In this retrospective analysis, systemic therapy appears to contribute to long-term local control in patients with lymph node-negative breast cancer treated with breast-conservation therapy.
Background To consistently prepare physical therapist students for their first full-time clinical experience, the entry-level curriculum must provide and assess competency in the essential knowledge, skills, attitudes, and professional behaviors. Objective The purpose of this Delphi study was to develop consensus on a core set of elements that should be demonstrated by physical therapist students prior to entry into their first full-time clinical experience. A second aim was to obtain the recommended competency levels and assessment methods. Design The study was conducted using the Delphi method. Methods Purposive selection and snowball sampling techniques were used to recruit clinical instructors, recent graduates, directors or academic coordinators of clinical education, and academic faculty. Four web-based survey rounds were used to achieve consensus, defined as agreement among ≥80% of respondents. The first round gathered demographic information on respondents and identified elements that were deemed essential; the second collected information about clarity and redundancy in the elements provided; the third asked participants to rank their agreement with elements and themes; and the fourth gathered the level of competency that physical therapist students should demonstrate prior to beginning a first full-time clinical experience. Results Consensus revealed 95 elements, categorized under 14 themes, which were deemed essential for readiness for the first clinical experience. Levels of competency for each element were identified. Limitations Participants might not have represented all academic programs, practice settings, and geographic locations. Conclusion This study identified the specific knowledge, skills, attitudes, and professional behaviors in which all physical therapist students in the United States need to demonstrate competency before their first clinical experience, regardless of school or setting, which would allow learning experiences to be tailored appropriately.
Purpose: Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy. Experimental Design: PF-07062119 activity was evaluated in vitro in multiple tumor cell lines, and in vivo in established subcutaneous and orthotopic human colorectal cancer xenograft tumors with adoptive transfer of human T cells. Efficacy was also evaluated in mouse syngeneic tumors using human CD3e transgenic mice. IHC and mass cytometry were performed to demonstrate drug biodistribution, recruitment of activated T cells, and to identify markers of immune evasion. Combination studies were performed with anti-PD-1/PD-L1 and anti-VEGF antibodies. Toxicity and pharmacokinetic studies were done in cynomolgus macaque. Results: We demonstrate that GUCY2C-positive tumors can be targeted with an anti-GUCY2C/anti-CD3e bispecific, with selective drug biodistribution to tumors. PF-07062119 showed potent T-cell-mediated in vitro activity and in vivo efficacy in multiple colorectal cancer human xenograft tumor models, including KRASand BRAF-mutant tumors, as well as in the immunocompetent mouse syngeneic tumor model. PF-07062119 activity was further enhanced when combined with anti-PD-1/ PD-L1 treatment or in combination with antiangiogenic therapy. Toxicity studies in cynomolgus indicated a monitorable and manageable toxicity profile. Conclusions: These data highlight the potential for PF-07062119 to demonstrate efficacy and improve patient outcomes in colorectal cancer and other gastrointestinal malignancies.
Hydroxychloroquine was found to be an effective and well-tolerated drug in rheumatoid arthritis in Indian patients.
We report here the discovery and optimization of a novel T cell retargeting anti-GUCY2C x anti-CD3ε bispecific antibody for the treatment of solid tumors. Using a combination of hybridoma, phage display and rational design protein engineering, we have developed a fully humanized and manufacturable CD3 bispecific antibody that demonstrates favorable pharmacokinetic properties and potent in vivo efficacy. Anti-GUCY2C and anti-CD3ε antibodies derived from mouse hybridomas were first humanized into well-behaved human variable region frameworks with full retention of binding and T-cell mediated cytotoxic activity. To address potential manufacturability concerns, multiple approaches were taken in parallel to optimize and de-risk the two antibody variable regions. These approaches included structure-guided rational mutagenesis and phage display-based optimization, focusing on improving stability, reducing polyreactivity and self-association potential, removing chemical liabilities and proteolytic cleavage sites, and de-risking immunogenicity. Employing rapid library construction methods as well as automated phage display and high-throughput protein production workflows enabled efficient generation of an optimized bispecific antibody with desirable manufacturability properties, high stability, and low nonspecific binding. Proteolytic cleavage and deamidation in complementarity-determining regions were also successfully addressed. Collectively, these improvements translated to a molecule with potent single-agent in vivo efficacy in a tumor cell line adoptive transfer model and a cynomolgus monkey pharmacokinetic profile (half-life>4.5 days) suitable for clinical development. Clinical evaluation of PF-07062119 is ongoing.
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