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Objectives Novel host‐targeted therapeutics could treat severe influenza A virus (IAV) infections, with reduced risk of drug resistance. LAT8881 is a synthetic form of the naturally occurring C‐terminal fragment of human growth hormone. Acting independently of the growth hormone receptor, it can reduce inflammation‐induced damage and promote tissue repair in an animal model of osteoarthritis. LAT8881 has been assessed in clinical trials for the treatment of obesity and neuropathy and has an excellent safety profile. We investigated the potential for LAT8881, its metabolite LAT9991F and LAT7771 derived from prolactin, a growth hormone structural homologue, to treat severe IAV infection. Methods LAT8881, LAT9991F and LAT7771 were evaluated for their effects on cell viability and IAV replication in vitro, as well as their potential to limit disease in a preclinical mouse model of severe IAV infection. Results In vitro LAT8881 treatment enhanced cell viability, particularly in the presence of cytotoxic stress, which was countered by siRNA inhibition of host lanthionine synthetase C‐like proteins. Daily intranasal treatment of mice with LAT8881 or LAT9991F, but not LAT7771, from day 1 postinfection significantly improved influenza disease resistance, which was associated with reduced infectious viral loads, reduced pro‐inflammatory cytokines and increased abundance of protective alveolar macrophages. LAT8881 treatment in combination with the antiviral oseltamivir phosphate led to more pronounced reduction in markers of disease severity than treatment with either compound alone. Conclusion These studies provide the first evidence identifying LAT8881 and LAT9991F as novel host‐protective therapies that improve survival, limit viral replication, reduce local inflammation and curtail tissue damage during severe IAV infection. Evaluation of LAT8881 and LAT9991F in other infectious and inflammatory conditions of the airways is warranted. Novel host‐targeted therapeutics could treat severe influenza A virus infections, with reduced risk of drug resistance. Our studies provide the first evidence identifying LAT8881 and LAT9991F compounds, as novel host‐protective therapies that improve survival, limit viral replication and reduce local inflammation during severe influenza virus infection.

The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody-drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vγ9Vδ2 T cell subset. Our goal was to examine obstacles preventing effective Vγ9Vδ2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vγ9Vδ2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vγ9Vδ2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy.

Messenger RNA (mRNA) vaccines offer an adaptable and scalable platform for cancer immunotherapy, requiring optimal design to elicit a robust and targeted immune response. Recent advancements in bioinformatics and artificial intelligence (AI) have significantly enhanced the design, prediction, and optimization of mRNA vaccines. This paper reviews technologies that streamline mRNA vaccine development, from genomic sequencing to lipid nanoparticle (LNP) formulation. We discuss how accurate predictions of neoantigen structures guide the design of mRNA sequences that effectively target immune and cancer cells. Furthermore, we examine AI-driven approaches that optimize mRNA-LNP formulations, enhancing delivery and stability. These technological innovations not only improve vaccine design but also enhance pharmacokinetics and pharmacodynamics, offering promising avenues for personalized cancer immunotherapy.

Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint. In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

BackgroundHepatic arterial infusion chemotherapy (HAIC) combined with targeted immunotherapy has emerged as a key therapeutic option for advanced (or unresectable) hepatocellular carcinoma (HCC). Nevertheless, treatment efficacy varies significantly among individuals. Sarcopenia, characterized by loss of muscle mass and strength, may adversely affect therapeutic outcomes and patient prognosis. This study investigates the clinical relevance of sarcopenia in patients undergoing HAIC combined with targeted immunotherapy.MethodsA total of 265 patients with unresectable HCC who received HAIC combined with targeted immunotherapy were retrospectively enrolled in this study and divided into two groups (sarcopenic and non-sarcopenic group). Sarcopenia was defined based on handgrip strength (HGS), with a cutoff value of less than 28kg(male) and 18kg(female). Overall survival (OS) and progression-free survival (PFS) were compared between groups using the log-rank test and multivariate Cox proportional hazards models. Additionally, propensity score matching (PSM) was applied to minimize baseline differences and enhance comparability. Then, differences in treatment response, survival outcomes, and adverse events between the sarcopenic and non-sarcopenic groups were evaluated using appropriate statistical analyses.ResultsPatients in sarcopenia group exhibited significantly poorer OS and PFS compared to those with non-sarcopenic group. Sarcopenia was also associated with lower objective response rates. Multivariate analysis confirmed that sarcopenia was an independent prognostic factor for poor outcomes.ConclusionSarcopenia is a significant predictor of poor prognosis in patients with unresectable HCC treated with HAIC combined with targeted immunotherapy. Incorporating HGS assessment into clinical practice may help optimize individualized treatment strategies and enhance patient management.

Low skeletal muscle mass (LSMM) has been associated with poor prognosis in hepatocellular carcinoma (HCC) patients receiving systemic therapy. However, its impact across different treatment regimens remains unclear. A retrospective study analyzed 714 patients with intermediate and advanced HCC, divided into immunotherapy (I, n=85), target-immunotherapy combination (I+T, n=545), and targeted therapy (T, n=84) groups based on treatment. Skeletal muscle was assessed via computed tomography (CT) at the third lumbar vertebral level (L3) before and after 3 months of treatment. LSMM was evaluated by the third lumbar skeletal muscle index (L3-SMI) using a predefined threshold. Patients were stratified by baseline values and treatment changes. Kaplan-Meier and Cox models were used to compare overall survival (OS) and progression-free survival (PFS). There was no significant difference in the loss of muscle mass among the three groups of LSMM patients; whereas, non-LSMM(NLSMM) patients in group T lost more muscle mass than those in group I (P=0.040).In the I+T group, patients who achieved an objective response (ORR) had less muscle mass loss than those without (P=0.013), while the changes in muscle mass for patients in the I group and T group were unrelated to treatment response. Baseline or post-treatment LSMM was associated with poorer median OS, especially in the I+T group. Progressive LSMM was linked to shorter median PFS (4.9 5.7 months) and OS (9.8 16.5 months), with similar results in the I+T group (mPFS, 4.2 . 5.8 months; mOS, 9.7 16.1 months). Patients with LSMM had a higher incidence of treatment-related SAEs, particularly ascites and fatigue. In patients with combined LSMM in hepatocellular carcinoma, muscle loss did not significantly differ between those treated with I, I+T, and T; however, T treatment contributed to muscle mass loss in NLSMM patients. Greater muscle loss correlated with poorer treatment outcomes and increased SAEs, and baseline, post-treatment, and progressive LSMM were linked to significantly worse prognoses, particularly with combined treatment regimens.

Background This study aims to identify symptom clusters in patients with intermediate and advanced liver cancer receiving targeted immunotherapy, focusing on core and bridge symptoms to establish a foundation for precise symptom management. Methods This study used a cross-sectional survey and utilized convenience sampling from May 2023 to January 2024 at a third-class hospital in Shanghai, China. The severity of symptoms in liver cancer patients during treatment was evaluated using the Memorial Symptom Assessment Scale. Network analysis was employed to depict the interrelation of symptom clusters and identify core and bridge symptoms. Results The symptoms were classified by severity into five clusters: oral, gastrointestinal, fatigue-related, body image, and pain-sleep. Within the symptom network, the core symptoms were pain, “I don’t look like myself,” and nausea, while the critical bridge symptoms included pain, itching, and feeling bloated. The strongest connections were observed between nausea and vomiting, followed by taste changes and dry mouth, as well as weight loss and “I don’t look like myself.” Conclusion In patients receiving targeted immunotherapy for intermediate and advanced liver cancer, multiple symptoms can emerge simultaneously, forming interconnected clusters. By identifying and intervening in core and bridge symptoms, personalized management strategies can be developed to relieve other symptoms and disrupt connections between symptom clusters, thereby enhancing symptom management efficacy. This study has significant clinical and research implications, offering new insights to improve patients’ quality of life and treatment outcomes.

Breast cancer has become the most common malignant tumor worldwide. Triple- negative breast cancer (TNBC) is a type of breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Compared with other molecular subtypes of breast cancer, TNBC is the most aggressive and highly heterogeneous. TNBC is insensitive to endocrine and anti-HER2 therapy, and chemotherapy is currently the main systemic treatment. With the continuous development of detection techniques and deepening research on TNBC molecular subtypes, drugs targeting immune checkpoints and different targets have emerged, such as atezolizumab, pembrolizumab, poly (ADP- ribose) polymerase (PARP) inhibitors, trophoblast cell-surface antigen 2 (TROP-2), and antibody-drug conjugates. These therapies provide new hope for TNBC treatment. Based on the analysis and classification of TNBC, this article summarizes the immunotherapy, targeted therapy, and new treatment combinations, providing references for the precise treatment of TNBC in the future. Keywords: triple-negative breast cancer, immunotherapy, targeted therapy, precision therapy

Plasmid DNA vectors are emerging as a versatile antigen delivery platform for personalized cancer vaccines. Here, we report a comprehensive preclinical evaluation of a modular DNA cancer vaccine that targets antigen-presenting cells and encodes tumor-specific antigens (TSAs), including neoantigens and endogenous retroviral (ERV) antigens. To specifically direct the TSAs to APCs, the chemokine C-C motif ligand 19 (CCL19) was incorporated, enhancing the magnitude and persistence of antigen-specific CD4+ and CD8+ T-cell responses. This resulted in strong anti-tumor activity in multiple murine models. Delivery via clinically relevant DNA methods, including electroporation and needle-free injection systems, further improved immune responses compared to standard syringe/needle injection. Pharmacokinetic and toxicological analyses of the CCL19 component demonstrated rapid systemic clearance and an absence of adverse effects, supporting its suitability for clinical application. The platform exhibited a favorable safety profile across repeated administrations at clinically relevant and escalated dosing regimens, including in combination with immune checkpoint blockade. Furthermore, in vitro and in vivo evaluation of multiple antigens confirmed consistent protein expression and sustained immunogenicity, irrespective of antigenic composition, underscoring the platform’s robustness and translational potential for individualized cancer vaccine strategies. These findings demonstrate that the CCL19-targeted DNA vaccine platform is both immunologically potent and holds strong potential in personalized cancer therapy.