Huizhong Li

Background: Renal carcinoma remains a highly lethal malignancy, and tumor vaccine efficacy is frequently hampered by a profoundly immunosuppressive tumor microenvironment. V-domain Ig suppressor of T-cell activation (VISTA), an inhibitory immune checkpoint enriched in myeloid cells and regulatory T cells (Tregs), represents a critical barrier to effective antitumor immunity. Targeting VISTA may therefore provide a promising strategy to overcome immune suppression and enhance tumor vaccine efficacy. Methods: Recombinant adenoviral vaccines encoding carbonic anhydrase IX (CAIX) and VISTA (Ad-CAIX and Ad-VISTA) were constructed and validated for efficient antigen expression. The antitumor efficacy of Ad-VISTA/CAIX co-immunization was evaluated in subcutaneous, lung metastatic, orthotopic, and anti-programmed cell death protein 1-resistant renal carcinoma models. Vaccine-induced immune responses were assessed by flow cytometry, immunohistochemistry, ELISA, cell proliferation assays, cytotoxic T lymphocyte (CTL) assays, and in vivo immune cell depletion experiments. Results: Ad-VISTA immunization markedly potentiated the therapeutic efficacy of CAIX-targeted vaccination, resulting in significant tumor growth inhibition and prolonged survival across multiple renal carcinoma models. Mechanistically, VISTA-targeting remodeled the tumor microenvironment by enhancing the infiltration and activation of dendritic cells (DCs) and CD8 ⁺ T cells while reducing immunosuppressive myeloid cells and Tregs. Ad-VISTA/CAIX co-immunization promoted the expansion and maturation of multiple DC subsets, characterized by increased expression of CD40, CD80, CD86, and major histocompatibility complex molecules, thereby facilitating efficient antigen presentation. VISTA immunization elicited robust antigen-specific antibody and neutralizing responses, restored CD8 ⁺ T-cell proliferation, and enhanced CTL-mediated tumor cell killing. Depletion of CD8 ⁺ T cells abrogated therapeutic efficacy of Ad-VISTA/CAIX vaccine, establishing its essential role in tumor control. Furthermore, combined vaccination induced durable memory CD8 ⁺ T-cell responses capable of preventing tumor recurrence on rechallenge. Conclusions: These results indicated that vaccine-induced VISTA blockade effectively amplifies DC-mediated CD8 ⁺ T-cell immunity and synergistically enhances tumor vaccine efficacy. Targeting VISTA represents a promising immunotherapeutic strategy for improving vaccine-based treatments in renal carcinoma.

Myasthenia gravis (MG) is an autoimmune disorder characterized by B cell dysfunction. Here, we designed B cell maturation antigen (BCMA)/CD19 chimeric antigen receptor T cell (CAR T cell) therapy for six refractory MGs, demonstrating favorable safety with grade 1 cytokine release syndrome observed. CAR T cell expansion induced profound B cell depletion, a sustained reduction in acetylcholine receptor (AChR) antibody titers, and symptom improvement. Five patients achieved drug-free remission with minimal manifestations by month 6, persisting through the 12-month follow-up despite B cell reconstitution. Reconstituted B cells showed naïve predominance with diminished AChR specificity and functional capacities. Olink proteomics revealed up-regulation of anti-inflammatory factors, along with down-regulation of proinflammatory molecules. Single-cell sequencing revealed that age-associated B cells (ABCs) were up-regulated in a relapsed patient, and differential gene analysis indicated that Fc receptor-like 5 (FCRL5) expression was elevated in ABCs, whereas CAR T cell responders exhibited a down-regulated trend. Notably, similar ABC expansion and FCRL5 up-regulation occurred in rituximab-relapsed patients. Our findings support BCMA/CD19 CAR T cell therapy as feasible, tolerable, and effective in MG, identifying FCRL5 as a previously unidentified target in relapse.

Background: Chimeric antigen receptor (CAR)-NK cells are a promising and safe alternative to CAR-T cells. However, the limited persistence in vivo restricts their clinical application and sustained therapeutic responses. IL-15 has been extensively used to improve CAR-NK cell persistence and effectiveness. Nevertheless, accumulation of IL-15 might induce uncontrolled proliferation of CAR-NK cells and thus lead to fatal side-effects. Therefore, it is essential to develop a safe and effective alternative strategy to improve the persistence and anti-tumor activity of CAR-NK cells.Methods: A signaling intact membrane-bound IL-15 (mbIL-15) was designed by fusing IL-15 and full-length IL-15Rα and was systematically compared with secretory IL-15 (sIL-15) in a B7H3-targeting CAR-NK cell system regarding their functionality and safety through various in vitro and in vivo experiments.Results: Both expression of sIL-15 or mbIL-15 significantly enhanced the proliferation by activating STAT5 and improved anti-tumor activity of CAR-NK cells in vitro and in vivo. Although CAR-NK cells with sIL-15 quickly eliminated intraperitoneal ovarian cancer, the mice experienced severe consequences, including dysregulated CAR-NK cell expansion, intense inflammatory responses, and irreversible organ damages. In contrast, CAR-NK cells carrying mbIL-15 showed moderate cell proliferation and potent tumor killing activity without observable adverse effects in both local treatment and systemic administration models.Conclusion: Head-to-head comparative studies demonstrated that signaling intact mbIL-15 significantly improved therapeutic efficacy and safety of CAR-NK cells compared to sIL-15, which provided preclinical evidence for future clinical development.

Background: Targeting kinases presents a potential strategy for treating solid tumors; however, the therapeutic potential of vaccines targeting kinases remains uncertain. Methods: Adenovirus (Ad) vaccines encoding Aurora kinase A (AURKA) or cyclin-dependent kinase 7 (CDK7) were developed, and their therapeutic potentials were investigated by various methods including western blot, flow cytometry, cytotoxic T lymphocyte assay, and enzyme-linked immunospot (ELISpot), in mouse and humanized solid tumor models. Results: Co-immunization with Ad-AURKA/CDK7 effectively prevented subcutaneous tumor growth in the Renca, RM-1, MC38, and Hepa1-6 tumor models. In therapeutic tumor models, Ad-AURKA/CDK7 treatment impeded tumor growth and increased immune cell infiltration. Administration of Ad-AURKA/CDK7 promoted the induction and maturation of dendritic cell subsets and augmented multifunctional CD8⁺ T-cell antitumor immunity. Furthermore, the vaccine induced a long-lasting antitumor effect by promoting the generation of memory CD8⁺ T cells. Tumor recovery on CD8⁺ T-cell depletion underscored the indispensable role of these cells in the observed therapeutic effects. The potent efficacy of the Ad-AURKA/CDK7 vaccine was consistently demonstrated in lung metastasis, orthotopic, and humanized tumor models by inducing multifunctional CD8⁺ T-cell antitumor immune responses. Conclusions: Our findings illustrate that the Ad-AURKA/CDK7 vaccine targeting dual kinases AURKA and CDK7 emerges as a promising and effective therapeutic approach for the treatment of solid tumors.

Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality in the world. However, clinical progress in the treatment of HCC has not shown a satisfactory therapeutic effect. Here, we have developed a novel strategy to treat HCC with an adenovirus (Ad)-based vaccine, which contains a specific antigen glypican-3 (GPC3) and an immunostimulatory cytokine IL-12. In the subcutaneous tumor model, Ad-IL-12/GPC3 vaccine was injected into muscles three times to evaluate its therapeutic effect. Compared with the control immunization group, the Ad-IL-12/GPC3 immunization group showed a significant tumor growth inhibition effect, which was confirmed by the reduced tumor volume and the increased tumor inhibition. Ad-IL-12/GPC3 co-immunization promoted the induction and maturation of CD11c⁺ or CD8⁺CD11c⁺ DCs and increased the number of tumor-infiltrating CD8⁺ T cells. Furthermore, in the Ad-IL-12/GPC3 group, the proliferation of CD8⁺ T cells, the induction of multifunctional CD8⁺ T cells, and CTL activity were significantly increased. Interestingly, the deletion of CD8⁺ T cells abolished tumor growth inhibition by Ad-IL-12/GPC3 treatment, suggesting that CD8⁺ T cell immune responses were required to eliminate the tumor. Likewise, Ad-IL-12/GPC3 vaccine also effectively inhibited lung tumor growth or metastasis by enhancing CD8⁺ DCs-mediated multifunctional CD8⁺ T cell immune responses in the lung metastasis model. Therefore, these results indicate that IL-12 combined with Ad-GPC3 vaccine co-immunization might provide a promising therapeutic strategy for HCC patients.

Background: Modern medical researches show that the health of a population is closely related to their behavior, environmental factors, social and economic conditions, aging and genetic susceptibility. Therefore, it is very important to study the relationship between these factors and health of a population. Objective: This study reviews the latest research progress in population health management and life/disease risk assessment, analyzes the existing problems in relevant researches, and proposes some improvement plans to solve the problems. Methods: It also introduces the general methods of human health management and life/disease risk assessment, analyzes the defects in these methods in practical application, and then draws conclusions regarding industrial system equipment health management and residual life prediction, and puts forward some new ideas to solve the problems. Results: In the study of health assessment, although self-assessment of health is a common method of determining health variables, its subjectivity and inaccuracy are problems that cannot be ignored. In life/disease risk assessment studies, medical effect and efficacy are mainly evaluated, and little consideration is given to other factors, such as behaviour, environment, and socio-economic status. In the construction of statistical graphs, great individual differences, internal symbiotic variables and external impact variables are seldom considered. Conclusion: This study helps to understand the basic ideas and methods of health management and life/disease risk assessment, and proposes some future research programs based on the author's knowledge.

[This corrects the article DOI: 10.1155/2018/4263520.].

Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR-NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-γ, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.