Pediatric high‐grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.
Purpose: The COVID-19 pandemic has forced healthcare stakeholders towards challenging decisions. We analyse the impact of the pandemic on the conduct of phase I-II trials for paediatric cancer during the first month of state of alarm in Spain.Methods: A questionnaire was sent to all five ITCC-accredited Spanish Paediatric Oncology Early-Phase Clinical Trial Units, including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects.Results: All units suffered personnel shortages and difficulties in enrolling patients, treatment continuity or performing trial assessments. Monitoring activity was frequently postponed (73%), and 49% of on-going trials interrupted recruitment. Only two patients could be recruited during this period (75% reduction in the expected rate).Conclusions: The COVID-19 crisis has significantly impacted clinical research practice and access to innovation for children with cancer. Structural and functional changes are under way to better cope with the expected future restrictions.
Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. Figure 1 Figure 1. Disclosures Soria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.
Backgrond: Donor selection is a critical step for the success of hematopoietic stem cell transplantation (HSCT). Donor/recipient sex-mismatch, donor age, and donor parity have been found to play an important role in the adult setting, and minor histocompatibility antigens (mHCA) encoded by the Y-chromosome presumed to be in the causal pathway. The pediatric sibling HSCT setting offers a special opportunity to evaluate donors and to see whether the observed importance of donor sex and age holds true when the donors are young and presumably immunologically naïve to Y-chromosome mHCAs. We hypothesized that if the presence of acquired T and B cells sensitized to H-Y antigens are in fact a major contributing factor to differences in outcomes between sex-matched and sex -mismatched transplants, there should be no such difference when a non-exposed (non-alloimmunized) female donor is involved. Methods: Retrospective review of pediatric patients receiving myeloablative sibling-donor HSCT from 1996 to 2012 in our institution. Donor sex, donor age, and sex-match were included among clinical predictors. Outcomes included acute and chronic graft versus host disease (aGVHD and cGVHD, respectively). Univariate and multivariate analyses were performed. Results: Of 244 patients included in this study, 50% were ≤10 years, 61% had a donor ≤12 years of age, 53% had a sex-matched donor, 46% had a female donor, 64% had an oncologic diagnosis, 62% were transplanted between 2005 and 2012, 96% were fully HLA-matched, 96% received bone marrow stem cells, and 91% received cyclosporine and methotrexate for GVHD prophylaxis. Forty-one (17%) patients developed acute GVHD, 31 (14%) of 229 patients alive past 100 days developed chronic GVHD, and 141 (73%) patients were alive at 5 years. No cGVHD was observed among 109 patients <10 years of age who received a 5/5 HLA-matched HSCT using bone marrow as the cell source; regardless of donor age or sex. However, 24 of 113 (21%) of patients ≥10 years of age developed cGVHD despite receiving 5/5 HLA-matched HSCT using bone marrow cells. Multivariate analysis showed older patient age, earlier transplant date and conditioning with cyclophosphamide and total body irradiation as significant predictors of acute GVHD. For cGVHD, older patient age and female donor increased risk of cGVHD while HLA-full match and use of bone marrow as stem cell source decreased risk of cGVHD. Effect modification occurred between donor age and donor sex (p=0.0473). The effect of female donor sex on cGVHD noted in the model adjusted for patient age, HLA-match, and cell source (OR 4.5; 95%CI 1.8-11.6), turned not significant if the donor was <12 years old (OR 2.6; 95%CI 0.7-10.2) and increased in magnitude and significance if the donor was ≥12 years old (OR 13.6; 95%CI 2.8-39.6). Conclusions: Patient age is a significant predictor of acute and chronic GVHD. However, our results suggest that in the pediatric population, younger donors (<12 years old) can be chosen to be good candidates for their siblings, independent of sex. Table I. Multivariate analysis and stratification of cGVHD results by donor age Odds Ratio (CI) Waldp-value Max-Rescaled R-Square aGVHD Patient age 1.1 (1.04, 1.2) 0.0018 0.26 Year of SCT 0.8 (0.7, 0.9) <0.0001 Cy-TBI Conditioning 3.2 (1.4, 7.3) 0.0059 cGVHD Patient age 1.2 (1.1, 1.3) <0.0001 0.27 Female donor 4.5 (1.8, 11.6) 0.0017 HLA-full match 0.2 (0.04, 0.93) 0.0405 BM stem cells source 0.2 (0.03, 0.91) 0.0385 cGVHD for Donor <12y/o Patient age 1.3 (1.1, 1.5) 0.0005 0.32 Female donor 2.6 (0.7, 10.2) 0.1737 HLA-full match 0.13 (0.02, 1.2) 0.0698 BM stem cells source 0.3 (0.04, 2.2) 0.2250 cGVHD for Donor ≥12y/o Patient age 1.3 (1.06, 1.4) 0.0066 0.33 Female donor 13.6 (2.8, 39.6) 0.0011 HLA-full match 0.8 (0.03, 28.7) 0.9237 BM stem cells source 0.03 (<0.001, 2.7) 0.1308 Disclosures No relevant conflicts of interest to declare.
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