We sought to examine the long-term clinical success rates of a bowel management program (BMP) for children with severe constipation or fecal incontinence.
A single center review was conducted of ...children (≤18 years) enrolled in a BMP and followed in a colorectal specialty clinic (2011–2017). All patients who completed an initial week of the BMP were included. Patients enrolled in a BMP after 2018 were excluded. Success was defined as no accidents and <2 stool smears per week.
A total of 285 patients were reviewed. BMP was initiated at a median age of 7 years (9 months-17 years). Primary diagnoses included functional constipation (112), anorectal malformation (ARM) (104), Hirschsprung Disease (HD) (41), rectal prolapse (14), spina bifida (6), fecal incontinence (3) and other (5; 4 sacral coccygeal teratomas and a GSW to the buttocks). Initial bowel regimen included large volume enema in 54% and high dose stimulant laxative in 46%. The initial Bowel Management Week (BMW) was successful in 233 (87% of adherent patients) patients with 17 (6%) non-adherent. One hundred twenty-two patients had follow-up at 12 months (72% success amongst adherent patients, 7% of patient non-adherent) and 98 patients had follow-up at 24 months (78% success amongst adherent patients, 10% of patients non-adherent). 21/154 (14%) patients started on enemas were later successfully transitioned to laxatives and 13/132 (10%) patients started on laxatives subsequently required enemas in order to stay clean. Clinic phone contact occurred outside of scheduled visits for adjustment to the BMP in 44% of patients. 33% of patients had surgery to aid bowel management (antegrade colonic enema (ACE) = 81, resection + ACE = 13, diverting stoma = 4). Median follow up was 2.5 years (5 weeks–7 years).
Children who follow a structured BMP with readily available personnel to provide outpatient assistance can experience successful treatment of severe constipation or fecal incontinence long-term. A multi-institutional collaboration is necessary to identify factors which predict failure of a BMP and non-adherence.
Single-center retrospective chart review.
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Unplanned intensive care unit readmission within 72 hours is an established metric of hospital care quality. However, it is unclear what factors commonly increase the risk of intensive care unit ...readmission in surgical patients. The objective of this study was to evaluate predictors of readmission among a diverse sample of surgical patients and develop an accurate and clinically applicable nomogram for prospective risk prediction.
We retrospectively evaluated patient demographic characteristics, comorbidities, and physiologic variables collected within 48 hours before discharge from a surgical intensive care unit at an academic center between April 2010 and July 2015. Multivariable regression models were used to assess the association between risk factors and unplanned readmission back to the intensive care unit within 72 hours. Model selection was performed using lasso methods and validated using an independent data set by receiver operating characteristic area under the curve analysis. The derived nomogram was then prospectively assessed between June and August 2017 to evaluate the correlation between perceived and calculated risk for intensive care unit readmission.
Among 3,109 patients admitted to the intensive care unit by general surgery (34%), transplant (9%), trauma (43%), and vascular surgery (14%) services, there were 141 (5%) unplanned readmissions within 72 hours. Among 179 candidate predictor variables, a reduced model was derived that included age, blood urea nitrogen, serum chloride, serum glucose, atrial fibrillation, renal insufficiency, and respiratory rate. These variables were used to develop a clinical nomogram, which was validated using 617 independent admissions, and indicated moderate performance (area under the curve: 0.71). When prospectively assessed, intensive care unit providers’ perception of respiratory risk was moderately correlated with calculated risk using the nomogram (ρ: 0.44; P < .001), although perception of electrolyte abnormalities, hyperglycemia, renal insufficiency, and risk for arrhythmias were not correlated with measured values.
Intensive care unit readmission risk for surgical patients can be predicted using a simple clinical nomogram based on 7 common demographic and physiologic variables. These data underscore the potential of risk calculators to combine multiple risk factors and enable a more accurate risk assessment beyond perception alone.
BackgroundChimeric antigen receptor (CAR) T cell therapy is being explored in early-stage clinical trials as a strategy to improve treatment outcomes for high-grade gliomas (HGGs). We report here, a ...completed phase I trial (NCT02208362) evaluating locoregionally delivered IL13Rα2-targeted CAR T cells in 65 patients with recurrent HGG (rHGG), the majority being recurrent glioblastoma (rGBM).MethodsThis five-arm trial evolved to evaluate three routes of locoregional CAR T cell administration: (i) intratumoral (ICT) following tumor biopsy (Arm 1) or resection (Arm 2); (ii) intraventricular (ICV; Arm 3); and (iii) dual ICT/ICV (Arm 4). The final treatment arm (Arm 5) evaluated dual ICT/ICV delivery with a modified manufacturing process. Primary objectives were feasibility and safety. Secondary objectives evaluated therapy-related cytokine dynamics by cytometric bead array, CAR T cell persistence by flow cytometry and PCR, and clinical outcomes by radiographic imaging and survival. The pretreatment tumor immune landscape was evaluated by immunohistochemistry.ResultsFeasibility and safety were established for all three routes of locoregional CAR T cell delivery (ICT, ICV and dual ICT/ICV). IL13Rα2-CAR T cells were well-tolerated with clinically manageable adverse events at all dose levels, and no dose limiting toxicities observed. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off protocol therapy. Median overall survival (OS) for rGBM patients (68% treated at 2nd recurrence or later) was 7.7 mo. Post-hoc analysis revealed that Arm 5 rGBM patients exhibited the best median OS of 10.2 months, compared to 6.1 months for other treatment arms (Arms 1–4). Increase in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, was observed in the cerebrospinal (CSF) and tumor fluid after each infusion. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival.ConclusionsWe report the largest CAR T cell clinical trial in brain tumors to date, assessing the feasibility, safety, and bioactivity of IL13Rα2-CAR T cells in rHGG. Key findings include: (1) repetitive locoregional administration of IL13Rα2-CAR T cells is feasible and safe, with clinical benefit observed in a subset of patients; (2) elevations in IFNγ-related chemokines in the CSF was associated with CAR T cell administration and bioactivity; and (3) tumor immune contexture was identified as a determinant of patient outcome to CAR T cell therapy. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors.Ethics ApprovalThis study was conducted I accordance with the Institutional Review Board and Independent Ethics Committee at The City of Hope National Medical Center as well as the U.S. Food and Drug Administration (FDA). All subjects provided written informed consent.
BackgroundA major barrier to achieving effective therapies for patients with glioblastoma multiforme (GBM) is the phenotypic heterogeneity seen both between patients and within individual tumors, the ...later creating multiple cell subpopulations contributing to disease recurrence. One strategy for creating more efficacious therapies is to design novel immunotherapies targeting higher proportions of tumors and tumor cells than current options. Chlorotoxin (CLTX) is a 36-amino acid peptide component of scorpion venom that selectively binds to glioma cells of all malignancy grades while sparing normal brain cells and non-malignant tissues.1 2 With this understanding, we developed chimeric antigen receptor (CAR) T cells incorporating the CLTX peptide as a tumor-recognizing ligand, thereby redirecting T cells to target GBM cells and tumors.3 Preclinical studies suggested broad yet specific CLTX binding to patient-derived GBM cells. Preclinical data also suggested a role for cell surface matrix metalloproteinase-2 (MMP-2) in CLTX-CAR T cell activation.MethodsWe designed a non-randomized and dose escalating phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells to patients with recurrent/progressing GBM (NCT04214392; approved by the City of Hope National Medical Center protocol review committee, written consent obtained for leukapheresis and treatment), with the primary objectives of feasibility and safety.ResultsHere we report clinical outcomes and correlative observations for four lead-in research participants, all of whom had a histopathological diagnosis of glioblastoma, idh wild type, grade 4, and who had received prior temozolomide as well as radiation and other treatments. The key enrollment criterion was MMP-2 expression in tissue biopsies at levels greater than 20% (moderate and/or high expression) as assessed by immunochemistry. Participants received three infusions of 4, 20, and 20 x 10^6 CLTX-CAR T cells at weekly intervals. There were no CRS events or DLTs observed. Three of the four participants (75%) achieved stable disease. Participants survived a median of 5.75 months (min = 2.4, max = 20.5) after CAR T cell infusion. The presence of CLTX-CAR T cells in tumor fluid collected before and one day after each infusion indicated persistence of CLTX-CAR T cells. IgG1 was absent in these samples, suggesting non-immunogenicity of CLTX-CAR T cells despite the presence of the exogenous CLTX peptide.ConclusionsPhase 1 clinical observations to date confirm the feasibility and safety of CLTX-CAR T cell immunotherapy for patients with GBM. These studies will lead to determination of a maximum tolerated dose/maximum feasible dose.ReferencesLyons SA, O’Neal J, Sontheimer H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia. 2022;39:162–173.Veiseh M, Gabikian P, Bahrami SB, Veiseh O, Zhang M, Hackman RC, Ravanpay AC, Stroud MR, Kusuma Y, Hansen SJ, Kwok D, Munoz NM, Sze RW, Grady WM, Greenberg NM, Ellenbogen RG, Olson JM. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci, Cancer Res. 2007;67:6882–6888.Wang D, Starr R, Chang WC, Aguilar B, Alizadeh D, Wright SL, Yang X, Brito A, Sarkissian A, Ostberg JR, Li L, Shi Y, Gutova M, Aboody K, Badie B, Forman SJ, Barish ME, Brown CE. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. 2020;12.Ethics ApprovalWe designed a non-randomized and dose escalating phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells to patients with recurrent/progressing GBM (NCT04214392; approved by the City of Hope National Medical Center protocol review committee, written consent obtained for leukapheresis and treatment), with the primary objectives of feasibility and safety.
Combined intracavitary and intraventricular administration of chimeric antigen receptor T cells targeting the interleukin-13 receptor produced a decrease in symptoms and tumor regression in a patient ...with refractory glioblastoma.
Glioblastoma, an aggressive primary brain tumor, is among the most lethal of human cancers. We present evidence of the potential therapeutic benefit of adoptive T-cell therapy against glioblastoma with the use of CAR-engineered T cells targeting IL13Rα2, a glioma-associated antigen linked to a reduced rate of survival.
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The clinical potential of CAR T-cell therapy has been most convincingly shown by the successful use of CD19-specific CAR T cells against refractory B-cell cancers.
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However, extension of the use of CAR therapy beyond hematologic cancers and the efficacy of this therapy against solid tumors remain to be established.
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,
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Our . . .
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 × 10
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 .
To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian ...cancer.
Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.
Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response.
there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced
recognition of p53 peptides was detectable after immunization in both the CD4
and CD8
T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.
p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4
and CD8
T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable.
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TPS2662
Background: Glioblastoma (GBM) is the most common and most aggressive primary brain tumor. Around 294,900 new cases are diagnosed globally with 241,000 deaths each year. The ...5-year survival is only 5%. Median overall survival from first recurrence is only 5-8 months. There is no established standard of care for recurrent GBM. City of Hope (COH) has developed and optimized a CAR T cell therapy utilizing the chlorotoxin peptide (CLTX) as the CAR’s tumor recognition domain against GBM. CLTX-CAR T cells specifically and broadly target GBM through recognition of a receptor complex including membrane-bound matrix metalloprotease 2 (MMP-2). CLTX-CAR T cells do not exhibit off-tumor recognition of normal human or murine cells and tissues in preclinical models. In in vitro studies, COH evaluated patient-derived brain tumor (PBT) cell lines for CLTX binding and expression of IL13Rα2, HER2 and EGFR, three targets of CAR T cell trials for GBMs. Strong CLTX binding to tumor cells was observed in of the majority of primary GBM lines, independent of these other antigens. In preclinical studies using in vivo mouse models, a single intratumoral (ICT) injection of CLTX-CAR T cells (1×10
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CAR+ T cells) exhibited robust anti-tumor activity against ffLuc+ PBT106 tumors orthotopically-engrafted in NSG mice. Overall, when compared to mice treated with mock-transduced Tn/mem (no CAR) T cells, the CLTX(EQ)28ζ/CD19t+ T cells reduced tumor burden and significantly increased survival. Taken together, these preclinical findings support the potential safety and efficacy of CLTX-CAR T cells, and provide the rationale for clinical testing of this therapy. As cellular heterogeneity intrinsic to GBM likely contributes to resistance to therapy and limited response rates, CLTX-CAR T cells may provide greater tumor eradication in a higher proportion of patients with GBM. Methods: This study is a phase 1, single center, safety and maximum tolerated dose (MTD) finding study of CLTX-CAR T cells for subjects with MMP2+ recurrent or progressive GBM. A safety lead-in of 3−6 participants receiving CLTX-CAR T cells by ICT delivery will be completed first. Subsequently, subjects would receive cells administered through both ICT and intraventricular (ICV catheters) (i.e. dual delivery) in two dose schedules. Subjects will be evaluated for safety and tolerability, and may continue to receive treatment until disease progression. Time to progression, overall survival, and disease response by Response Assessment in Neuro-Oncology (RANO) criteria, will be evaluated and descriptively compared to historical data. The study is actively enrolling patients. Clinical trial information: NCT04214392.
Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of ...intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas. CD-NSCs were given every 2 weeks using an indwelling brain catheter, followed each time by a 7-d course of oral 5-FC (and leucovorin in the final patient cohort). Fifteen evaluable patients received a median of 4 (range 2-10) intracerebral CD-NSC doses; doses were escalated from 50 × 10
to 150 × 10
CD-NSCs. Neuropharmacokinetic data confirmed that CD-NSCs continuously produced 5-FU in the brain during the course of 5-FC. There were no clinical signs of immunogenicity, and only three patients developed anti-NSC antibodies. Our results suggest intracerebral administration of serial doses of CD-NSCs is safe and feasible and identified a recommended dose for phase II testing of 150 × 10
CD-NSCs.
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