Redirecting B7-H3.CAR T cells to Chemokines Expressed in Osteosarcoma Enhances Homing and Antitumor Activity in Preclinical Models.

PURPOSE: Clinical efficacy of CAR T cells against pediatric osteosarcoma (OS) has been limited. One strategy to improve efficacy may be to drive chemokine-mediated homing of CAR T cells to tumors. We investigated the primary chemokines secreted by OS and evaluated efficacy of B7-H3.CAR T cells expressing the cognate receptors. EXPERIMENTAL DESIGN: We developed a pipeline to identify chemokines secreted by OS by correlating RNA-seq data with chemokines detected in media from fresh surgical specimens. We identified CXCR2 and CXCR6 as promising receptors for enhancing CAR T cell homing against OS. We evaluated the homing kinetics and efficiency of CXCR2- and CXCR6.T cells and homing, cytokine production, and antitumor activity of CXCR2- and CXCR6.B7-H3.CAR T cells in vitro and in vivo. RESULTS: T cells transgenically expressing CXCR2 or CXCR6 exhibited ligand-specific enhanced migration over T cells modified with nonfunctional receptors. Differential homing kinetics were observed, with CXCR2.T cells homing quickly and plateauing early, while CXCR6.T cells homed more slowly but achieved a similar plateau. When expressed in B7-H3.CAR T cells, CXCR2- and CXCR6 modification conferred enhanced homing towards OS in vitro and in vivo. CXCR2- and CXCR6-B7-H3.CAR treated mice experienced prolonged survival in a metastatic model compared to B7-H3.CAR T cell treated mice. CONCLUSIONS: Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for OS patients.

A CT scan-based formula for predicting central venous catheter length in pediatric patients.

PURPOSE: Placement of a central venous catheter (CVC) is the most commonly performed pediatric procedure. This study aims to develop simple formulas to calculate intravascular length of CVCs prior to insertion to minimize reliance on fluoroscopic and radiographic imaging, which may not be uniformly available. METHODS: We performed a single-institution, retrospective review of 115 pediatric patients who received both CVC placement and computed tomography (CT) imaging of the chest within 3 months of the procedure. Using measurements from the CT imaging, formulas calculating the length of the intravascular component of the CVC based on height and insertion laterality were developed and compared to previously published formulas. These formulas were then trialed prospectively to validate reliability and application. RESULTS: Formulas were developed for right-sided and left subclavian insertion. The right-side formula accurately predicted CVC length in 52.6% of patients, compared to 47.4% by the Andropoulos formula. The left subclavian formula accurately estimated 62.5%, compared to 34.5% by the Stroud formula. CONCLUSIONS: The optimal intravascular length of central venous catheters may be determined by simple formulas based on patient height and insertion site. LEVEL OF EVIDENCE: III.

Complications associated with totally implantable access ports in children less than 1 year of age.

BACKGROUND: Long term central venous access is necessary for the treatment of several conditions affecting young children. Totally implantable access ports (ports) offer the advantage of containing no external components, thus simplifying their care and maintenance. However, there is no consensus on the safety of port placement in infants (birth to 1-year of age). The aim of this study was to describe complications associated with port placement in infants, including which specific factors may be associated with risk for developing complications among these patients, and thereby assess the safety of port placement in this young population. METHODS: A two-institution, retrospective cohort study identified patients under 1-year old who underwent port placement. Intraoperative, early postoperative (within 30 days), and late postoperative (greater than 30 days) complications were recorded. Multivariate logistic regression models were employed to assess factors associated with port-related complications. RESULTS: Among 121 patients who received a port, 36 (30%) experienced a complication with a median time to complication of 299.5 days [IQR 67.5-440.75]. Of those, 26 required unplanned port removal. Only 3 patients (2.5%) experienced an intraoperative complication, and 3 patients (2.5%) experienced a complication within 30 days of port placement. A diagnosis of cancer was found to be protective against early catheter malfunction (OR=0.31, p = 0.03). A non-statistically significant trend associated with increased complications for large caliber devices (>6.0Fr) and weight <7-kg (OR 2.20, p = 0.06 and OR=2.26, p = 0.11 respectively) was observed. CONCLUSIONS: Port placement appears to be safe for most infants with low or acceptable rates of intra- or post-operative complications. Smaller patient size (< 7 kg) and larger-sized catheters (> 6.0Fr) may be associated with an increased risk for complications among this population. LEVEL OF EVIDENCE: III.