Association Between 18F-FDG PET Activity and HER2 Status in Breast Cancer Brain Metastases.

Purpose: The objective of this study was to evaluate whether uptake on 18F-fluorodeoxyglucose (18F-FDG) PET could help differentiate HER2-positive from HER2-negative breast cancer brain metastases. Methods: In this retrospective, cross-sectional study of a cohort of 14 histologically proven breast cancer brain metastases, we analyzed both preoperative 18F-FDG PET/CT and HER2 status of the resected/biopsied brain specimens. The maximum standardized uptake values (SUVmax) of the lesions were normalized to contralateral normal white matter and compared using Mann-Whitney U tests. Results: The study cohort was comprised of 12 women with breast cancer with a mean age of 59 years (range: 43-76 years) with a total of 14 distinct brain metastatic lesions. The SUVmax ratio of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (3.98 vs 1.79, U = 38.00, p = 0.008). Conclusion: The SUVmax ratio may help to identify the HER2 status of breast cancer brain metastases, if validated prospectively.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Association of Relative Cerebral Blood Volume from Dynamic Susceptibility Contrast-Enhanced Perfusion MR with HER2 Status in Breast Cancer Brain Metastases.

RATIONALE AND OBJECTIVES: With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 expression in breast cancer brain metastases has become increasingly important. The purpose of this study was to investigate whether relative cerebral blood volume (rCBV) from dynamic susceptibility contrast-enhanced (DSC) perfusion MR could help identify the HER2 status of breast cancer brain metastases. MATERIALS AND METHODS: With IRB approval for this HIPAA-compliant cross-sectional study and a waiver of informed consent, we queried our institution's electronic medical record to derive a cohort of 14 histologically proven breast cancer brain metastases with preoperative DSC perfusion MR and HER2 analyses of the resected/biopsied brain specimens from 2011-2021. The rCBV of the lesions was measured and compared using Mann-Whitney tests. Receiver operating characteristic analyses were performed to evaluate the performance of rCBV in identifying HER2 status. RESULTS: The study cohort was comprised of 14 women with a mean age of 56 years (range: 32-81 years) with a total of 14 distinct lesions. The rCBV of HER2-positive breast cancer brain metastases was significantly greater than the rCBV of HER2-negative lesions (8.02 vs 3.97, U=48.00, p=0.001). rCBV differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.98 (standard error=0.032, p<0.001). The accuracy-maximizing rCBV threshold (4.8) was associated with an accuracy of 93% (13/14), a sensitivity of 100% (7/7), and a specificity of 86% (6/7). CONCLUSION: rCBV may assist in identifying the HER2 status of breast cancer brain metastases, if validated in a large prospective trial.

Association of lesion contour and lesion composition on MR with HER2 status in breast cancer brain metastases.

BACKGROUND AND PURPOSE: With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 status in breast cancer brain metastases has become increasingly important, particularly given the risks of tissue sampling within the brain and the possibility of a change in receptor expression from the primary tumor to the brain metastasis. The purpose of this study was to evaluate whether lesion contour and composition on MR could help identify the HER2 status of breast cancer brain metastases. MATERIALS AND METHODS: We derived a cohort of 34 women with a mean age of 55 years (range: 31-81 years) with a total of 47 distinct histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MR and HER2 immunohistochemistry and/or fluorescent in-situ hybridization (FISH) of the resected/biopsied brain specimens from 2018 to 2021. Two fellowship-trained neuroradiologists evaluated the lesion contour and lesion composition of each lesion. Logistic regression analyses were performed. RESULTS: In a logistic regression model, an irregular contour had an odds ratio of 170 (p = 0.007) in differentiating HER2-positive from HER2-negative lesions. In a logistic regression model, when compared to a predominantly cystic lesion composition, a solid lesion composition had an odds ratio of 17 (p = 0.016) in differentiating HER2-positive from HER2-negative lesions. CONCLUSION: Lesion contour and lesion composition on MR were significantly associated with the HER2 status of breast cancer brain metastases. Current assessment of HER2 status requires tissue sampling and immunochemical and/or FISH analyses. A non-invasive imaging biomarker that may help predict HER2 status may be of great clinical value.

Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma.

BACKGROUND: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach. METHODS: We generated for clinical use a healthy-donor derived IL13Rα2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day). RESULTS: The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500-5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects. CONCLUSIONS: This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.

Performance of enhancement on brain MRI for identifying HER2 overexpression in breast cancer brain metastases.

PURPOSE: To investigate whether enhancement on MRI could help identify HER2 overexpression in breast cancer brain metastases. METHODS: We derived a cohort of 38 histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MRI and HER2 fluorescent in-situ hybridization of the resected/biopsied brain specimens from 2018 to 2021. Enhancement of the lesions was measured and compared using t-tests. Receiver operating characteristic and logistic regression analyses were performed to evaluate the performance of MRI enhancement in identifying HER2 overexpression. RESULTS: The study cohort was comprised of 29 women with a mean age of 55 years (range: 31-81 years) with a total of 38 distinct lesions. The HER2-positive subcohort was comprised of 17 patients, while the HER2-negative subcohort was comprised of 13 patients. The percent signal intensity change (PSIC) of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (310 v. 153, P = 0.002). The PSIC differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.88 (P < 0.001). In a model controlling for lesion size, lesion location, tumor grade, patient age, scanner magnetic field strength, and contrast agent, the PSIC had an accuracy of 92% (35/38), sensitivity of 96% (23/24), and specificity of 86% (12/14) in differentiating HER2-positive lesions from HER2-negative lesions. CONCLUSION: Enhancement on MRI may assist in identifying HER2 overexpression in breast cancer brain metastases, if validated prospectively.

Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy.

A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).

Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.

PURPOSE: A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)-engineered, autologous primary human CD8(+) cytotoxic T lymphocytes (CTL) targeting IL13Rα2 for the treatment of recurrent glioblastoma (GBM). EXPERIMENTAL DESIGN: Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8(+) CTL targeting IL13Rα2. Patients received up to 12 local infusions at a maximum dose of 10(8) CAR-engineered T cells via a catheter/reservoir system. RESULTS: We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Rα2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine(+) CTL clones into the resection cavity of 3 patients with recurrent disease was well-tolerated, with manageable temporary brain inflammation. Following infusion of IL13-zetakine(+) CTLs, evidence for transient anti-glioma responses was observed in 2 of the patients. Analysis of tumor tissue from 1 patient before and after T-cell therapy suggested reduced overall IL13Rα2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine(+) T-cell administration. CONCLUSIONS: These findings provide promising first-in-human clinical experience for intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T-cell therapies can be applied.

Early lactate clearance is associated with improved outcome in severe sepsis and septic shock.

OBJECTIVE: Serial lactate concentrations can be used to examine disease severity in the intensive care unit. This study examines the clinical utility of the lactate clearance before intensive care unit admission (during the most proximal period of disease presentation) as an indicator of outcome in severe sepsis and septic shock. We hypothesize that a high lactate clearance in 6 hrs is associated with decreased mortality rate. DESIGN: Prospective observational study. SETTING: An urban emergency department and intensive care unit over a 1-yr period. PATIENTS: A convenience cohort of patients with severe sepsis or septic shock. INTERVENTIONS: Therapy was initiated in the emergency department and continued in the intensive care unit, including central venous and arterial catheterization, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, and inotropes when appropriate. MEASUREMENTS AND MAIN RESULTS: Vital signs, laboratory values, and Acute Physiology and Chronic Health Evaluation (APACHE) II score were obtained at hour 0 (emergency department presentation), hour 6, and over the first 72 hrs of hospitalization. Therapy given in the emergency department and intensive care unit was recorded. Lactate clearance was defined as the percent decrease in lactate from emergency department presentation to hour 6. Logistic regression analysis was performed to determine independent variables associated with mortality. One hundred and eleven patients were enrolled with mean age 64.9 +/- 16.7 yrs, emergency department length of stay 6.3 +/- 3.2 hrs, and overall in-hospital mortality rate 42.3%. Baseline APACHE II score was 20.2 +/- 6.8 and lactate 6.9 +/- 4.6 mmol/L. Survivors compared with nonsurvivors had a lactate clearance of 38.1 +/- 34.6 vs. 12.0 +/- 51.6%, respectively (p =.005). Multivariate logistic regression analysis of statistically significant univariate variables showed lactate clearance to have a significant inverse relationship with mortality (p =.04). There was an approximately 11% decrease likelihood of mortality for each 10% increase in lactate clearance. Patients with a lactate clearance> or =10%, relative to patients with a lactate clearance <10%, had a greater decrease in APACHE II score over the 72-hr study period and a lower 60-day mortality rate (p =.007). CONCLUSIONS: Lactate clearance early in the hospital course may indicate a resolution of global tissue hypoxia and is associated with decreased mortality rate. Patients with higher lactate clearance after 6 hrs of emergency department intervention have improved outcome compared with those with lower lactate clearance.