Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors.

Development of the retinoic acid receptor alpha-specific antagonist YCT-529 for male contraception: A brief review.

Genetic studies in mice have demonstrated that retinoic acid receptor alpha (RARα) deficiency leads to male infertility without affecting overall viability, suggesting that pharmacological inhibition of this receptor could be a viable contraceptive strategy. This review describes the use of experimental approaches to develop RARα-selective antagonists for male contraception. Initial studies with BMS-189453, a pan-RAR antagonist, showed significant testicular degeneration and reversible infertility in mice.

Development of small molecule non-covalent coronavirus 3CL protease inhibitors from DNA-encoded chemical library screening.

Variants of SARS-CoV-2 have continued to emerge across the world and cause hundreds of deaths each week. Due to the limited efficacy of vaccines against SARS-CoV-2 and resistance to current therapies, additional anti-viral therapeutics with pan-coronavirus activity are of high interest. Here, we screen 2.

Mixed exposure to PFOA and PFOS induces oocyte apoptosis and subfertility in mice by activating the Hippo signaling pathway.

Per- and polyfluoroalkyl substances (PFAS) are synthetic perfluorinated compounds known for their persistence in the environment and reproduction toxicity. PFAS, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), have been identified in the follicular fluid of infertile women. However, the specific of PFOA and PFOS mixture on oocyte quality and female fertility remain unclear.

Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy.

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs).

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Regulation of metastatic organotropism.

Metastasis is responsible for most cancer-related deaths. Different cancers have their own preferential sites of metastases, a phenomenon termed metastatic organotropism. The mechanisms underlying organotropism are multifactorial and include the generation of a pre-metastatic niche (PMN), metastatic homing, colonization, dormancy, and metastatic outgrowth.

SOHO State of the Art Updates and Next Questions | Venetoclax + Obinutuzumab Therapy in Chronic Lymphocytic Leukemia.

In the past decade, the treatment paradigm for chronic lymphocytic leukemia (CLL) has markedly shifted from traditional chemoimmunotherapy towards targeted therapies. A fixed-duration, targeted regimen with venetoclax, a potent oral BCL-2 inhibitor, combined with obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody (Ven-Obi), has become the standard to beat for time-limited therapy in CLL. Ven-Obi allows for the rapid induction of remissions with high rates of undetectable minimal residual disease (uMRD) in patients across different treatment settings.

Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis.

B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not.

Neoadjuvant atezolizumab + chemotherapy for resectable NSCLC: 3-year clinical update of phase II clinical trial results and translational findings.

Introduction: Neoadjuvant chemoimmunotherapy has achieved overall survival (OS) benefit for patients with resectable non-small cell lung cancer (NSCLC). Here, we present outcomes after 3 years of follow-up from the first reported study of neoadjuvant atezolizumab+chemotherapy.

Methods: This open-label, multicenter single-arm investigator-initiated phase II study conducted at three US hospitals tested up to four cycles of atezolizumab, carboplatin, and nab-paclitaxel prior to surgery.

Harnessing the TAF1 Acetyltransferase for Targeted Acetylation of the Tumor Suppressor p53.

Pharmacological reactivation of the tumor suppressor p53 remains a key challenge for the treatment of cancer. Acetylation Targeting Chimera (AceTAC), a novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate the p53Y220C mutant. However, p300/CBP are the only acetyltransferases harnessed for AceTAC development to date.

SOX2-induced IL1α-mediated immune suppression drives epithelial dysplasia malignant transformation.

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return.

Heme alters biofilm formation in .

(Mabs) is commonly found in the cystic fibrosis (CF) lung. During infection, Mabs can form biofilms in the lung which reduce both the ability of the immune response to clear infection and the effectiveness of antibiotic therapy. In the CF lung, heme and hemoglobin levels are increased and may provide both iron and heme to Mabs cells.

Weight loss in patients on osimertinib for metastatic EGFR-mutant non-small cell lung cancer.

Background: Cachexia is characterized by weight loss and decline in muscle mass and function and is a poor prognostic factor among patients with cancer. Patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC) derive remarkable survival benefits with osimertinib, a third-generation EGFR tyrosine kinase inhibitor. It is not known whether patients treated with osimertinib experience any weight loss or whether weight loss impacts patient outcomes.

Stereotactic Body Radiotherapy vs Sorafenib Alone in Hepatocellular Carcinoma: The NRG Oncology/RTOG 1112 Phase 3 Randomized Clinical Trial.

Importance: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy.

Objective: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone.

Design, Setting, And Participants: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion.

Targeting Epigenetic Dysregulations in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is one of the deadliest human cancers, with the overall 5-year survival rate stagnating in recent decades due to the lack of innovative treatment approaches. Apart from the recently Food and Drug Administration-approved epidermal growth factor receptor inhibitor and immune checkpoint inhibitor, alternative therapeutic strategies that target epigenetic abnormalities, an emerging cancer hallmark, remain to be fully explored. A pathological epigenetic landscape, characterized by widespread reprogramming of chromatin modifications such as DNA methylation and histone modifications, which drives transcription deregulation and genome reorganization, has been extensively documented in numerous cancers, including HNSCC.

Effectiveness and Safety of Irreversible Electroporation When Used for the Ablation of Stage 3 Pancreatic Adenocarcinoma: Initial Results from the DIRECT Registry Study.

Background/objectives: Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled in a multicenter registry study.

Menopausal hormone therapy: assessing associations with breast and colorectal cancers by familial risk.

Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.

The CALERIE Genomic Data Resource.

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from the CALERIE randomized, controlled trial of long-term CR in healthy, nonobese humans broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n = 218 participants during the trial.

Household income and county income inequality are associated with financial hardship among cancer survivors in New Jersey.

Purpose: To examine how household income and county income inequality are linked to financial hardship among cancer survivors.

Methods: Cancer survivors (n = 864) identified through the New Jersey State Cancer Registry were surveyed from August 2018 to January 2022. Local area income inequality was reflected by the Gini index a measure of income inequality at the county level.

Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression.

Treatment sequence with tebentafusp and immune checkpoint inhibitors in patients with metastatic uveal melanoma and metastatic GNA11/GNAQ mutant melanocytic tumors.

Background: Metastatic uveal melanoma (mUM) is rare. Immune checkpoint inhibitors (ICIs) have shown modest efficacy in mUM. Tebentafusp prolonged overall survival (OS) in a phase 3 study.

From brain to blood and back again: Linking chronic stress, myelopoiesis, and depression.

In this issue of Cell Stem Cell, Mou et al. identified a brain-bone marrow axis reinforcing myelopoiesis and neuroinflammation during psychological stress, culminating in depression. The identification of this pathway provides insights into hematopoietic stem cell homeostasis and regulatory neuronal function with potentially significant implications for the treatment of stress-related disorders.