Immune-based Therapies Research Articles

ATAD2 is a potential immunotherapy target for patients with small cell lung cancer harboring HLA-A∗0201.

Small cell lung cancer (SCLC) represents a highly aggressive neuroendocrine tumour with a dismal prognosis. Currently, the identification of a specific tumour antigen that can facilitate immune-based therapies for SCLC remains elusive. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyse cancer/testis antigens (CTAs) in SCLC cell lines and human tumour specimens. Immunohistochemistry of clinical specimens was performed to compare protein expression in SCLC, non-small cell lung cancer (NSCLC), and matched normal-adjacent tissues. Additionally, publicly available RNA sequencing databases were interrogated to identify gene expression patterns in different SCLC subtypes and in different disease stages. Distinct numbers and types of CTAs were identified across SCLC subtypes, with significantly higher expression levels of ATPase family AAA domain-containing protein 2 (ATAD2) observed in SCLC compared to normal adjacent tissues and NSCLC tissues. A dynamic expression pattern of ATAD2 was found throughout the clinical course of SCLC and exhibited a positive correlation with achaete-scute family bHLH transcription factor 1 (ASCL1) expression in SCLC. Immunopeptidomics analysis identified the YSDDDVPSV sequence derived from the HLA-A∗02:01 restriction epitope of ATAD2 as a highly promising tumour antigen candidate for potential immunotherapy applications. YSDDDVPSV immunopeptides were confirmed to be present in SCLC-A and SCLC-N with HLA-A∗02:01 restriction. Notably, HLA-A∗02:01T cells exhibited a robust response upon stimulation with YSDDDVPSV immunopeptide pulsed by T2 cells. Our findings highlight the potential of targeting the ATAD2 YSDDDVPSV immunopeptide for SCLC immunotherapy, thereby offering a promising avenue for the development of adoptive T cell therapies to effectively treat ASCL1-positive or NEUROD1-positive SCLC carrying HLA-A∗02:01. This study was supported by the National key R&D program of China (2022YFC2505000); National Natural Science Foundation of China (NSFC) general program (82272796) NSFC special program (82241229); CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-1-009); CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035); Aiyou foundation (KY201701). National key R&D program of China (2022YFC2505004). NSFC general program (81972905). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022012).

Pan-cancer analysis of DCBLD1 and its association with the diagnosis, immunotherapy, and prognosis of cervical cancer.

Cervical cancer (CESC) is a leading cause of death attributed to cancer worldwide. Advanced-stage cervical cancer presents unique challenges, such as few treatment modalities. Though DCBLD1 has been earlier connected to a variety of cancers, there has been no extensive investigation on DCBLD1 regarding cervical cancer. This study seeks to assess the expression and prognostic significance of DCBLD1 in multiple cancer types, heavily relying on cervical cancer, as well as its implications on immune modulation. The pan-cancer expression of box-like genes in DCBLD1 was investigated in 33 cancer types using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Survival analyses involving Overall Survival (OS) and Progression-Free Survival (PFS) were conducted to evaluate the relationship between DCBLD1 expression and the prognosis of these neoplasms. Furthermore, immune infiltration gene co-expression and tumor microenvironment (TME) analyses were performed. In vitro assays in cervical cancer cell lines were done to analyze the functional impact of silencing DCBLD1 on cell proliferation, migration, and invasion. DCBLD1 was significantly overexpressed in 16 cancer types, including cervical cancer, and was associated with poor prognosis for several of these cancer types. In CESC, the expression of DCBLD1 was significantly associated with shorter OS and PFS. While immune infiltration analysis showed a significant association for DCBLD1 with several immune cells, including CD4+ memory T cells and macrophages, the functional assays demonstrated that silencing DCBLD1 in cervical cancer cells inhibited their cell proliferation, migration, and invasion, implicating it in tumor progression. DCBLD1 could serve as an amendable biomarker of poor prognosis in cervical cancer and other cancers whose high expression level correlates with immune infiltration, which may suggest its role in modulating the tumor microenvironment. This shows that targeting DCBLD1 could prove effective as a potential therapeutic modality in conjunction with other immune-based therapies for cervical cancer.

AGX101: A TM4SF1-directed tubulin inhibitor conjugate in ongoing first-in-human trial including GI cancers.

829 Background: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates (NHP), with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: Notable cancers with high TM4SF1 scoring intensity include pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. In esophageal cancer, 20% of patients have a TM4SF1 copy number amplification, and these have worse prognosis. In NHP, AGX101 exhibited a favorable safety profile. In preclinical efficacy studies, monotherapy demonstrated robust efficacy through each of the three MoAs in syngeneic models in mice including CT26 colon carcinoma, and human tumor xenograft models including MIA PaCa-2 pancreatic cancer. Measured by exposure, TI was large. In syngeneic mouse models including CT26, the effects of ICIs were potentiated, suggesting a potential synergistic approach in cancer therapy. The first two dose levels of AGX101 monotherapy in humans has cleared without DLTs. Three patients with pancreatic adenocarcinoma have been treated thus far. Conclusions: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing and initial outcome data will become available by the conference. Clinical trial information: NCT06440005 .

P-1967. Characteristics of the first immunocompromised patients to receive Sipavibart as an early access treatment for COVID-19 pre-exposure prophylaxis in France

Abstract Background Immunocompromised patients account for a large proportion of COVID-19 hospitalizations and deaths, even in the most recent periods, despite having received several COVID-19 vaccine doses. Monoclonal antibodies effectively prevented COVID-19 in the general population in randomized control trials and the immunocompromised population in real-world studies. Unfortunately, the emergence of new variants precluded their use. Sipavibart (AZD3152) is an investigational long-acting monoclonal antibody designed to provide broad coverage across Omicron and ancestral viral variants currently being studied in the SUPERNOVA prevention trial. France was the first country to grant Sipavibart as a COVID-19 pre-exposure prophylaxis treatment in immunocompromised individuals with an early access authorization in December 2023. Methods We performed a retrospective multicentric study in France, including the first consecutive patients to receive one intramuscular dose of Sipavibart in January and February 2024, to collect their characteristics and COVID-19-related medical history. Results Overall, we included 47 patients with a median age of 61 years (IQR:64—69) and 64% male. The three main immunosuppressive conditions were Stem cell transplants (38%), solid organ transplants (32%), and immune-based therapies (mostly Rituximab) (19%) for chronic inflammatory diseases or haematologic malignancies. Nearly half had hypogammaglobulinemia and 71% had at least another key comorbidity (Table 1). 15% and 11% had a history of severe and persistent COVID-19, respectively. The median number of COVID-19 doses was 4 (IQR 3-6), and nearly one-third had previously received previous generation of monoclonal antibodies for COVID-19 prophylaxis (Casirivimab/imdevimab or Tixagevimab/Cilgavimab). SARS-CoV-2 serology results before Sipavibart administration were available in 11 patients (without Immunoglobulins substitution). The median anti-Spike IgG titers was 30 UI/L (IQR 0-179). Conclusion The first patients to receive Sipavibart in France had different profiles, but they were all highly immunocompromised with frequently associated hypogammaglobulinemia and other chronic conditions. Disclosures Paul LOUBET, MD, PhD, Astrazeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant Iliès Benotmane, n/a, Astrazeneca: Advisor/Consultant|Astrazeneca: Board Member

Abstract B022: Systematic analysis of tumor and immune EV subset changes with radiation therapy

Abstract Background: Although radiation is known to modulate immune responses, it remains challenging to identify effective combinations of radiation and immune-based therapies. Because tumor, immune, and other cells release extracellular vesicles (EVs) continuously and because those vesicles are composed of lipid membrane-bound complexes of proteins and nucleic acids, we have developed a suite of tools to enable systematic subset characterization of tumor and immune EV subsets. Broadly speaking, these tools provide a new, informative approach for interrogating tumor and immune biomarkers that may be used not only for predictive and prognostic purposes, but also for adaptive treatment strategies. In this study, we hypothesized that EV subsets could be used to monitor tumor and immune responses to radiation. The objective of this study was to evaluate radiation-induced changes in tumor-cell derived EVs from cell culture and from patient serum EV subsets. Methods: For these studies, we have developed and refined a set of rigorous tools and protocols for the enumeration, labeling, and sorting of EVs individually or as subsets. We applied these methods to EVs isolated at a series of timepoints from a panel of tumor cell lines irradiated at different doses. In a parallel fashion, we also applied these methods to clinical serum samples obtained from patients before, at the completion of, and one month following radiation therapy. For all samples, EV repertoires were evaluated by multiplex EV repertoire assays, and selected EV subsets were further enriched by immunoaffinity for cargo analysis. Results: EV surface marker repertoires demonstrated both donor-specific and treatment response-specific signatures, for both tumor-associated and immune-associated EVs. For patients with bladder and colon cancer, characteristic EV tumor and immune marker signatures were noted between patients, including CD326 and CD69, and various donor-specific changes in tetraspanins (CD63, -81, and -9), CD42a, and CD62P were observed at the completion of radiation treatment. Certain EV subsets could be consistently isolated with affinity chromatography from donor serum samples but were not strongly represented in multiplex assay based on co-expression of tetraspanins. Conclusions: Our results establish feasibility for future EV subset studies, particularly in clinical trials investigating tumor and immune biomarkers for patients receiving combined radiation and immunotherapy treatments. Specifically, we demonstrate a robust method for evaluation of individual donor responses, including kinetic changes in tumor-associated markers (CD326) and immune-associated markers (CD69). Furthermore, each patient’s serum EVs demonstrated distinctive treatment-response patterns, with inter-donor differences appearing to relate to tumor-specific attributes and/or radiation parameters, such as marrow volume irradiated. Ongoing studies are further exploring EV-borne RNA signatures using a total RNAseq pipeline that is customized for EV RNA. Citation Format: Jubin George, Stephanie Chidester, Michelle L. Pleet, Kevin Camphausen, Freddy Escorcia, Jennifer C. Jones. Systematic analysis of tumor and immune EV subset changes with radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B022.

Molecular Subtyping and Genomic Profiling Expand Precision Medicine in KRAS Wild-Type Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and limited treatment options. While the majority of PDAC cases harbor KRAS mutations, approximately 8%-10% are KRAS wild-type (KRAS-WT). These KRAS-WT tumors often contain actionable mutations and gene fusions, making them more suitable for precision therapies. Identifying these molecular alterations is crucial for improving outcomes in this subset of patients. This retrospective study involved 34 patients with KRAS-WT PDAC. Genomic profiling was performed using next-generation sequencing (NGS) and RNA sequencing to detect mutations and fusions. Comparative analysis was conducted with TCGA-PAAD data, and immune infiltration was assessed using bioinformatic deconvolution methods. Targetable alterations were identified in multiple pathways. Key mutations included ATM (18%), PIK3CA (15%), and ROS1 (15%), while actionable gene fusions such as CCDC6-RET and ETV6-NTRK3 were present in 10.3% of patients. The gene mutations associated with homologous recombination deficiency (HRD) are predicted to increase sensitivity to platinum-based chemotherapy (p = 0.047). Tumors with epigenetic regulatory genes mutations (e.g., ARID1A, KMT2C/D) exhibited enhanced immune cell infiltration, highlighting potential responsiveness to immune checkpoint inhibitors (ICIs). Kinase fusions (NTRK and RET) were linked to response to larotinib and RET-specific inhibitors, respectively. KRAS-WT PDAC contains actionable mutations and fusions, offering significant potential for targeted and immune-based therapies. Further clinical studies are needed to validate these therapeutic approaches.

Immune-Based and Novel Therapies in Variant Histology Renal Cell Carcinomas.

Renal cell carcinoma (RCC) is a heterogeneous disease that represents the most common type of kidney cancer. The classification of RCC is primarily based on distinct morphological and molecular characteristics, with two broad categories: clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). Clear cell RCC is the predominant subtype, representing about 70-80% of all RCC cases, while non-clear cell subtypes collectively make up the remaining 20-30%. Non-clear cell RCC encompasses many histopathological variants, each with unique biological and clinical characteristics. Additionally, any RCC subtype can undergo sarcomatoid dedifferentiation, which is associated with poor prognosis and rapid disease progression. Recent advances in molecular profiling have also led to the identification of molecularly defined variants, further highlighting the complexity of this disease. While immunotherapy has shown efficacy in some RCC variants and subpopulations, significant gaps remain in the treatment of rare subtypes. This review explores the outcomes of immunotherapy across RCC subtypes, including rare variants, and highlights opportunities for improving care through novel therapies, biomarker-driven approaches, and inclusive clinical trial designs.

The prognostic value of systemic immune-inflammation index in patients with unresectable hepatocellular carcinoma treated with immune-based therapy

BackgroundPredicting the efficacy of immune-based therapy in patients with unresectable hepatocellular carcinoma (HCC) remains a clinical challenge. This study aims to evaluate the prognostic value of the systemic immune-inflammation index (SII) in forecasting treatment response and survival outcomes for HCC patients undergoing immune-based therapy.MethodsWe analyzed a cohort of 268 HCC patients treated with immune-based therapy from January 2019 to March 2023. A training cohort of 93 patients received atezolizumab plus bevacizumab (T + A), while a validation cohort of 175 patients underwent treatment with tyrosine kinase inhibitors (TKIs) combined with anti-PD-(L)1 therapy. The SII cutoff value, determined using X-tile analysis based on overall survival (OS) in the training cohort, divided patients into high (> 752*109) and low (≤ 752*109) SII groups. Prognostic factors were identified through univariate and multivariate logistic and Cox regression analyses, and survival outcomes were assessed using Kaplan–Meier methods. The predictive accuracy of SII was evaluated using receiver operating characteristic (ROC) curves.ResultsAn optimal SII cutoff of 752*109 stratified patients into high and low SII groups. Univariate and multivariate logistic regression indicated that SII was a significant predictor of the objective response rate (ORR), which was markedly different between the low and high SII subgroups (34.72% vs. 9.52%, P = 0.019). This finding was consistent in the validation cohort (34.09% vs. 16.28%, P = 0.026). SII also demonstrated prognostic value in Cox regression and Kaplan–Meier analyses. ROC curves confirmed that SII had superior predictive accuracy compared to common clinical indicators, with predictive relevance even in AFP-negative patients. Furthermore, a lower SII was associated with a higher T cell ratio and an increased number of CD8+ T cells and Granzyme B+ CD8+ T cells in peripheral blood.ConclusionSII is a promising predictor of both therapeutic efficacy and prognosis in HCC patients undergoing immune-based treatments. Its application may enhance clinical decision-making, thereby improving patient outcomes from immune-based therapy.

Characterization of a chitinase from Trichinella spiralis and its immunomodulatory effects on allergic airway inflammation in mice.

A fundamental tenet of the hygiene theory is the inverse association between helminth infections and the emergence of immune-mediated diseases. Research has been done to clarify the processes by which helminth-derived molecules can inhibit immunological disorders. This study aimed to evaluate the ability of Trichinella spiralis chitinase (Ts-chit) to ameliorate the symptoms of allergic airway inflammation. Recombinant Trichinella spiralis chitinase (rTs-chit) was expressed in Escherichia coli BL21, and its structural homology to murine acidic mammalian chitinase (AMCase) was comprehensively analyzed. The expression of Ts-chit was examined across all T. spiralis life stages. To explore its immunomodulatory potential, a murine model of allergen-induced airway inflammation was established. The effects of rTs-chit were evaluated by assessing airway hyperresponsiveness and cytokine profiles in bronchoalveolar lavage fluid and performing detailed histopathological and immunohistochemical analyses. Recombinant Ts-chit (rTs-chit) was successfully expressed in E. coli BL21, showing strong structural similarity to murine acidic mammalian chitinase (AMCase). Expression profiling revealed that Ts-chit is present throughout all stages of the T. spiralis life cycle. In an allergic airway inflammation model, rTs-chit reduced weight loss and lung inflammation, lowering inflammatory cell infiltration and Th2 cytokines (IL-4, IL-5, IL-13) while increasing the immunosuppressive cytokine IL-10. Additionally, rTs-chit treatment decreased the expression of GATA3, arginase-1, MCP-1, CCL-11, and AMCase, along with reducing OVA-specific IgE, IgG, and IgG1 levels, suggesting its potential as an immunomodulatory agent. This study highlights rTs-chit's potential as a therapeutic agent for allergic airway diseases, leveraging its structural similarity to host chitinases to regulate Th2 responses and inflammatory pathways. The findings provide new insights into helminth-derived proteins as promising candidates for immune-based therapies.

Host tissue factors predict immune surveillance and therapeutic outcomes in gastric cancer.

The immune composition of solid tumors is typically inferred from biomarkers, such as histologic and molecular classifications, somatic mutational burden, and PD-L1 expression. However, the extent to which these biomarkers predict the immune landscape in gastric adenocarcinoma-an aggressive cancer often linked to chronic inflammation-remains poorly understood. We leveraged high-dimensional spectral cytometry to generate a comprehensive single-cell immune landscape of tumors, normal tissue, and lymph nodes from patients in the Western Hemisphere with gastric adenocarcinoma. The immune composition of gastric tumors could not be predicted by traditional metrics such as tumor histology, molecular classification, mutational burden, or PD-L1 expression via IHC. Instead, our findings revealed that innate immune surveillance within tumors could be anticipated by the immune profile of the normal gastric mucosa. Additionally, distinct T-cell states in the lymph nodes were linked to the accumulation of activated and memory-like CD8+ tumor-infiltrating lymphocytes (TILs). Unbiased re-classification of patients based on tumor-specific immune infiltrate generated four distinct subtypes with varying immune compositions. Tumors with a T-cell-dominant immune subtype, which spanned TCGA molecular subtypes, were exclusively associated with superior responses to immunotherapy. Parallel analysis of metastatic gastric cancer patients treated with immune checkpoint blockade showed that patients who responded to immunotherapy had a pre-treatment tumor composition that corresponded to a T-cell-dominant immune subtype from our analysis. Taken together, this work identifies key host-specific factors associated with intratumoral immune composition in gastric cancer and offers an immunological classification system that can effectively identify patients likely to benefit from immune-based therapies.

Ignoring Gender-Based Immunometabolic Reprograming, a Risky Business in Immune-Based Precision Medicine.

Immunology advances have increased our understanding of autoimmune, auto-inflammatory, immunodeficiency, infectious, and other immune-mediated inflammatory diseases (IMIDs). Furthermore, evidence is growing for the immune involvement in aging, metabolic and neurodegenerative diseases, and different cancers. However, further research has indicated sex/gender-based immune differences, which further increase higher incidences of various autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE), myasthenia gravis, and rheumatoid arthritis (RA) in females. On the other hand, reproductive-age females also show a more potent immune response against infections and vaccines than their age-matched males-furthermore, some immune-based therapies, including immune checkpoint inhibitors (ICIs), show gender-based efficacy and adverse events. Metabolic demands are different in males and females. Immune cell function and polarization are also governed by their metabolic reprogramming, called immunometabolism and immunometabolic reprogramming (IR). Therefore, sex/gender-associated immune differences and their involvement in immune-mediated diseases and immune-based therapeutics indicate the demand for gender-based IR studies to increase the efficacy of immune-based precision medicine.

Cellular interactions in self-directed immune mediated liver diseases.

The lymphocyte population must traverse a complex path throughout their journey to the liver. The signals which these cells must detect, including cytokines, chemokines and other soluble factors, steer their course towards further crosstalk with other hepatic immune cells, hepatocytes and biliary epithelial cells. A series of specific chemokine receptors and adhesion molecules drive not only the recruitment, migration, and retention of these cells within the liver, but also their localisation. Perturbation of these interactions and failure of self-recognition drives the development of several autoimmune liver diseases. Understanding the nature of these interactions develops our understanding of immune mediated liver disease pathogenesis, providing new opportunities for intervention to resolve uncontrolled inflammation. In this review, we provide an overview of the complex recruitment pathways and cellular interactions which position lymphocyte populations in the liver. We discuss how these are disrupted in autoimmune diseases and highlight the mechanism of immune cells inside hepatocytes (emperipolesis) in autoimmune hepatitis and immune cells inside biliary epithelial cells (intra-epithelial lymphocyte) in primary biliary cholangitis as well as avenues to manipulate these pathways for therapy. We also cover the immune mediated tissue injury mechanisms impacted by checkpoint inhibitors, leading to checkpoint inhibitor-induced liver injury (CHILI). Finally, we describe emerging immune-based therapies, including regulatory T cell, anti-cytokine and anti-chemokine therapies, cytokine supplementation such as interleukin-2 as well as numerous modalities of co-inhibitory molecule manipulation, including bispecific T cell engagers (BiTEs) and checkpoint inhibitor bispecific T cell engagers (CiTEs) and discuss their potential application in the treatment of autoimmune liver diseases. Immune-mediated liver disease encompasses two broad categories: autoimmune and inflammatory liver injury, the former resulting from a breakdown in immunological self-tolerance. These share common features, namely histologically dense immune infiltrates, autoantibody positivity and immunoglobulin elevation. Whilst well defined in their epidemiology, presentation and diagnostic evaluation, their treatment remains an unmet clinical need. Our incomplete understanding of the mechanisms leading to breakdown in immunological self-tolerance and our inability to restore immune homeostasis hampers present progress in treatment. This review summarises recent advances in our understanding of the loss of hepatic tolerance and the cellular interactions leading to this, including immune cell invasion towards hepatocytes and biliary epithelial cells, checkpoint-induced immune-mediated liver injury (CHILI) and concludes with current progress in treatment strategies.

Evolving Therapeutic Strategies in Esophageal Squamous Cell Carcinoma: Advances and Perspectives.

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent forms of esophageal cancer globally, with a particularly high incidence in developing countries. Notably, Asia accounts for approximately 80% of global esophageal cancer cases, with China alone contributing to 54% of this burden. The primary treatment modality for ESCC remains esophagectomy, primarily employed for locally advanced disease, often in combination with chemotherapy and radiotherapy for advanced-stage cases. Despite significant advancements in surgical techniques and the advent of precision medicine, which has facilitated the development of targeted and immune-based therapies, critical challenges persist, including suboptimal therapeutic efficacy and the emergence of drug resistance. A comprehensive understanding of the current treatment landscape for ESCC is essential to overcoming these barriers and improving patient outcomes.

Sex Disparities in Bladder Cancer Diagnosis and Treatment.

Gender differences in prevalence, tumor invasiveness, response to treatment, and clinical outcomes exist in different types of cancer. The aim of this article is to summarize the sex disparities in bladder cancer diagnosis and treatment and try to suggest areas for improvement. Although men are at a higher risk of developing bladder tumors, women tend to be diagnosed with more advanced stages at diagnosis and are more likely to present with upfront muscle-invasive disease. Non-urothelial histological subtypes are more frequently reported in women. Regarding non-muscle-invasive bladder cancer (NMIBC), several studies have shown that women have a higher risk of disease recurrence after treatment with Bacillus Calmette-Guerin, due to different immunogenicities. In localized muscle-invasive bladder cancer (MIBC), neoadjuvant chemotherapy and cystectomy are less likely to be performed on women and sexual-sparing procedures with neobladder diversion are rarely offered. Finally, women appear to have a poorer prognosis than men, potentially due to the sex-associated intrinsic features of hosts and tumors that may drive differential therapeutic responses, particularly to immune-based therapies. Women are also more likely to develop severe adverse events related to systemic therapies and are underrepresented in randomized studies, leading to a gap between the real world and trials. In conclusion, studies investigating the role of sex and gender are urgently needed to improve the management of urothelial carcinoma.

T-cell-based therapies for treating relapsed or refractory mantle cell lymphoma.

While targeted therapies such as Bruton's tyrosine kinase and BCL2 inhibitors have fundamentally changed the treatment of mantle cell lymphoma (MCL), not all patients respond to these therapies, and responses are finite and can be fleeting, especially with high-risk MCL. As patients progress through successive therapies, the clinical course is characterized by shortening response times,1 frequent disease acceleration, and limited survival outcomes. Recently, the sensitivity of MCL to novel immune-based therapies is being realized with favorable results, as chimeric antigen receptor-modified T cells and bispecific T-cell-engaging antibodies are being investigated and implemented into practice for patients. However, critical issues remain to understand the role of these agents in routine practice. In this review, we discuss the current landscape regarding these agents, examine our approach to incorporating them into practice, and consider unanswered questions that we must ultimately address to improve outcomes for patients.

Regulation and application of m6A modification in tumor immunity.

The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.

Inhibition of the chemokine receptors CXCR1 and CXCR2 synergizes with docetaxel for effective tumor control and remodeling of the immune microenvironment of HPV-negative head and neck cancer models

BackgroundRelapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC.MethodsExpression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel.ResultsHigh levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8+ T cells in the combination therapy treated tumors compared to controls.ConclusionsThis study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.

Synergistic effects of immunotherapy and adjunctive therapies in prostate cancer management.

In recent years, cancer immunotherapy has received widespread attention due to significant tumor clearance in some malignancies. Various immunotherapy approaches, including vaccines, immune checkpoint inhibitors, oncolytic virotherapy, bispecific T cell engagers, and adoptive T cell transfer, have completed or are undergoing clinical trials for prostate cancer. Despite immune checkpoint blockade's extraordinary effectiveness in treating a variety of cancers, targeted prostate cancer treatment using the immune system is still in its infancy. Multiple factors including the heterogeneity of prostate cancer, the cold tumor microenvironment, and a low level of neoantigens, contribute to the poor immunotherapy response. Significant effort is being devoted to improving immune-based prostate cancer therapy. Recently, several key discoveries demonstrate that prostate cancer immunotherapy agents may be used to promise better prognosis for patients as part of combination strategies with other agents targeting tumor-associated immune mechanism of resistance. Here, this review comprehensively examines the recent advancements in immunotherapy for prostate cancer, exploring its potential synergistic effects when combined with other treatment modalities to enhance clinical efficacy.

Multi-omics decipher the immune microenvironment and unveil therapeutic strategies for postoperative ovarian cancer patients.

Ovarian cancer (OC) is a highly aggressive and often fatal disease that frequently goes undetected until it has already metastasized. The classic treatment for OC involves surgery followed by chemotherapy. However, despite the effectiveness of surgery, relapse is still a common occurrence. Unfortunately, there is currently no ideal predictive model for the progression and drug sensitivity of postoperative OC patients. Cell death patterns play an important role in tumor progression. So we aimed to investigate their potential to be used as indicators of postoperative OC prognosis and drug sensitivity. A total of 12 programmed cell death (PCD) patterns were employed to construct novel classification and prognosis model. Bulk transcriptome, genomics, and clinical information were collected from The Cancer Genome Atlas (TCGA) Program-OV, GSE9891, GSE26712, GSE49997 and GSE63885. In addition, single-cell transcriptome data GSE210347 were procured from the Gene Expression Omnibus (GEO) database for subsequent analysis. In this study, a novel PCD classification has been employed to phenotype postoperative OC patients, revealing that patients in cluster 1 exhibited heightened sensitivity to immune-based therapies combined with high expression of chemokines, interleukins, interferons, and checkpoints. Meanwhile, a programmed cell death index (PCDI) was established using an 8-gene signature with the help of a machine learning algorithm. The patients with high-PCDI had a worse prognosis after surgery in OC. In addition, we also found that patients with low PCDI patients may exhibit sensitivity to immunotherapy, while those with high PCDI patients may display increased responsiveness to tyrosine kinase inhibitors. This study provides a novel PCD model and nomogram that can effectively predict the clinical prognosis and drug sensitivity of OC patients post-surgery.

What have we learned about TP53-mutated acute myeloid leukemia?

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.