Intraperitoneal Nivolumab After Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort.

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). PATIENTS AND METHODS: Patients received IP nivolumab (0.5, 1 and 3 mg/kg) using a 3+3 dose-escalation design, starting 5-7 days after CRS and HIPEC. Four IP Q2W nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity (DLT). Secondary objectives were to assess changes in tolerance of CRS and HIPEC. RESULTS: A total of 17 patients were enrolled including 10 patients in the dose-escalation and 7 patients in the expansion phase. No DLT was observed at any dose-level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications, 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAEs), mainly transitory grade 3-4 transaminases elevations (6/11), and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3-4 adverse events related to IP nivolumab occurred. CONCLUSIONS: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer; further investigation at 3 mg/kg is warranted.

Cultural and Ethical Barriers to Cancer Treatment in Nursing Homes and Educational Strategies: A Scoping Review.

(1) Background: The aging of the population, the increase in the incidence of cancer with age, and effective chronic oncological treatments all lead to an increased prevalence of cancer in nursing homes. The aim of the present study was to map the cultural and ethical barriers associated with the treatment of cancer and educational strategies in this setting. (2) Methods: A systematic scoping review was conducted until April 2021 in MEDLINE, Embase, and CINAHL. All articles assessing continuum of care, paramedical education, and continuing education in the context of older cancer patients in nursing homes were reviewed. (3) Results: A total of 666 articles were analyzed, of which 65 studies were included. Many factors interfering with the decision to investigate and treat, leading to late- or unstaged disease, palliative-oriented care instead of curative, and a higher risk of unjustified transfers to acute care settings, were identified. The educational strategies explored in this context were generally based on training programs. (4) Conclusions: These results will allow the co-construction of educational tools intended to develop knowledge and skills to improve diagnostic and therapeutic decision-making, the consistency of care, and, ultimately, the quality of life of older cancer patients in nursing homes.

Feasibility of a prehabilitation programme dedicated to older patients with cancer before complex medical-surgical procedures: the PROADAPT pilot study protocol.

BACKGROUND: Ageing is associated with an increased prevalence of comorbidities and sarcopenia as well as a decline of functional reserve of multiple organ systems, which may lead, in the context of the disease-related and/or treatment-related stress, to functional deconditioning. The multicomponent 'Prehabilitation & Rehabilitation in Oncogeriatrics: Adaptation to Deconditioning risk and Accompaniment of Patients' Trajectories (PROADAPT)' intervention was developed multiprofessionally to implement prehabilitation in older patients with cancer. METHODS: The PROADAPT pilot study is an interventional, non-comparative, prospective, multicentre study. It will include 122 patients oriented to complex medical-surgical curative procedures (major surgery or radiation therapy with or without chemotherapy). After informed consent, patients will undergo a comprehensive geriatric assessment and will be offered a prehabilitation kit that includes an advice booklet with personalised objectives and respiratory rehabilitation devices. Patients will then be called weekly and monitored for physical and respiratory rehabilitation, preoperative renutrition, motivational counselling and iatrogenic prevention. Six outpatient visits will be planned: at inclusion, a few days before the procedure and at 1, 3, 6 and 12 months after the end of the procedure. The main outcome of the study is the feasibility of the intervention, defined as the ability to perform at least one of the components of the programme. Clinical data collected will include patient-specific and cancer-specific characteristics. ETHICS AND DISSEMINATION: The study protocol was approved by the Ile de France 8 ethics committee on 5 June 2018. The results of the primary and secondary objectives will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03659123. Pre-results of the trial.

ZEBRA cell-penetrating peptide as an efficient delivery system in Candida albicans.

There is increasing interest in drug delivery systems, such as nanoparticles, liposomes, and cell-penetrating peptides, for the development of new antimicrobial treatments. In this study, we investigated the transduction capacity of a carrier peptide derived from the Epstein-Barr virus ZEBRA protein in the pathogenic fungus Candida albicans. ZEBRA-minimal domain (MD) was able to cross the cell wall and cell membrane, delivering eGFP to the cytoplasm. Uptake into up to 70% of the cells was observed within two hours, without toxicity. This new delivery system could be used in C. albicans as a carrier for different biological molecules including peptides, proteins, and nucleic acids. Thereby, in antifungal therapy, MD may carry promising bioactive fungal inhibitors that otherwise penetrate poorly into the cells. Furthermore, MD will be of interest for deciphering molecular pathways involving cell-cycle control in yeast or signaling pathways. Short interfering peptides could be internalized using MD, providing new tools for the inhibition of metabolic or signaling cascades essential for the growth and virulence of C. albicans, such as yeast-to-hyphae transition, cell wall remodeling, stress signaling and antifungal resistance. These findings create new possibilities for the internalization of cargo molecules, with applications for both treatment and functional analyses.

Tumor burden influences exposure and response to rituximab: pharmacokinetic-pharmacodynamic modeling using a syngeneic bioluminescent murine model expressing human CD20.

Clinical studies have shown a large interindividual variability in rituximab exposure and its significant influence on clinical response in patients receiving similar doses of antibody. The aim of this study was to evaluate the influence of tumor burden on dose-concentration-response relationships of rituximab. Murine lymphoma cells (EL4, 8 x 10(3)), transduced with human CD20 cDNA and transfected with luciferase plasmid (EL4-huCD20-Luc), were intravenously injected into C57BL/6J mice. Tumor burden detection, dissemination, and progression were evaluated quantitatively by in vivo bioluminescence imaging. Different doses of rituximab (6, 12, 20, or 40 mg/kg) were infused 13 days after lymphoma cell inoculation, and rituximab serum concentrations were measured by enzyme-linked immunosorbent assay. Without rituximab, all mice developed disseminated lymphoma and died within 30 days, whereas a significant dose-response relationship was observed in mice receiving rituximab. The 20-mg/kg dose was adequate to study interindividual variability in response because 23% of mice were cured, 59% had partial response, and 18% had disease progression. Rituximab concentrations were inversely correlated with tumor burden; mice with low tumor burden had high rituximab concentrations. Furthermore, rituximab exposure influenced response and survival. Finally, using a pharmacokinetic-pharmacodynamic model, we demonstrated that tumor burden significantly influenced rituximab efficacy.

Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment.

Antibody humanisation through recombinant DNA technology was a key step in allowing monoclonal antibodies (mAbs) to reach the clinic, particularly for the treatment of cancer. As a consequence, they are less adapted to animal studies, although these studies continue to be important tools to study antibody distribution and action at the level of a whole organism. Moreover, preclinical studies in animals are mandatory before the approval of biologics license applications for mAbs by the U.S. Food and Drug Administration (FDA) or European Agency for the Evaluation of Medicinal Products (EMEA). Different parameters should be taken in consideration before starting animal experiments with recombinant mAbs, including antibody cross-reactivity, immunogenicity, pharmacokinetics, and possible interactions with the host immune system. The various interspecies differences are reviewed and discussed in light of the pharmacological properties expected in patients. In doing so, this article aims to provide a critical review of the animal models used in preclinical studies of mAbs for cancer treatment. In particular, their relevance, advantages and limitations will be discussed.