Objectives The current treatment of acute lower limb ischemia (ALLI) includes open surgical and percutaneous pharmaco-mechanical thromboembolectomy (TE). We hereby report our results with open surgical TE over a 10-year period and compare our outcomes using routine fluoroscopic assisted TE (FATE) with blind and selective on demand fluoroscopic-assisted TE (BSTE). Methods This is a retrospective analysis of all patients who underwent open surgical TE for acute lower limb ischemia at a single tertiary center between 2008 and 2018. Patients were divided into a group who underwent BSTE and another who underwent routine FATE. Data on presentation, medical history, surgery performed, and short-term outcomes were retrieved from medical record. Comparison between baseline characteristics and outcomes of both groups were made using t-test and chi-square analysis. Results Over 10 years, 108 patients underwent surgical TE. Thirty-day mortality rate and 30-day major lower extremity amputation rate in the cohort were 12.0% and 6.5%, respectively. On subgroup analysis, 53 patients were treated by BSTE and 55 patients by FATE. There was no significant difference in 30-day mortality rate (11.3% vs 12.7%, p-value = .82) and 30-day major amputation rate (9.4% vs 3.6%, p-value = .454) between the two groups. Local anesthesia was more frequently performed in patients undergoing FATE (58.2% vs 24.5%, p-value < .001). More than one arteriotomy was more frequently required in patients undergoing BSTE (2.6% vs 45.5%, p-value < .001). Patients with infrapopliteal involvement undergoing FATE required less further interventions such as patch angioplasty (2.6% vs 36.4%, p-value < .001) and bypass (2.6% vs 22.7%, p-value = .01). Conclusion ALLI remains a disease of high morbidity and mortality. Open surgical TE offers an effective approach to treat ALLI. The addition of fluoroscopy to the conduction of TE could be associated with valuable benefits, especially in patients with infra-popliteal involvement. Randomized controlled trials are needed to objectively assess the therapeutic potential of FATE.

2023-03-01·Molecular Therapy - Oncolytics

Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors

Article

作者: Havunen, Riikka ; Heiniö, Camilla ; Clubb, James H A ; Hemminki, Akseli ; Kanerva, Anna ; Quixabeira, Dafne C A ; Pakola, Santeri ; Basnet, Saru ; Santos, Joao M ; Arias, Victor ; Sorsa, Suvi ; Anttila, Marjukka ; Cervera-Carrascon, Victor ; Grönberg-Vähä-Koskela, Susanna A M ; Kudling, Tatiana V

Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321). TILT-321 is engineered to replicate only in cancer cells, leading to a high concentration of the aMUC1aCD3 molecule in the tumor microenvironment. Infection and cell viability assays were performed to determine the oncolytic potential of the novel construct. The functionality of the virus-derived aMUC1aCD3 was evaluated in vitro. When TILT-321 was combined with allogeneic T cells, rapid tumor cell lysis was observed. TILT-321-infected cells secreted functional aMUC1aCD3, as shown by increased T cell activity and its binding to MUC1 and CD3. In vivo, TILT-321 treatment led to effective antitumor efficacy mediated by increased intratumoral T cell activity in an A549 and patient-derived ovarian cancer xenograft mouse model humanized with peripheral blood mononuclear cells (PBMC). This study provides a proof of concept for an effective strategy to overcome the key limitations of recombinant bispecific T cell engager delivery for solid tumor treatment.

Cancer Immunology, Immunotherapy

The expression of PD-L1 on tumor-derived exosomes enhances infiltration and anti-tumor activity of αCD3 × αPD-L1 bispecific antibody-armed T cells

Article

作者: Cho, Jaewon ; Lee, Kwang-Ho ; Lee, Byung-Hyun ; Kim, Chae-Won ; Kim, Dae Hee ; Ahn, Jae-Hee ; Song, Yujeong ; Tae, Nara ; Chang, Sun-Young ; Lee, Seung-Joo ; Kim, Byung Soo ; Ko, Hyun-Jeong

AbstractAnti-cluster of differentiation (CD) 3 × α programmed death-ligand 1 (PD-L1) bispecific T-cell engager (BsTE)-bound T-cells (BsTE:T) are a promising new cancer treatment agent. However, the mechanisms of action of bispecific antibody-armed activated T-cells are poorly understood. Therefore, this study aimed to investigate the anti-tumor mechanism and efficacy of BsTE:T. The BsTE:T migration was assessed in vivo and in vitro using syngeneic and xenogeneic tumor models, flow cytometry, immunofluorescence staining, transwell migration assays, microfluidic chips, Exo View R100, western blotting, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 technology. In murine B16 melanoma, MC38 colon cancer, and human multiple myeloma cells, BsTE:T exhibited superior tumor elimination relative to that of T-cells or BsTE alone. Moreover, BsTE:T migration into tumors was significantly enhanced owing to the presence of PD-L1 in tumor cells and secretion of PD-L1-containing exosomes. Furthermore, increased infiltration of CD44highCD62Llow effector memory CD8+ T-cells into tumors was closely associated with the anti-tumor effect of BsTE:T. Therefore, BsTE:T is an innovative potential anti-tumor therapy, and exosomal PD-L1 plays a crucial role both in vitro and in vivo in the anti-tumor activity of BsTE:T.Graphical abstract

100 项与 aMUC1aCD3 coding virus(TILT) 相关的药物交易

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