Systemic delivery of oncolytic herpes virus using CAR-T cells enhances targeting of antitumor immuno-virotherapy.

Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.

Improved antitumor effects elicited by an oncolytic HSV-1 expressing a novel B7H3nb/CD3 BsAb.

Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.

An Anti-CD7 Antibody-Drug Conjugate Target Showing Potent Antitumor Activity for T-Lymphoblastic Leukemia (T-ALL).

Acute T-lymphoblastic leukemia (T-ALL) is a type of leukemia that can occur in both pediatric and adult populations. Compared to acute B-cell lymphoblastic leukemia (B-ALL), patients with T-cell T-ALL have a poorer therapeutic efficacy. In this study, a novel anti-CD7 antibody-drug conjugate (ADC, J87-Dxd) was successfully generated and used for T-ALL treatment. Firstly, to obtain anti-CD7 mAbs, we expressed and purified the CD7 protein extracellular domain. Utilizing hybridoma technology, we obtained three anti-CD7 mAbs (J87, G73 and A15) with a high affinity for CD7. Both the results of immunofluorescence and Biacore assay indicated that J87 (KD = 1.54 × 10-10 M) had the highest affinity among the three anti-CD7 mAbs. In addition, an internalization assay showed the internalization level of J87 to be higher than that of the other two mAbs. Next, we successfully generated the anti-CD7 ADC (J87-Dxd) by conjugating DXd to J87 via a cleavable maleimide-GGFG peptide linker. J87-Dxd also possessed the ability to recognize and bind CD7. Using J87-Dxd to treat T-ALL cells (Jurkat and CCRF-CEM), we observed that J87-Dxd bound to CD7 was internalized into T-ALL cells. Moreover, J87-Dxd treatment significantly induced the apoptosis of Jurkat and CCRF-CEM cells. The IC50 (half-maximal inhibitory concentration) value of J87-Dxd against CCRF-CEM obtained by CCK-8 assay was 6.3 nM. Finally, to assess the antitumor efficacy of a J87-Dxd in vivo, we established T-ALL mouse models and treated mice with J87-Dxd or J87. The results showed that on day 24 after tumor inoculation, all mice treated with J87 or PBS died, whereas the survival rate of mice treated with J87-Dxd was 80%. H&E staining showed no significant organic changes in the heart, liver, spleen, lungs and kidneys of all mice. In summary, we demonstrated that the novel anti-CD7 ADC (J87-Dxd) had a potent and selective effect against CD7-expressing T-All cells both in vitro and in vivo, and could thus be expected to be further developed as a new drug for the treatment of T-ALL or other CD7-expression tumors.

Associations between prenatal metal exposure and growth rate in children: Based on Hangzhou Birth Cohort Study.

BACKGROUND: It has been reported that prenatal metal exposure is associated with child anthropometry. However, studies focusing on the growth rate of anthropometry among children have not been conducted. This study aimed to examine associations between the exposure of multiple metals during pregnancy and the growth rate of anthropometry among offspring. METHODS: 743 mother-child pairs from the Hangzhou Birth Cohort Study (HBCS) were included. Levels of eleven metals in mother's blood during pregnancy were measured. Offspring had a mean of 5.7 measurements on anthropometric indicators including weight, length/height, head circumference, and body mass index (BMI) within 1.5 years of birth. Generalized estimating equation (GEE) model was used to investigate the associations between maternal metal exposure and growth rate of anthropometric indicators in children. Stratification analysis by sex was also examined. RESULTS: Levels of selenium (Se, ß = 0.213, 95 % CI = 0.017 to 0.409, P = 0.033) were positively associated with length/height gain per month in children. Levels of chromium (Cr, ß = 0.025, 95 % CI = 0.018 to 0.033, P < 0.001) were positively associated with the rate of weight gain. Levels of manganese (Mn, ß = -0.030, 95 % CI = -0.052 to -0.008, P = 0.009) and cobalt (Co, ß = -0.012, 95 % CI = -0.024 to -0.000, P = 0.044) were inversely associated with growth rate of head circumference. Children with higher maternal Mn levels had a lower BMI change rate. Associations between metals and growth rate were stronger in girls than in boys. Besides, significant associations between metal mixtures and growth rate were found. CONCLUSION: Prenatal exposure to Se, Cr, Mn, and Co was associated with growth rate in children, with sex-specific disparities. Our results suggested important effects of maternal exposure to multiple metals on development in offspring.