ABSTRACT
BACKGROUND: Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab. METHODS: In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity. RESULTS: Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8). CONCLUSION: Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.
Subject(s)
Adenocarcinoma/therapy , Antineoplastic Agents, Immunological/therapeutic use , Electroporation/methods , Nivolumab/therapeutic use , Pancreatic Neoplasms/therapy , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adult , Aged , Animals , Antineoplastic Agents, Immunological/adverse effects , B7-H1 Antigen/genetics , Cell Line, Tumor , Combined Modality Therapy , Female , Gene Expression , Humans , Interferon-gamma/physiology , Male , Mice, Inbred C57BL , Middle Aged , Neoplasm Staging , Nivolumab/adverse effects , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Programmed Cell Death 1 Receptor/genetics , T-Lymphocyte Subsets , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Human Skin Substitute (Apligraf, Organogenesis, Inc., Canton, MA) is a bi-layered tissue-engineered living biological dressing developed from neonatal foreskin. It consists of a bovine collagen matrix containing human fibroblasts with an overlying sheet of stratified human epithelium containing living human keratinocytes. Human Skin Substitute (HSS) appears to be immunologically inert, and has shown usefulness in the treatment of chronic and acute wounds. OBJECTIVE: Primary objectives were to evaluate the safety and efficacy of HSS in the treatment of full-thickness wounds in a prospective case series. Secondary objectives were to determine the rate of complete wound reepithelialization, incidence of complete wound healing, pain at wound site, overall cosmetic outcome, and patient satisfaction. METHODS: Fourteen patients were enrolled in the study, of which 12 were evaluable. HSS was applied in a blinded fashion to 6 of the patients immediately following Mohs or excisional surgery for skin cancer. The remaining 6 patients were allowed to heal by secondary intention. Both groups were evaluated at weekly appointments until complete reepithelialization occurred. During each evaluation, wound quality was assessed through the Vancouver Burn Scar Assessment Scale by the investigator and an independent blinded dermatologist. The investigator, blinded observer, and patient further evaluated the cosmetic outcome of the wound through the use of a Visual Analog Scale over a 6-month period. RESULTS: HSS patients and secondary intention patients were equivalent in comorbid factors such as pain, erythema, edema, exudate, infection, or hematoma between the groups. The incidence of complete wound healing at 6 months was 100% for both groups. Both groups also appeared to heal at similar rates, as defined by the complete reepithelialization of the wound. HSS patients ultimately resulted in more pliable and less vascular wounds as defined by the Vancouver Burn Scar Assessment Scale. Patient satisfaction with cosmetic outcome in both groups was positive at 6 months. CONCLUSIONS: HSS appears to be a safe, well-tolerated biological dressing with equivalent comorbid factors to secondary intention healing. HSS, however, seems to produce a more pliable and less vascular scar than those developed through healing by secondary intention. HSS also appears to produce more satisfactory cosmetic results when compared to secondary intention healing.
