The constitutive expression of Cas12a in the mice did not lead to discernible pathology and enabled efficient multiplexed genome engineering.

Persistent postremission clonal hematopoiesis shapes the relapse trajectories of acute myeloid leukemia.

Mutations found in acute myeloid leukemia (AML) such as DNMT3A, TET2, and ASXL1 can be found in the peripheral blood of healthy adults, a phenomenon termed clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations after induction chemotherapy.

Multiplexed inhibition of immunosuppressive genes with Cas13d for combinatorial cancer immunotherapy.

The complex nature of the immunosuppressive tumor microenvironment (TME) requires multi-agent combinations for optimal immunotherapy. Here we describe multiplex universal combinatorial immunotherapy via gene silencing (MUCIG), which uses CRISPR-Cas13d to silence multiple endogenous immunosuppressive genes in the TME, promoting TME remodeling and enhancing antitumor immunity. MUCIG vectors targeting four genes delivered by adeno-associated virus (AAV) (Cd274/Pdl1, Lgals9/Galectin9, Lgals3/Galectin3 and Cd47; AAV-Cas13d-PGGC) demonstrate significant antitumor efficacy across multiple syngeneic tumor models, remodeling the TME by increasing CD8 T-cell infiltration while reducing neutrophils.

Phenotypic evaluation of deep learning models for classifying germline variant pathogenicity.

Deep learning models for predicting variant pathogenicity have not been thoroughly evaluated on real-world clinical phenotypes. Here, we apply state-of-the-art pathogenicity prediction models to hereditary breast cancer gene variants in UK Biobank participants. Model predictions for missense variants in BRCA1, BRCA2 and PALB2, but not ATM and CHEK2, were associated with breast cancer risk.

Early drivers of clonal hematopoiesis shape the evolutionary trajectories of acute myeloid leukemia.

Mutations commonly found in AML such as , and can be found in the peripheral blood of otherwise healthy adults - a phenomenon referred to as clonal hematopoiesis (CH). These mutations are thought to represent the earliest genetic events in the evolution of AML. Genomic studies on samples acquired at diagnosis, remission, and at relapse have demonstrated significant stability of CH mutations following induction chemotherapy.

In vivo AAV-SB-CRISPR screens of tumor-infiltrating primary NK cells identify genetic checkpoints of CAR-NK therapy.

Natural killer (NK) cells have clinical potential against cancer; however, multiple limitations hinder the success of NK cell therapy. Here, we performed unbiased functional mapping of tumor-infiltrating NK (TINK) cells using in vivo adeno-associated virus (AAV)-SB (Sleeping Beauty)-CRISPR (clustered regularly interspaced short palindromic repeats) screens in four solid tumor mouse models. In parallel, we characterized single-cell transcriptomic landscapes of TINK cells, which identified previously unexplored subpopulations of NK cells and differentially expressed TINK genes.

Real-world evaluation of deep learning algorithms to classify functional pathogenic germline variants.

Deep learning models for variant pathogenicity prediction can recapitulate expert-curated annotations, but their performance remains unexplored on actual disease phenotypes in a real-world setting. Here, we apply three state-of-the-art pathogenicity prediction models to classify hereditary breast cancer gene variants in the UK Biobank. Predicted pathogenic variants in , and , but not and were associated with increased breast cancer risk.

CTLA-4 tail fusion enhances CAR-T antitumor immunity.

Chimeric antigen receptor (CAR)-T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail, we reprogram CAR function and substantially enhance CAR-T efficacy in vivo. CAR-T cells with monomeric, duplex or triplex CTLA-4 cytoplasmic tails (CCTs) fused to the C terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of proinflammatory cytokines.

DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner.

Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception.

mRNA Staining Distinguishes Palmoplantar Psoriasis from Hyperkeratotic Palmoplantar Eczema in Diagnostic Skin Biopsies.

Acral dermatoses, including hyperkeratotic palmoplantar eczema (HPE), palmoplantar psoriasis (PP), and mycosis fungoides palmaris et plantaris (MFPP), can be challenging to diagnose clinically and histopathologically. In this setting, cytokine biomarkers may be able to help provide diagnostic clarity. Therefore, we evaluated IL-17A, IFN-γ, and IL-13 expression in PP, HPE, and MFPP and compared their expression profiles with nonacral sites.

Disparities in immune and targeted therapy utilization for older US patients with metastatic renal cell carcinoma.

Disparities in metastatic renal cell carcinoma (mRCC) outcomes persist in the era of oral anticancer agents (OAAs) and immunotherapies (IOs). We examined variation in the utilization of mRCC systemic therapies among US Medicare beneficiaries from 2015 to 2019. Logistic regression models evaluated the association between therapy receipt and demographic covariates including patient race, ethnicity, and sex.

Cas12a/Cpf1 knock-in mice enable efficient multiplexed immune cell engineering.

Cas9 transgenic animals have drastically accelerated the discovery of novel immune modulators. But due to its inability to process its own CRISPR RNAs (crRNAs), simultaneous multiplexed gene perturbations using Cas9 remains limited, especially by pseudoviral vectors. Cas12a/Cpf1, however, can process concatenated crRNA arrays for this purpose.

CTLA-4 tail fusion enhances CAR-T anti-tumor immunity.

Chimeric antigen receptor (CAR) T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here, utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail (CT), we reprogram CAR function and substantially enhance CAR-T efficacy . CAR-T cells with monomeric, duplex, or triplex CTLA-4 CTs (CCTs) fused to the C-terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of pro-inflammatory cytokines.

Perturbomics of tumor-infiltrating NK cells.

Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential, however, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly reveal the functional genetic landscape underlying critical NK cell characteristics against cancer, we perform perturbomics mapping of tumor infiltrating NK cells by joint AAV-CRISPR screens and single cell sequencing.

Mutations in IFN-γ signaling genes sensitize tumors to immune checkpoint blockade.

Song and Chow demonstrate that while tumor-intrinsic mutations in the IFN-γ signaling pathway confer immune resistance across in vitro co-culture systems, such alterations associate with enhanced anti-tumor immunity in vivo and improved responsiveness to immune checkpoint blockade therapy in patients with cancer.

Massively parallel knock-in engineering of human T cells.

The efficiency of targeted knock-in for cell therapeutic applications is generally low, and the scale is limited. In this study, we developed CLASH, a system that enables high-efficiency, high-throughput knock-in engineering. In CLASH, Cas12a/Cpf1 mRNA combined with pooled adeno-associated viruses mediate simultaneous gene editing and precise transgene knock-in using massively parallel homology-directed repair, thereby producing a pool of stably integrated mutant variants each with targeted gene editing.

Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma.

Unlabelled: Mismatch repair-deficient (MMRd) cancers have varied responses to immune-checkpoint blockade (ICB). We conducted a phase II clinical trial of the PD-1 inhibitor pembrolizumab in 24 patients with MMRd endometrial cancer (NCT02899793). Patients with mutational MMRd tumors (6 patients) had higher response rates and longer survival than those with epigenetic MMRd tumors (18 patients).

LRRC15 inhibits SARS-CoV-2 cellular entry in trans.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is mediated by the entry receptor angiotensin-converting enzyme 2 (ACE2). Although attachment factors and coreceptors facilitating entry are extensively studied, cellular entry factors inhibiting viral entry are largely unknown. Using a surfaceome CRISPR activation screen, we identified human LRRC15 as an inhibitory attachment factor for SARS-CoV-2 entry.

Comparison of Cancer-Related Spending and Mortality Rates in the US vs 21 High-Income Countries.

Importance: Studies using data from before 2011 concluded that the cost of US cancer care is justified given improved outcomes compared with European countries. However, it is unclear whether contemporary US cancer care provides better value than that of other high-income countries.

Objective: To assess whether cancer mortality rates in 2020 were lower in countries with higher cancer-related spending, and to estimate across countries the incremental cost per averted cancer death.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical.

Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617.

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical.