Pediatric liposarcoma: A case series and literature review.

Liposarcoma is arare soft tissue sarcoma in children. While prognosis, clinical behavior, and response to therapy among the various histologic subtypes are well described in adults, data in children are limited. Here, we describe our experience treating 14 children with liposarcoma at a large, academic pediatric center and review the available pediatric literature. This comprehensive report adds treatment, survival, and genomic data to pediatric liposarcoma literature.

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.

Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(-) disease. We report that CD19(-) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(-) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(-) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.

Incidence and predictors of treatment-related conjugated hyperbilirubinemia during early treatment phases for children with acute lymphoblastic leukemia.

Conjugated hyperbilirubinemia (CHB) and liver transaminase elevation are known complications of acute lymphoblastic leukemia (ALL) therapy, but host risk factors are poorly understood. Among 373 children diagnosed with ALL between 2011 and 2016, clinically significant CHB and transaminase elevation were observed in 15 (4.0%) and 12 (3.2%) children, respectively, during induction and consolidation. Body mass index ≥95th percentile (odds ratio 9.20, 95% confidence interval 2.56-32.96) was the only host factor independently associated with CHB, and no host factors were associated with transaminase elevation. Obese patients warrant closer monitoring of hepatic function to facilitate early intervention prior to the development of severe, adverse hepatic events.

Malignant melanoma incidence among children and adolescents in Texas and SEER 13, 1995-2013.

BACKGROUND: Epidemiological knowledge and predictors of melanoma among children and adolescents in multiethnic populations are limited. PROCEDURE: Using data from the Texas Cancer Registry (TCR) and the Surveillance, Epidemiology, and End Results (SEER) 13 database, we identified incident melanoma cases diagnosed at 0-20 years old during 1995-2013 in Texas and the United States, respectively. Using negative binomial regression, associations between demographic factors and melanoma incidence rates (IR) were evaluated by calculating incidence rate ratios (IRR) and 95% confidence intervals (CI). Annual percent change in IRs was assessed with joinpoint regression. RESULTS: Overall, the melanoma IR was 4.16 (TCR, n = 634) and 4.84 (SEER, n = 1260) per million. Females, adolescents, non-Hispanic (NH) whites, and Hispanics had higher IRs compared with other groups (P < 0.05). In adjusted analyses, Hispanics had a higher incidence of melanoma than NH non-whites (Texas IRR = 2.17; 95% CI, 1.30-3.61; SEER IRR = 2.88; 95% CI, 1.97-4.21). In Texas, NH whites with melanoma were more likely to live in low poverty areas, whereas the opposite trend was observed in Hispanics. Melanoma IRs increased throughout 1995-2004 followed by an average annual decrease of 7.6% (95% CI, -12.6%, -2.2%) in Texas and 6.0% (95% CI, -8.5%, -3.4%) in SEER during 2005-2013 (P < 0.05). However, these decreasing trends were not observed among Hispanics or those <10 years old. CONCLUSION: Although the overall melanoma IR in children and adolescents appears to be decreasing, this trend is not evident among Hispanics and young children, implicating the need for further research investigating the etiologies and risk factors in these groups.

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape.

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

Targeting the tumour profile using broad spectrum chimaeric antigen receptor T-cells.

A variety of distinct and redundant mechanisms support tumour propagation and survival. Tumour parenchyma consists of a variety of geographically diverse cells with varying genetic expression among subclonal populations. Additionally, the solid tumour microenvironment consists of a dense network of stromal, vascular and immune cells altered by a number of mechanisms not only to tolerate but often to enhance cancer growth. The limited spectrum of chimaeric antigen receptor (CAR) T-cell specificity in the face of this dynamic landscape is one of the greatest challenges facing CAR T-cell therapy for solid tumours. Thus targeting multiple cancer-specific markers simultaneously could result in improved efficacy by broadening the therapeutic reach to include multiple subclonal populations of the tumour parenchyma as well as elements of the tumour microenvironment. Over the last 10 years, we and others have developed multiplex platforms that target the tumour profile rather than single tumour-restricted antigens. These platforms introduce a new dimension that may be key to the successful development of T-cell therapies for solid tumours and to the mitigation of relapses due to antigen escape.