TRAIL-R1-Targeted CAR-T Cells Exhibit Dual Antitumor Efficacy

Tumor necrosis factor–related apoptosis-inducing ligand receptor 1 (TRAIL-R1) has limited expression in normal tissues but was highly expressed in various types of tumors, making it an attractive target for cancer immunotherapy. Here, we utilized the single-chain variable fragment (scFv) from our previously identified TRAIL-R1–targeting monoclonal antibody (TR1419) with antitumor efficacy and produced the TR1419 chimeric antigen receptor (CAR) T cells. We characterized the phenotypes and functions of these CAR-T cells and found that the third-generation TR1419-28BBζ CAR-T cells exhibited greater target sensitivity and proliferative capability, with slightly higher PD-1 expression after antigen stimulation. Importantly, we found that the TR1419 CAR-T cells could induce TRAIL-R1–positive tumor cell death via a dual mechanism of the death receptor–dependent apoptosis as well as the T-cell–mediated cytotoxicity. Altogether, the TR1419 CAR-T cells could serve as a promising strategy for targeting the TRAIL-R1–positive tumors.

Efficient Intravenous Tumor Targeting Using the αvβ6 Integrin-Selective Precision Virotherapy Ad5NULL-A20

We previously developed a refined, tumor-selective adenovirus, Ad5NULL-A20, harboring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20-mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6-positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 h post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6-selective manner, whilst cell killing mediated by oncolytic Ad5NULL-A20 was αvβ6-selective. Biodistribution analysis following intravenous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor-to-liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20-based virotherapies efficiently target αvβ6-integrin-positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic applications, enabling tumor-selective overexpression of virally encoded therapeutic transgenes.

Efficient Intravenous Tumor Targeting Using the αVβ6 Integrin Selective Precision Virotherapy Ad5NULL-A20

Background: We previously developed a refined, tumor selective adenovirus, Ad5NULL-A20, har-boring tropism ablating mutations in each major capsid protein, to ablate all native means of infection. We incorporated a 20mer peptide (A20) in the fiber knob for selective infection via αvβ6 integrin, a marker of aggressive epithelial cancers. Methods: To ascertain the selectivity of Ad5NULL-A20 for αvβ6 positive tumor cell lines of pancreatic and breast cancer origin, we performed reporter gene and cell viability assays. Biodistribution of viral vectors in mice harboring xenografts with low, medium, and high αvβ6 levels was quantified by qPCR for viral genomes 48 hours post intravenous administration. Results: Ad5NULL-A20 vector transduced cells in an αvβ6 selective manner, whilst cell killing me-diated by oncolytic Ad5NULL-A20 was αvβ6 selective. Biodistribution analysis following intrave-nous administration into mice bearing breast cancer xenografts demonstrated that Ad5NULL-A20 resulted in significantly reduced liver accumulation coupled with increased tumor accumulation compared to Ad5 in all three models, with tumor: liver ratios improved as a function of αvβ6 expression. Conclusions: Ad5NULL-A20 based virotherapies efficiently target αvβ6 integrin positive tumors following intravenous administration, validating the potential of Ad5NULL-A20 for systemic ap-plications, enabling tumor selective overexpression of virally encoded therapeutic transgenes.

Perbaikan Kualitas Hidup pada Pasien Solitary Fibrous Tumor Mediastinum: Perspektif Kemoterapi Paliatif

Background: Mediastinal solitary fibrous tumor (SFT) is a rare spindle cell neoplasm. Approximately 1 to 8% of these intrathoracic tumors have been reported to occur in the mediastinum. The chief complaints of mediastinal SFT are cough, shortness of breath or chest pain, or may occur as asymptomatic incidental mass. The treatment of choice for SFT is extensive surgical resection. However, when the tumor cannot be removed surgically or when metastases occur, chemotherapy and or radiotherapy can be proposed as palliative treatments. Case: A 19-year-old man with chief complaint of left chest pain and referred to his left back. The complaint is accompanied by cough without sputum and hoarseness. In thoracic CT scan with contrast, we found giant cystic mass suspect malignancy around 17x12x18 cm in left hemithorax, a minimal pericardial effusion, and left pleural effusion. There were positive tumor cell cytoplasm results in vimentin, negative tumor cell cytoplasm in CK, positive tumor cell membrane in CD99, cytoplasm of focal positive tumor cells in EMA, and negative tumor cells in CD34 which supported a solitary fibrous tumor in the immunohistochemical staining analysis. Doxorubicin-Ifosfamide regimen was the choice of chemotherapy palliative treatment in the case report. In the CT scan evaluation of thorax with contrast, we found stable disease (RECIST criteria) with improve quality of life (QOL) according to EQ-5D-3L, 11111 indicated no problems in 5 dimensions, such as mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Conclusion: Mediastinal SFT is a rare spindle cell neoplasm, and the diagnosis requires pathological and immunohistochemical staining analysis. Doxorubicin-Ifosfamide regimen can be proposed as a palliative chemotherapy regimen, which has been shown to improve QOL patients in Mediastinal SFT. EQ-5D is a simple tool that can be used to measure QOL such as mobility, self-care, usual activities, pain or discomfort, and anxiety or depression.

Cisplatin Nanoparticles for Folate Targeted Delivery in Ovarian Cancer: Study in SKOV-3 Cancer Cells

Tumor targeting of drug to specific site via use of folate is one the choicest method for enhancing specificity of Cisplatin. Chitosan was conjugated with folate via amino acylation method and Folate-chitosan-Cisplatin-nanoparticles (FA-CS-Cis-NP's) were prepared using ionotropic gelation method. Thus prepared nanoparticles were evaluated for various parameters such as particles size, % encapsulation efficiency, % drug release, cytotoxic assay, cellular uptake. The average particle size of nanoparticles was found to be 265 nm with encapsulation efficiency of 89.43%. The cumulative release of drug from dosage form was found to be 82.31% for 240 min. The higher level of intra-cellular accumulation of Cisplatin was found to be in case of FA-CS-Cis-NP's than conventional drug delivery when cultured with folate. The results indicate that targeting of FA-CSCis-NP's is possible with folate targeting and are proved as potential folate receptor positive tumor cell targeting drug delivery system.

Isolation of rabbit single domain antibodies to B7-H3 via protein immunization and phage display

Single domain antibodies have certain advantages including their small size, high stability and excellent tissue penetration, making them attractive drug candidates. Rabbit antibodies can recognize diverse epitopes, including those that are poorly immunogenic in mice and humans. In the present study, we established a method to isolate rabbit VH single domain antibodies for potential cancer therapy. We immunized rabbits with recombinant human B7-H3 (CD276) protein, made a phage-displayed rabbit VH single domain library with a diversity of 7 × 109, and isolated two binders (A1 and B1; also called RFA1 and RFB1) from phage panning. Both rabbit VH single domains exhibited antigen-dependent binding to B7-H3-positive tumor cell lines but not B7-H3 knockout tumor cell lines. Our study shows that protein immunization followed by phage display screening can be used to isolate rabbit single domain antibodies. The two single domain antibodies reported here may have potential applications in cancer immunotherapy.