Phase II Parallel Arm Study of Sacituzumab Govitecan-Hziy in Patients With Advanced Thymoma or Thymic Carcinoma.

Background: Thymic epithelial tumors (TETs), including thymoma and thymic carcinoma, are rare thoracic tumors of the anterior mediastinum. For those with advanced disease, platinum-based chemotherapy is used as first-line treatment. However, there is no standard regimen established for TET at progression after initial therapy, and treatment options for advanced/recurrent TETs are limited.

Intratumor heterogeneity of EGFR expression mediates targeted therapy resistance and formation of drug tolerant microenvironment.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are commonly used to treat non-small cell lung cancers with EGFR mutations, but drug resistance often emerges. Intratumor heterogeneity is a known cause of targeted therapy resistance and is considered a major factor in treatment failure. This study identifies clones of EGFR-mutant non-small cell lung tumors expressing low levels of both wild-type and mutant EGFR protein.

RNA sensing induced by chromosome missegregation augments anti-tumor immunity.

Viral mimicry driven by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts during cancer therapy remain unclear. Here, we demonstrate that dsRNA is significantly accumulated in cancer cells following pharmacologic induction of micronuclei, stimulating mitochondrial antiviral signaling (MAVS)-mediated dsRNA sensing in conjunction with the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway.

Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.

Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. In this study, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of central nervous system (CNS)-specific outcomes.

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial.

Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.

Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.

miR126-mediated impaired vascular integrity in Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder that is caused by mutations in melty-CpG binding protein 2 (MeCP2). MeCP2 is a non-cell type-specific DNA binding protein, and its mutation influences not only neural cells but also non-neural cells in the brain, including vasculature associated with endothelial cells. Vascular integrity is crucial for maintaining brain homeostasis, and its alteration may be linked to the pathology of neurodegenerative disease, but a non-neurogenic effect, especially the relationship between vascular alternation and Rett syndrome pathogenesis, has not been shown.

AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived. Thus, there is an urgent need to develop more effective treatments.

Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses.

The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E.

Patient-specific vascularized tumor model: Blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, often linked to the infiltration of monocyte-derived tumor-associated macrophages (TAMs), which are associated with poor prognosis in various cancers. To advance immunotherapies, testing on immunocompetent pre-clinical models of human tissue is crucial. We have developed an in vitro model of microvascular networks with tumor spheroids or patient tissues to assess monocyte trafficking into tumors and evaluate immunotherapies targeting the human tumor microenvironment.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.

Detecting Small Cell Transformation in Patients with Advanced EGFR Mutant Lung Adenocarcinoma through Epigenomic cfDNA Profiling.

Purpose: Histologic transformation to small cell lung cancer (SCLC) is a mechanism of treatment resistance in patients with advanced oncogene-driven lung adenocarcinoma (LUAD) that currently requires histologic review for diagnosis. Herein, we sought to develop an epigenomic cell-free DNA (cfDNA)-based approach to noninvasively detect small cell transformation in patients with EGFR mutant (EGFRm) LUAD.

Experimental Design: To characterize the epigenomic landscape of transformed (t)SCLC relative to LUAD and de novo SCLC, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to profile the histone modifications H3K27ac, H3K4me3, and H3K27me3; methylated DNA immunoprecipitation sequencing (MeDIP-seq); assay for transposase-accessible chromatin sequencing; and RNA sequencing on 26 lung cancer patient-derived xenograft (PDX) tumors.

Transmural Flow Upregulates PD-L1 Expression in Microvascular Networks.

Endothelial programmed death-ligand 1 (PD-L1) expression is higher in tumors than in normal tissues. Also, tumoral vasculatures tend to be leakier than normal vessels leading to a higher trans-endothelial or transmural fluid flow. However, it is not clear whether such elevated transmural flow can control endothelial PD-L1 expression.

Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma (PRAD) and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.

TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.

Unlabelled: A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA.

Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers.

Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers.

Patient-Specific Vascularized Tumor Model: Blocking TAM Recruitment with Multispecific Antibodies Targeting CCR2 and CSF-1R.

Tumor-associated inflammation drives cancer progression and therapy resistance, with the infiltration of monocyte-derived tumor-associated macrophages (TAMs) associated with poor prognosis in diverse cancers. Targeting TAMs holds potential against solid tumors, but effective immunotherapies require testing on immunocompetent human models prior to clinical trials. Here, we develop an in vitro model of microvascular networks that incorporates tumor spheroids or patient tissues.

Unraveling the Intricacies of CD73/Adenosine Signaling: The Pulmonary Immune and Stromal Microenvironment in Lung Cancer.

CD73 and adenosine have gained prominence in lung cancer research. The gene encodes CD73, known as an ectonucleotidase, which plays a crucial role within tumor cells, with immune-suppressive properties. Beyond cancer, CD73 exerts an influence on cardiac, neural, and renal functions, affecting cardiac, neural, and renal functions.

Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

Unlabelled: Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity.

ALK peptide vaccination restores the immunogenicity of ALK-rearranged non-small cell lung cancer.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is treated with ALK tyrosine kinase inhibitors (TKIs), but the lack of activity of immune checkpoint inhibitors (ICIs) is poorly understood. Here, we identified immunogenic ALK peptides to show that ICIs induced rejection of ALK tumors in the flank but not in the lung. A single-peptide vaccination restored priming of ALK-specific CD8 T cells, eradicated lung tumors in combination with ALK TKIs and prevented metastatic dissemination of tumors to the brain.