Prolonged Survival Research Articles

Inhibition of RhoA prevents Cryptococcus neoformans capsule glucuronoxylomannan-stimulated brain endothelial barrier disruption.

Cryptococcus neoformans (Cn) is an opportunistic fungus that causes severe central nervous system (CNS) disease in immunocompromised individuals. Brain parenchyma invasion requires fungal traversal of the blood-brain barrier. In this study, we describe that Cn alters the brain endothelium by activating small GTPase RhoA, causing reorganization of the actin cytoskeleton and tight junction modulation to regulate endothelial barrier permeability. We confirm that the main fungal capsule polysaccharide glucuronoxylomannan is responsible for these alterations. We reveal a therapeutic benefit of RhoA inhibition by CCG-1423 in vivo. RhoA inhibition prolonged survival and reduced fungal burden in a murine model of disseminated cryptococcosis, supporting the therapeutic potential targeting RhoA in the context of cryptococcal infection. We examine the complex virulence of Cn in establishing CNS disease, describing cellular components of the brain endothelium that may serve as molecular targets for future antifungal therapies to alleviate the burden of life-threatening cryptococcal CNS infection.

Incorporating IL7 receptor alpha signaling in the endodomain of B7H3-targeting chimeric antigen receptor T cells mediates antitumor activity in glioblastoma.

CAR-T-cell therapy has shown promise in treating hematological malignancies but faces challenges in treating solid tumors due to impaired T-cell function in the tumor microenvironment. To provide optimal T-cell activation, we developed a B7 homolog 3 protein (B7H3)-targeting CAR construct consisting of three activation signals: CD3ζ (signal 1), 41BB (signal 2), and the interleukin 7 receptor alpha (IL7Rα) cytoplasmic domain (signal 3). We generated B7H3 CAR-T cells with different lengths of the IL7Rα cytoplasmic domain, including the full length (IL7R-L), intermediate length (IL7R-M), and short length (IL7R-S) domains, and evaluated their functionality in vitro and in vivo. All the B7H3-IL7Rα CAR-T cells exhibited a less differentiated phenotype and effectively eliminated B7H3-positive glioblastoma in vitro. Superiority was found in B7H3 CAR-T cells contained the short length of the IL7Rα cytoplasmic domain. Integration of the IL7R-S cytoplasmic domain maintained pSTAT5 activation and increased T-cell proliferation while reducing activation-induced cell death. Moreover, RNA-sequencing analysis of B7H3-IL7R-S CAR-T cells after coculture with a glioblastoma cell line revealed downregulation of proapoptotic genes and upregulation of genes associated with T-cell proliferation compared with those in 2nd generation B7H3 CAR-T cells. In animal models, compared with conventional CAR-T cells, B7H3-IL7R-S CAR-T cells suppressed tumor growth and prolonged overall survival. Our study demonstrated the therapeutic potential of IL7Rα-incorporating CAR-T cells for glioblastoma treatment, suggesting a promising strategy for augmenting the effectiveness of CAR-T cell therapy.

Caspase-resistant ROCK1 expression prolongs survival of Eµ-Myc B cell lymphoma mice.

Apoptosis is characterized by membrane blebbing and apoptotic body formation. Caspase cleavage of ROCK1 generates an active fragment that promotes actin-myosin mediated contraction and membrane blebbing during apoptosis. Expression of caspase-resistant non-cleavable ROCK1 (Rock1 NC) prolonged survival of mice that rapidly develop B cell lymphomas due to Eµ-Myc transgene expression. Eµ-Myc; Rock1 NC mice had significantly fewer bone marrow cells relative to Eµ-Myc mice expressing wild-type ROCK1 (Rock1 WT), which was associated with altered cell cycle profiles. Circulating macrophage numbers were lower in Eµ-Myc; Rock1 NC mice, but there were higher levels of bone marrow macrophages, consistent with spontaneous cell death in Eµ-Myc; Rock1 NC mice bone marrows being more inflammatory. Rock1 WT recipient mice transplanted with pre-neoplastic Eµ-Myc; Rock1 NC bone marrow cells survived longer than mice transplanted with Eµ-Myc; Rock1 WT cells, indicating that the survival benefit was intrinsic to the Eµ-Myc; Rock1 NC bone marrow cells. The results suggest that the apoptotic death of Eµ-Myc; Rock1 NC cells generates a proliferation-suppressive microenvironment in bone marrows that reduces cell numbers and prolongs B cell lymphoma mouse survival.

Clinical analysis of multiple primary gastrointestinal malignant tumors: A 10-year case review of a single-center

BACKGROUND Multiple primary malignant tumors (MPMTs) was first described by Billroth as early as 1889, with the first report published by Warren and Gates in 1932. Since then, numerous cases have been reported. A literature review of 1104269 patients with cancer revealed that the incidence of MPMTs ranged from 0.73 to 11.7%. In recent years, however, there has been a significant upward trend in the incidence of this phenomenon, which may be associated with many different factors, including the advancement of modern diagnostic procedures facilitating the examination and diagnosis of more MPMTs, increased exposure to chemotherapy and radiotherapy that exacerbate the risk of new malignant tumors in patients with cancer, and prolonged survival of patients with cancer allowing sufficient time for the development of new primary cancers. AIM To analyze the incidence, clinical features, treatment factors, prevalence, and prognosis of patients with MPMTs in the gastrointestinal tract treated in a single center. Additionally, we analyzed the different tumor combinations, time interval between the occurrence of tumors, and staging. METHODS This retrospective cohort study analyzed 8059 patients with pathologically confirmed gastrointestinal malignant tumors treated at the Gansu Province Hospital in Lanzhou, Gansu, China between June 2011 and June 2020. Of these, 85 patients had MPMTs. The clinical features, treatment factors, prevalence, and prognosis of this latter cohort were analyzed. RESULTS The incidence of MPMTs in patients with gastrointestinal malignant tumors was 1.05% (85/8059), including 83 double primary malignant tumors and two triple primary malignant tumors of which 57 (67.06%) were synchronous MPMTs (SMPMTs) and 28 (32.94%) were metachronous MPMTs (MMPMTs). The most frequent associations were found between the rectum colon cancers within the SMPMT category and the gastric-colon cancers within the MMPMT category. For the MMPMTs, the median interval was 53 months. The overall 1-, 3- and 5-year survival rates from diagnosis of the first primary cancer were 91.36%, 65.41%, and 45.97%, respectively; those from diagnosis of the second primary cancer were 67.90%, 29.90%, and 17.37%, respectively. CONCLUSION MPMTs in the gastrointestinal tract have a high incidence and poor prognosis. Thus, it is necessary to perform both gastroscopy and colonoscopy in patients with gastrointestinal tumors. Multidisciplinary comprehensive diagnosis and treatment may improve the diagnosis rate and treatment efficiency of MPMTs.

Current status of liver transplantation for human immunodeficiency virus-infected patients in mainland China

According to the report from the Chinese Center for Disease Control and Prevention, the prevalence of human immunodeficiency virus (HIV) infection exceeded 1.2 million individuals by the year 2022, with an annual increase of about 80000 cases. The overall prevalence of hepatitis B surface antigen among individuals co-infected with HIV reached 13.7%, almost twice the rate of the general population in China. In addition to the well-documented susceptibility to opportunistic infections and new malignancies, HIV infected patients frequently experience liver-related organ damage, with the liver and kidneys being the most commonly affected. This often leads to the development of end-stage liver and kidney diseases. Therefore, organ transplantation has emerged as an important part of active treatment for HIV infected patients. However, the curative effect is not satisfactory. HIV infection has been considered a contraindication for organ transplantation. Until the emergence of highly active anti-retroviral therapy in 1996, the once intractable replication of retrovirus was effectively inhibited. With prolonged survival, the failure of important organs has become the main cause of death among HIV patients. Therefore, transplant centers worldwide have resumed exploration of organ transplantation for HIV-infected individuals and reached a positive conclusion. This study provides an overview of the current landscape of HIV-positive patients receiving liver transplantation (LT) in mainland China. To date, our transplant center has conducted LT for eight end-stage liver disease patients co-infected with HIV, and all but one, who died two months postoperatively due to sepsis and progressive multi-organ failure, have survived. Comparative analysis with hepatitis B virus-infected patients during the same period revealed no statistically significant differences in acute rejection reactions, cytomegalovirus infection, bacteremia, pulmonary infections, acute kidney injury, new-onset cancers, or vascular and biliary complications.

The impact of phospholipids with high transition temperature to enhance Redox-Sensitive liposomal doxorubicin efficacy in colon carcinoma model

In this study, we have developed a redox-sensitive (RS) liposomal doxorubicin formulation by incorporating 10,10′-diselanediylbis decanoic acid (DDA) organoselenium compound as the RS moiety. Hence, several RS liposomal formulations were prepared by using DOPE, HSPC, DDA, mPEG2000-DSPE, and cholesterol. In situ drug loading using a pH gradient and citrate complex yielded high drug to lipid ratio and encapsulation efficiency (100%) for RS liposomes. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell uptake and cytotoxicity, as well as therapeutic efficacy in BALB/c mice bearing C26 tumor cells. The formulations showed an average particle size of 200nm with narrow size distributions (PDI < 0.3), and negative surface charges varying from -6 mV to -18.6mV. Our study confirms that the presence of the DDA compound in liposomes is highly sensitive to hydrogen peroxide at 0.1% w/v, resulting in a significant burst release of up to 40%. The in vivo therapeutic efficacy study in BALB/c mice bearing C26 colon carcinoma confirmed the promising function of RS liposomes in the tumor microenvironment which led to a prolonged median survival time (MST). The addition of hydrogenated soy phosphatidylcholine (HSPC) with a high transition temperature (Tm: 52–53.5°C) extended the MST of our 3-component formulation of F14 (DOPE/HSPC/DDA) to 60 days in comparison to Caelyx (PEGylated liposomal Dox), which is not RS-sensitive (39 days). Overall, HSPC liposomes bearing RS-sensitive moiety enhanced therapeutic efficacy against colon cancer in vitro and in vivo. This achievement unequivocally underscores the criticality of high-TM phospholipids, particularly HSPC, in significantly enhancing liposome stability within the bloodstream. In addition, RS liposomes enable the on-demand release of drugs, leveraging the redox environment of tumor cells, thereby augmenting the efficacy of the formulation.

Patient-Derived Exosomes as siRNA Carriers in Ovarian Cancer Treatment

RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC.

Understanding the Tumor Microenvironment in Melanoma Patients with In-Transit Metastases and Its Impacts on Immune Checkpoint Immunotherapy Responses

Melanoma is the leading cause of global skin cancer-related death and currently ranks as the third most commonly diagnosed cancer in Australia. Melanoma patients with in-transit metastases (ITM), a type of locoregional metastasis located close to the primary tumor site, exhibit a high likelihood of further disease progression and poor survival outcomes. Immunotherapies, particularly immune checkpoint inhibitors (ICI), have demonstrated remarkable efficacy in ITM patients with reduced occurrence of further metastases and prolonged survival. The major challenge of immunotherapeutic efficacy lies in the limited understanding of melanoma and ITM biology, hindering our ability to identify patients who likely respond to ICIs effectively. In this review, we provided an overview of melanoma and ITM disease. We outlined the key ICI therapies and the critical immune features associated with therapy response or resistance. Lastly, we dissected the underlying biological components, including the cellular compositions and their communication networks within the tumor compartment, to enhance our understanding of the interactions between immunotherapy and melanoma, providing insights for future investigation and the development of drug targets and predictive biomarkers.

Prognostic and onco-immunological value of immune-related eRNAs-driven genes in lung adenocarcinoma

BackgroundWe aimed to comprehensively analyze the clinical value of immune-related eRNAs-driven genes in lung adenocarcinoma (LUAD) and find the potential biomarkers for prognosis and therapeutic response to improve the survival of this malignant disease.Materials and methodsPearson’s correlation analysis was performed to identify the immune-related eRNAs-driven genes. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were used to construct this prognostic risk signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to investigate the underlying molecular mechanism. The single sample gene set enrichment analysis (ssGSEA) algorithm was conducted to evaluate the immune status based on the signature. The quantitative real-time PCR (qRT-PCR) analysis was performed to evaluate the expression value of the signature genes between LUAD tissues and adjacent lung tissues.ResultsFive immune-related eRNAs-driven genes (SHC1, GDF10, CCL14, FYN, and NOD1) were identified to construct a prognostic risk signature with favorable predictive capacity. The patients with high-risk scores based on the signature were significantly associated with the malignant clinical features compared with those with low-risk scores. Kaplan–Meier analysis demonstrated that the sample in the low-risk group had a prolonged survival compared with those in the high-risk group. This risk signature was validated to have a promising predictive capacity and reliability in diverse clinical situations and independent cohorts. The functional enrichment analysis demonstrated that humoral immune response and intestinal immune network for IgA production pathway might be the underlying molecular mechanism related to the signature. The proportion of the vast majority of immune infiltrating cells in the high-risk group was significantly lower than that in the low-risk group, and the immunotherapy response rate in the low-risk group was significantly higher than that in the high-risk group. Moreover, BI-2536, sepantronium bromide, and ULK1 were the potential drugs for the treatment of patients with higher risk scores. Finally, the experiment in vivo and database analysis indicated that CCL14, FYN, NOD1, and GDF10 are the potential LUAD suppressor and SHC1 is a potential treatment target for LUAD.ConclusionAbove all, we constructed a prognostic risk signature with favorable predictive capacity in LUAD, which was significantly associated with malignant features, immunosuppressive tumor microenvironment, and immunotherapy response and may provide clinical benefit in clinical decisions.

Transitioning to a Personalized Approach in Molecularly Subtyped Small-Cell Lung Cancer (SCLC)

Lung cancer has become a major public health concern, standing as the leading cause of cancer-related deaths worldwide. Among its subtypes, small-cell lung cancer (SCLC) is characterized by aggressive and rapid growth, poor differentiation, and neuroendocrine features. Typically, SCLC is diagnosed at an advanced stage (extensive disease, ED-SCLC), with distant metastases, and is strongly associated with tobacco smoking and has a poor prognosis. Recent clinical trials, such as CASPIAN and IMpower133, have demonstrated promising outcomes with the incorporation of immune checkpoint inhibitors in first-line chemotherapy, leading to prolonged progression-free survival and overall survival in patients with ED-SCLC compared to standard chemotherapy. Other studies have emphasized the potential for future development of molecularly targeted therapies in SCLC patients, including inhibitors of IGF-1R, DLL3, BCL-2, MYC, or PARP. The molecular subdivision of SCLC based on transcriptomic and immunohistochemical analyses represents a significant advancement in both diagnostic and clinical approaches in SCLC patients. Specific molecular pathways are activated within distinct transcriptome subtypes of SCLC, offering the potential for personalized treatment strategies, such as targeted therapies and immunotherapies. Such tailored approaches hold promise for significantly improving outcomes in SCLC patients.

A novel approach toward the multigram synthesis of a novel Bcl2-specific inhibitor, and evaluation of its biological activity

The antiapoptotic protein BCL2 is overexpressed in several cancers. It contributes to prolonged cell survival and chemoresistance, making it an excellent target for targeted cancer therapy. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential; however, most of them were abolished before clinical use due to their pan activity. There is only one FDA-approved BCL2-specific inhibitor, Venetoclax, currently used in clinics. Previously, we reported the characterization and development of a novel BCL2 inhibitor, Disarib, which is selective against BCL2 and predominantly binds to the BH1 domain of BCL2. Importantly, the efficacy of Disarib was equally good or better than Venetoclax in various in vitro and in vivo assays. In the present study, we report the development of a scalable and practical method for the large-scale synthesis of Disarib to support the ongoing pre-clinical studies. The parameters of each step were optimized through prior knowledge, helping in improving the yield and purity to 98.8 %. Further, we compared the efficiency of a large-scale synthesized Disarib in a GLP-certified laboratory with that of an in-house synthesized Disarib. The results showed that the biological activity, including Disarib-induced cytotoxicity and cell cycle progression, were comparable. Besides, the tumor regression efficacy and pharmacokinetics analysis of Disarib have shown comparable results when Disarib synthesized in both routes were tested. Thus, a robust and scalable synthetic pathway of Disarib has developed to address small-scale synthesis's limitations in supporting their expanded applications and use.

Association between quality of life and mortality risk in patients with breast cancer: a systematic review and meta-analysis.

Patients with breast cancer present with various problems that have an adverse effect on the quality of life (QOL). However, the association between the QOL and mortality among patients with breast cancer remains controversial. Therefore, this systematic review and meta-analysis aimed to determine whether QOL impacts prognosis in patients with breast cancer. The databases of CINAHL, Scopus, and PubMed databases were searched to retrieve observational studies that assessed the QOL and mortality risk in patients with breast cancer published before December 2022. Among the 119,061 articles retrieved, six observational studies were included in the meta-analysis. Physical QOL (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.01-1.07, p = 0.003), emotional QOL (HR: 1.01, 95% CI: 1.00-1.03, p = 0.05), and role QOL (HR: 1.01, 95% CI: 1.00-1.01, p = 0.007) showed significant associations with mortality risk. In contrast, global QOL, cognitive QOL, and social QOL showed no associations with mortality risk. Subgroup analysis performed according to treatment time points revealed that the post-treatment physical QOL was associated with mortality risk. Physical QOL, emotional QOL, and role QOL are associated with mortality risk in patients with breast cancer. Furthermore, post-treatment physical QOL showed a more significant association with prolonged survival than pre-treatment physical QOL.

Immunoinformatics Design and In Vivo Immunogenicity Evaluation of a Conserved CTL Multi-Epitope Vaccine Targeting HPV16 E5, E6, and E7 Proteins

Human papillomavirus type 16 (HPV16) infection is responsible for more than 50% of global cervical cancer cases. The development of a vaccine based on cytotoxic T-lymphocyte (CTL) epitopes is a promising strategy for eliminating pre-existing HPV infections and treating patients with cervical cancer. In this study, an immunoinformatics approach was used to predict HLA-I-restricted CTL epitopes in HPV16 E5, E6, and E7 proteins, and a set of conserved CTL epitopes co-restricted by human/murine MHCs was screened and characterized, with the set containing three E5, four E6, and four E7 epitopes. Subsequently, the immunogenicity of the epitope combination was assessed in mice, and the anti-tumor effects of the multi-epitope peptide vaccine E5E6E7pep11 and the recombinant protein vaccine CTB-Epi11E567 were evaluated in the TC-1 mouse tumor model. The results demonstrated that mixed epitope peptides could induce antigen-specific IFN-γ secretion in mice. Prophylactic immunization with E5E6E7pep11 and CTB-Epi11E567 was found to provide 100% protection against tumor growth in mice. Moreover, both types of the multi-epitope vaccine significantly inhibited tumor growth and prolonged mouse survival. In conclusion, in this study, a multi-epitope vaccine targeting HPV16 E5, E6, and E7 proteins was successfully designed and evaluated, demonstrating potential immunogenicity and anti-tumor effects and providing a promising strategy for immunotherapy against HPV-associated tumors.

IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). The symbiotic interactions between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAM) in the TME are critical for tumor progression. Here, we identified that IFI35, a transcriptional regulatory factor, plays both cell-intrinsic and cell-extrinsic roles in maintaining GSCs and the immunosuppressive TME. IFI35 induced non-canonical NF-kB signaling through proteasomal processing of p105 to the DNA-binding transcription factor p50, which heterodimerizes with RELB (RELB/p50), and activated cell chemotaxis in a cell-autonomous manner. Further, IFI35 induced recruitment and maintenance of M2-like TAMs in TME in a paracrine manner. Targeting IFI35 effectively suppressed in vivo tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Collectively, these findings reveal the tumor-promoting functions of IFI35 and suggest that targeting IFI35 or its downstream effectors may provide effective approaches to improve GBM treatment.

Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib’s effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1–10 µM and 25 mg/kg) and in combination with doxil (10–100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell–cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a − 53% versus − 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib’s ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Abstract CT074: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Endocrine therapy (ET) + cyclin dependent kinase 4/6 inhibitor (CDK4/6i) is the mainstay for the management of ER+/HER2- mBC as 1st-line therapy. However, tumors eventually develop resistance to ET, leading to disease progression. In the EMERALD phase 3 trial, single-agent elacestrant was associated with significantly prolonged progression-free survival (PFS) and a manageable safety profile vs standard of care (SOC) ET, leading to the first oral SERD approval. Patients receiving elacestrant experienced a median PFS (mPFS) of 3.8 months vs 1.9 months with SOC (Bidard, 2022). Patients who received ≥12 months of prior CDK4/6i experienced a mPFS of 8.6 months with elacestrant vs 1.9 months with SOC (SABCS, 2022). Currently, there are no approved systemic treatments for patients with ER+/HER2- BC who have brain metastasis. The rationale for the ELECTRA study is to combine elacestrant with abemaciclib in patients with brain metastasis, given both compounds have demonstrated the ability to cross the blood-brain barrier (Conlan, 2020; Tolaney, 2020). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib. Eligibility includes patients with ER+/HER2- locally advanced or metastatic BC and measurable brain metastasis. For phase 1b, the presence of brain metastasis is not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 endocrine therapy, ≤ 2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The phase 1b primary objective is to determine the recommended phase 2 dose (RP2D); secondary objectives include safety, pharmacokinetics (PK), overall response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). The phase 2 primary objective is ORR per RECIST v1.1; secondary objectives include intracranial response rate, DoR, CBR, PFS, OS, PK, and quality of life. The phase 1b portion of the trial is actively ongoing to determine the RP2D with study sites open worldwide. Citation Format: Erika Hamilton, Sung-Bae Kim, Nancy U. Lin, Ahmad Awada, Eva Ciruelos Gil, Alessandro Di Sanzo, Bartomeu Piza Vallespir, Kathy Puyana Theall, Nuhad Ibrahim. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT074.

Abstract LB048: Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors

Abstract The p53 protein, recognized as the guardian of the genome, plays a pivotal role in suppressing tumor formation. The TP53 gene, which encodes the p53 protein, is commonly subject to mutations and deletions in many cancer types resulting in loss of tumor suppressor activity. A significant proportion of patients diagnosed with lung, pancreatic, ovarian, and head and neck cancers exhibit the expression of mutant p53 in their tumors, correlating with unfavorable prognosis and survival outcomes.This study endeavors to assess the efficacy of therapeutic tumor suppressive mRNA which induces expression of wild-type p53 protein across diverse cancer types. Optimization of the 5’ and 3’ untranslated regions (UTRs) and the 5’ cap has been undertaken to enhance the efficient expression of p53 mRNA. The growth inhibitory potential of p53 mRNA therapy has been evaluated across p53 mutant cancer cell lines representing various cancer origins, along with normal or p53 wild-type cancer cell lines. We have substantiated that the p53 mRNA therapeutics can selectively inhibit the proliferation of p53 mutant cancer cells. Furthermore, we have confirmed that p53 mRNA treatment upregulated modulator of apoptosis (PUMA) and B-cell translocation gene 2 (BTG2) and cell cycle arrest via p21 upregulation. In vivo efficacy assessments of the lipid nanoparticle (LNP)-encapsulated p53 mRNA have been conducted in lung, pancreatic, and ovarian cancer xenograft models. Both regional intratumoral (i.t) and systemic intravenous (i.v) administrations of the p53 mRNA therapeutics have shown substantial suppression of tumor growth, leading to prolonged mouse survival. These results underscore the potential of the p53 mRNA therapeutics as a promising avenue for targeted cancer treatment, offering insights into the selective inhibition of p53 mutant cancer cells. Citation Format: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Gunwoo Lee, Seongju Jeong, Yunjae Kim, Jooyun Byun, Daejin Kim, In Young Choi. Unleashing the power of p53 mRNA therapeutics to suppress proliferation of p53 mutant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB048.

Efficacy and safety of lenalidomide in the treatment of B-cell non-Hodgkin lymphoma

BackgroundThe combination of rituximab and chemotherapy is a first-line treatment for patients with B-cell non-Hodgkin lymphoma. Lenalidomide is an immunomodulatory drug that has shown promising properties and activity in a variety of hematological malignancies. This study evaluated the efficacy and safety of lenalidomide-based regimens in the treatment of B-cell non-Hodgkin lymphoma.MethodsThe PubMed, Science Direct, ClinicalTrials.gov, and Web of Science databases were searched for relevant studies published up to May 2022. Studies with patients diagnosed with non-Hodgkin B-cell lymphoma, who were randomly assigned to a lenalidomide treatment group or a non-lenalidomide control group were considered for inclusion in this review and meta-analysis. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of the time-to-event outcomes and risk ratios (RRs) with 95% CIs of dichotomous data were estimated.ResultsA total of 3593 patients from 10 studies were evaluated. The results of the pooled analysis indicated that the lenalidomide-based regimen was associated with prolonged overall survival (HR, 0.85; 95% CI 0.74–0.97; P = 0.02) and progression-free survival (HR, 0.70; 95% CI 0.57–0.88; P = 0.002). Significant differences were found in the overall response rate (RR, 1.18; 95% CI 1.04–1.33; P = 0.01) and complete response rate (RR, 1.18; 95% CI 1.00–1.39; P = 0.05) between the treatment and control groups.ConclusionsLenalidomide appears to be a promising therapeutic agent that offers the possibility of a novel combination of chemotherapy free regimen for patients with B-cell non-Hodgkin lymphoma.

Abstract LB117: Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy

Abstract VerImmune is pioneering a First-in-Class treatment known as “Anti-tumor Immune Redirection” (AIR). This approach repurposes a patient’s pre-existing anti-viral or childhood vaccine immunity towards tumor cells for targeted destruction. VerImmune’s lead product, VERI-101, leverages pre-existing CD8+ T-cell immune memory acquired from past human cytomegalovirus (HCMV) infections. VERI-101 consists of VerImmune’s proprietary platform technology known as ViPs (Virus-inspired Particles) that are conjugated on their surface with a CD8+ T cell viral peptide antigen. ViPs are based on a modified mouse papillomavirus capsid protein of which 60 copies self-assemble into a 20-30nm T=1 icosahedral structure. In the case of VERI-101, the ViP is conjugated with an HLA-A*0201 restricted peptide epitope (NLVPMVATV, [NLV]), derived from the CMV pp65 antigen with an upstream furin protease cleavage site. The mechanism of action of AIR-ViPs including VERI-101 has been previously presented and involves three steps. Briefly, (1) VERI-101 targets the surface of the tumor cells and (2) enables the presentation of the CMV viral epitopes on their surface MHC, together (3) stimulating a recall of the pre-existing CMV memory response to attack the cancer cells (Dorrier et al., 2023 AACR). Here, we sought to study the in vivo anti-tumor efficacy of AIR-ViPs via both intra-tumoral and systemic treatment routes in two murine tumor models with pre-existing murine CMV (MCMV) immunity: (1) MC38 subcutaneous tumors for local and (2) B16.F10 lung metastasis for systemic treatments. As human CMV is species-specific, instead of VERI-101, a surrogate product, VERI-003 which redirects MCMV immunity, was tested as a single agent or in combination with anti-PD-1 in these tumor models. Our intra-tumoral studies with VERI-003 alone showed a dose-dependent anti-tumor effect (from 5 to 100ug) compared to no treatment controls. Surprisingly, no dose dependence was observed across the same three dose levels when combined with anti-PD-1, although significantly better anti-tumor effects occurred leading to complete tumor clearances in 50% of mice. Statistically significant prolonged survival was observed in most treated groups compared to controls. Our systemic studies with VERI-003 were consistent with our intratumoral studies in showing statistically significant single agent anti-tumor efficacy against B16.F10 lung metastases compared to no treatment. Anti-tumor effects of anti-PD-1 and combination were also observed. Additional studies are on-going to assess dose dependence and analysis of PK/PD effects. Taken together, our initial in vivo results demonstrate the tumor antigen-agnostic therapeutic potential of AIR and our AIR-ViP technology as a novel class of immuno-therapeutic drugs that could be used either as a monotherapy or in combination with checkpoint inhibitors. Citation Format: Cayce Dorrier, Felagot Abebe, Olivia Pak, Emily De-Bodene, Joshua Wang. Virus-inspired Particles (ViPs) harnessing cytomegalovirus immune memory for local and systemic cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB117.

Clinical features and molecular landscape of cuproptosis signature‐related molecular subtype in gastric cancer

AbstractRecent studies have highlighted the biological significance of cuproptosis in disease occurrence and development. However, it remains unclear whether cuproptosis signaling also has potential impacts on tumor initiation and prognosis of gastric cancer (GC). In this study, 16 cuproptosis‐related genes (CRGs) transcriptional profiles were harnessed to perform the regularized latent variable model‐based clustering in GC. A cuproptosis signature risk scoring (CSRS) scheme, based on a weighted sum of principle components of the CRGs, was used to evaluate the prognosis and risk of individual tumors of GC. Four distinct cuproptosis signature‐based clusters, characterized by differential expression patterns of CRGs, were identified among 1136 GC samples across three independent databases. The four clusters were also associated with different clinical outcomes and tumor immune contexture. Based on the CSRS, GC patients can be divided into CSRS‐High and CSRS‐Low subtypes. We found that DBT, MTF1, and ATP7A were significantly elevated in the CSRS‐High subtype, while SLC31A1, GCSH, LIAS, DLAT, FDX1, DLD, and PDHA1 were increased in the CSRS‐Low subtype. Patients with CSRS‐Low score were characterized by prolonged survival time. Further analysis indicated that CSRS‐Low score also correlated with greater tumor mutation burden (TMB) and higher mutation rates of significantly mutated genes (SMG) in GC. In addition, the CSRS‐High subtype harbored more significantly amplified focal regions related to tumorigenesis (3q27.1, 12p12.1, 11q13.3, etc.) than the CSRS‐Low tumors. Drug sensitivity analyses revealed the potential compounds for the treatment of gastric cancer with CSRS‐High score, which were experimentally validated using GC cells. This study highlights that cuproptosis signature‐based subtyping is significantly associated with different clinical features and molecular landscape of GC. Quantitative evaluation of the CSRS of individual tumors will strengthen our understanding of the occurrence and development of cuproptosis and the treatment progress of GC.