Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the ...appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.
We generated MHC-independent chimeric antigen receptors (CARs) directed to the GD2 antigen expressed by neuroblastoma tumor cells and treated patients with this disease. Two distinguishable forms of ...this CAR were expressed in EBV-specific cytotoxic T lymphocytes (EBV-CTLs) and activated T cells (ATCs). We have previously shown that EBV-CTLs expressing GD2-CARs (CAR-CTLs) circulated at higher levels than GD2-CAR ATCs (CAR-ATCs) early after infusion, but by 6 weeks, both subsets became low or undetectable. We now report the long-term clinical and immunologic consequences of infusions in 19 patients with high-risk neuroblastoma: 8 in remission at infusion and 11 with active disease. Three of 11 patients with active disease achieved complete remission, and persistence of either CAR-ATCs or CAR-CTLs beyond 6 weeks was associated with superior clinical outcome. We observed persistence for up to 192 weeks for CAR-ATCs and 96 weeks for CAR-CTLs, and duration of persistence was highly concordant with the percentage of CD4+ cells and central memory cells (CD45RO+CD62L+) in the infused product. In conclusion, GD2-CAR T cells can induce complete tumor responses in patients with active neuroblastoma; these CAR T cells may have extended, low-level persistence in patients, and such persistence was associated with longer survival. This study is registered at www.clinialtrials.gov as #NCT00085930.
Genomic sequencing (GS) is increasingly used for diagnostic evaluation, yet follow-up care is not well understood. We assessed clinicians' recommendations after GS, parent-reported follow-up, and ...actions parents initiated in response to learning their child's GS results.
We surveyed parents of children who received GS through the Clinical Sequencing Evidence Generating Research consortium ∼5 to 7 months after return of results. We compared the proportion of parents who reported discussing their child's result with a clinician, clinicians' recommendations, and parents' follow-up actions by GS result type using χ2 tests.
A total of 1188 respondents completed survey measures on recommended medical actions (n = 1187) and/or parent-initiated actions (n = 913). Most parents who completed recommended medical actions questions (n = 833, 70.3%) reported having discussed their child's GS results with clinicians. Clinicians made recommendations to change current care for patients with positive GS results (n = 79, 39.1%) more frequently than for those with inconclusive (n = 31, 12.4%) or negative results (n = 44, 11.9%; P < .001). Many parents discussed (n = 152 completed, n = 135 planned) implications of GS results for future pregnancies with a clinician. Aside from clinical recommendations, 13.0% (n = 119) of parents initiated changes to their child's health or lifestyle.
In diverse pediatric clinical contexts, GS results can lead to recommendations for follow-up care, but they likely do not prompt large increases in the quantity of care received.
Availability of clinical genomic sequencing (CGS) has generated questions about the value of genome and exome sequencing as a diagnostic tool. Analysis of reported CGS application can inform uptake ...and direct further research. This scoping literature review aims to synthesize evidence on the clinical and economic impact of CGS.
PubMed, Embase, and Cochrane were searched for peer-reviewed articles published between 2009 and 2017 on diagnostic CGS for infant and pediatric patients. Articles were classified according to sample size and whether economic evaluation was a primary research objective. Data on patient characteristics, clinical setting, and outcomes were extracted and narratively synthesized.
Of 171 included articles, 131 were case reports, 40 were aggregate analyses, and 4 had a primary economic evaluation aim. Diagnostic yield was the only consistently reported outcome. Median diagnostic yield in aggregate analyses was 33.2% but varied by broad clinical categories and test type.
Reported CGS use has rapidly increased and spans diverse clinical settings and patient phenotypes. Economic evaluations support the cost-saving potential of diagnostic CGS. Multidisciplinary implementation research, including more robust outcome measurement and economic evaluation, is needed to demonstrate clinical utility and cost-effectiveness of CGS.
Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare, costly condition linked to human papillomavirus. Standard of care is serial surgical debridement. Many adjunctive therapies have ...been trialed, with recent success with systemic bevacizumab. This paper examines healthcare spending associated with systemic bevacizumab use for JoRRP and compares it to healthcare spending for surgical care alone to determine whether bevacizumab has a financial benefit.
Five patients treated with systemic bevacizumab for JoRRP were identified at a single institution. Spending data was derived from the electronic medical record. Sensitivity analysis was performed using variation in spending and frequency of treatments.
Patients had an average of 4.2 treatments per year prior to bevacizumab (95% confidence interval CI 1.4–7.0) and 1.1 after (0.2–2.0). Patients underwent an average of 9.2 bevacizumab treatments in their first year after initiation, 4.0 in the second, and 4.5 in their third. Mean payment per debridement was $3198 ($2856–3539), with mean total surgical payment per year of $17,966 ($11,673–24,259) prior to initiating bevacizumab. Mean payment on a single bevacizumab infusion visit was $6508 ($6063–6952). Mean total surgical and bevacizumab spending per year after bevacizumab initiation were $83,951 ($12,938–154,964).
Accounting for variations in the number of treatments per year with bevacizumab after initiation, healthcare spending after bevacizumab initiation is similar to spending on surgery alone for JoRRP in patients with severe disease.
4.
Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of ...interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells. An analysis of the expression of IL-6 and its receptor, IL-6R, in 11 neuroblastoma cell lines indicated the expression of IL-6 in 4 cell lines and of IL-6R in 9 cell lines. Treatment of IL-6R-positive cells with recombinant human IL-6 resulted in signal transducer and activator of transcription-3 and extracellular signal-regulated kinase-1/2 activation. Culturing IL-6R-positive neuroblastoma cells in the presence of BMSC or recombinant human IL-6 increased proliferation and protected tumor cells from etoposide-induced apoptosis, whereas it had no effect on IL-6R-negative tumor cells. In vivo, neuroblastoma tumors grew faster in the presence of a paracrine source of IL-6. IL-6 induced the expression of cyclooxygenase-2 in neuroblastoma cells with concomitant release of prostaglandin-E2, which increased the expression of IL-6 by BMSC. Supporting a role for stromal-derived IL-6 in patients with neuroblastoma bone metastasis, we observed elevated levels of IL-6 in the serum and bone marrow of 16 patients with neuroblastoma bone metastasis and in BMSC derived from these patients. Altogether, the data indicate that stromal-derived IL-6 contributes to the formation of a bone marrow microenvironment favorable to the progression of metastatic neuroblastoma.
Background
The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone ...or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective.
Methods
A decision‐analytic model was used to estimate the incremental cost‐effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol‐required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life‐years (LY) were estimated from life‐expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs.
Results
Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191‐$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices.
Conclusions
Neither arm was clearly more cost‐effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug‐pricing policy decisions.
Lay Summary
Two chemotherapy regimens recently tested side‐by‐side for rhabdomyosarcoma had similar tumor outcomes, but different side effects.
The health care costs of each regimen were compared; neither was clearly more cost‐effective.
However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment.
Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.
Vincristine, dactinomyin, and cyclosphosphamide alone, as well as alternating with vincristine plus irinotecan were not clearly more cost‐effective for intermediate‐risk rhadomyosarcoma. Pharmaceutical pricing and location of treatment drove costs and may influence future treatment decisions.
Children with neuroblastoma rarely present with metastatic disease without identifiable primary tumors. We describe the clinical and histopathologic characteristics of 4 patients aged 1, 7, 7, and 11 ...years with neuroblastoma involving bone or bone marrow without an apparent primary site. One patient presented with a periorbital bone lesion, 1 presented with a distal femoral lesion, and 2 presented with diffuse bone marrow involvement. All tumors were negative for MYCN amplification. All patients were alive without evidence of disease 5 years after completion of multimodality therapy. Patients with neuroblastoma of the bone and bone marrow without an apparent primary site may constitute a unique group characterized by older age at diagnosis, nonamplified MYCN tumors, and good response to treatment.
Information obtained from clinical exome sequencing (ES) may impact clinical care or other aspects of a patient's life. Little is known about clinicians' perceptions regarding either the value of ES ...results or which among various outcomes are most relevant to determine value. This study aims to assess clinicians' opinions of the importance of ES results for medical decision making and identify a set of outcomes to be measured in future ES evaluations.
Expert opinion regarding the value of remarkable (diagnostic/positive) and unremarkable (nondiagnostic/negative) ES results was elicited via the Delphi method, consisting of two survey rounds and a teleconference. Participants had expertise in caring for clinically diverse infants and children with suspected underlying genetic etiologies. Descriptive statistics and (dis)agreement were calculated for each survey item.
Remarkable ES results were considered important for 17 outcome domains. Unremarkable ES results were also perceived as important in terms of psychological impact and ability to inform follow-up diagnostic test decisions.
Clinicians regard remarkable ES results as more important in many ways than findings from other diagnostic modalities. Unremarkable ES results were not considered unimportant for decision making, but rather uncertain in most outcome domains.
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