Children with high-grade gliomas (pHGGs) represent a clinical population in substantial need of new therapeutic options given the inefficacy and toxicity of current standard-of-care modalities. ...Although immunotherapy has emerged as a promising modality, it has yet to elicit a significant survival benefit for pHGG patients. While preclinical studies address a variety of underlying challenges, translational clinical trial design and management also need to reflect the most updated progress and lessons from the field.
The authors will focus our discussion on the design of clinical trials, the management of potential toxicities, immune monitoring, and novel biomarkers. Clinical trial design should integrate appropriate patient populations, novel, and preclinically optimized trial design, and logical treatment combinations, particularly those which synergize with standard of care modalities. However, there are caveats due to the nature of immunotherapy trials, such as patient selection bias, evidenced by the frequent exclusion of patients on high-dose corticosteroids. Robust immune-modulating effects of modern immunotherapy can have toxicities. As such, it is important to understand and manage these, especially in pHGG patients.
Adequate integration of these considerations should allow us to effectively gain insights on biological activity, safety, and biomarkers associated with benefits for patients.
Abstract
BACKGROUND: The development of effective chimeric antigen receptor (CAR) T-cell therapies for malignant pediatric brain tumors remains a challenge due to multiple barriers, including ...antigenic heterogeneity, on-target off-tumor toxicities, and T cell exhaustion. We have adopted a novel synthetic Notch “synNotch” receptor system and developed innovative T-cell circuits that recognize tumor cells based on the “prime-and-kill” strategy.
METHODS: We created a novel synNotch-CAR circuit in which the brain/glioma-specific antigen Brevican (BCAN) primes the T cells to induce expression of a CAR that recognizes interleukin-13 receptor α2 (IL-13Rα2) and ephrin type A receptor (EphA2), thereby eradicating glioma cells expressing either antigen. Immunocompromised mice bearing the SF8628 DIPG cell line in the frontal lobe or brain stem received a single intravenous (IV) infusion of synNotch CAR T-cells (2.5 x 106 each of CD4+ and CD8+ T cells) on day 6 following the tumor inoculation. Mice were monitored for toxicity and tumor growth.
RESULTS: Following this synNotch CAR T-cell dose, although tumors in the brainstem did not regress, 3 of the 5 mice with frontal lobe tumors demonstrated complete and sustained remission. Our histological analyses revealed primed CAR T-cells both within and surrounding the tumor in both settings. By flow cytometry, we confirmed the CAR T-cells in the CNS were primed and mostly did not express an exhaustive phenotype. In the spleen, we also found the CAR T-cells in a more naïve and central memory state.
CONCLUSIONS: Our work so far has demonstrated that synNotch-CAR T-cells are able to traffic to the tumor microenvironment even in the brainstem, are primed to express the CAR, and most do not express an exhaustive phenotype. Future work will include CAR T-cell dose optimization, continued assessments of the tumor microenvironment, and investigating for antigen escape.
Abstract
Background
Levofloxacin prophylaxis in pediatric oncology patients with chemotherapy-induced severe prolonged neutropenia has been shown to reduce risk for febrile neutropenia and systemic ...infections. With increased use of prophylaxis there is concern for development of antibiotic-resistant infections. We analyzed bloodstream infections (BSI) in pediatric oncology patients exposed to levofloxacin prophylaxis during prolonged severe neutropenic episodes to determine the rate of antibiotic resistance
Methods
We performed a retrospective chart review of pediatric oncology patients who received levofloxacin prophylaxis between January 2015 – December 2019. Patients were placed on levofloxacin prophylaxis based on institutional guidelines for patients at risk for severe prolonged neutropenia (i.e., absolute neutrophil count ANC < 500 cells/µL for >7 days). Demographic information, start and end dates for levofloxacin prophylaxis, and all BSI episodes within 2 months after exposure to the fluoroquinolone were collected
Results
Thirty-five patients were identified who received levofloxacin prophylaxis. There were 32 BSI in 12 patients. Twenty-five BSI involved gram-positive organisms (GP), including nine (36%) due to coagulase negative Staphylococcus and seven (28%) due to viridans Streptococcus. Seven BSI episodes involved gram-negative (GN) organisms with 4 (57%) from E.coli. Resistance to fluroquinolones was noted in 42% and 48% of BSI from GN and GP organisms respectively. The vast majority (85%) of viridans Streptococcus isolates were resistant to levofloxacin. In contrast, 8% of viridans Streptococcus isolates were resistant to fluoroquinolones from the same time frame per our hospital antibiogram.
Conclusion
In this recent cohort of pediatric oncology patients with BSI after exposure to levofloxacin prophylaxis, there was a high percentage infected with fluoroquinolone-resistant organisms.This contrasts with some of the earlier published data from adults which reported low rate of fluoroquinolone resistance. This case series highlights the need for close monitoring for development of antibiotic resistance as utilization of prophylactic levofloxacin increases in pediatric oncology patients.
Disclosures
All Authors: No reported disclosures
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