Choosing T-cell sources determines CAR-T cell activity in neuroblastoma.

Introduction: The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2. Methods: We compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 versus IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines. Results: The IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h. Conclusion: CB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

Resilience and family quality of life in parents of children with autism spectrum disorders.

INTRODUCTION: Resilience and quality of life (QOL) can involve a positive approach in group interventions for parents of children with autism spectrum disorders (ASD). This study aims to evaluate resilience and family QOL at the start of a psychoeducational group. METHODS: Cross-sectional assessment of resilience and family QOL used the Family Quality of Life Scale (ECVF) and 14-item Resilience Scale (RS-14). RESULTS: The study group showed high levels of resilience. Parents considered the resources/support domain crucial, although satisfaction in this area was comparatively lower. Concerns about low satisfaction with available resources and support were notable. Gender differences were observed but not statistically significant. DISCUSSION: The study's findings support prior research on parental resilience in families of children with ASD. The literature on the QOL for these families presents mixed findings. The importance of parental involvement in service planning is highlighted. CONCLUSIONS: This study emphasizes the importance of resilience in parents of children with ASD, suggesting it as a potential therapeutic target. The findings underscore the need to address the perceived low quality of available resources and support. Further investigation is needed.

Urachal Pathology: Review of Cases.

INTRODUCTION: The urachus is an embryologic remnant which is formed from the obliteration of the allantois. Urachal abnormalities are caused when defective obliteration of the urachus happens. They are an infrequent condition. Incidence is estimated to be between 5,000 and 8,000 live births. Its diagnosis and management remain a challenge due to the lack of an specific clinical picture and the controversy about the management. OBJECTIVE: The objective of this study is to assess the clinical presentation, diagnosis, therapeutic management, and outcomes of urachal anomalies in our health area. MATERIALS AND METHODS: We performed a retrospective review of all cases of urachal anomalies recorded Tenerife (southern health area), La Gomera, and El Hierro Islands during a 5 year period. RESULTS: Twenty-three cases of urachal pathology were included. The mean age of presentation was 32 years old. 73.9% were male. 65% were diagnosed in adults. In 30.3% of the cases, it was a casual finding. Symptoms included fever, umbilical exudate, hematuria, abdominal pain, and umbilical granuloma. The main diagnostic tests were ultrasound and computed tomography scan. Treatments were selected conservative management (43.5%), selective resection, partial cystectomy, and radical cystectomy. All patients had a good evolution. However, 2 cases where benign tumors were suspected, clinically, had a final histology of cancer in the specimen. CONCLUSIONS: Due to the lack of a specific clinical picture and undefined findings in image tools, diagnosis is difficult and it may be inaccurate. Despite more data are needed, our results suggest that the systematic excision of urachal lesions could result in safer outcomes since cases where a benign lesion is clinically suspected might result in malignant tumors.

Systemic oncolytic adenovirus delivered in mesenchymal carrier cells modulate tumor infiltrating immune cells and tumor microenvironment in mice with neuroblastoma.

Celyvir (autologous mesenchymal cells -MSCs- that carry an oncolytic adenovirus) is a new therapeutic strategy for metastatic tumors developed by our research group over the last decade. There are limitations for studying the immune effects of human oncolytic adenoviruses in murine models since these viruses do not replicate naturally in these animals. The use of xenografts in immunodeficient mice prevent assessing important clinical aspects of this therapy such as the antiadenoviral immune response or the possible intratumoral immune changes, both of tumor infiltrating leukocytes and of the microenvironment. In our strategy, the presence of MSCs in the medicinal product adds an extra level of complexity. We present here a murine model that overcomes many of these limitations. We found that carrier cells outcompeted intravenous administration of naked particles in delivering the oncolytic virus into the tumor masses. The protection that MSCs could provide to the oncolytic adenovirus did not preclude the development of an antiadenoviral immune response. However, the presence of circulating antiadenoviral antibodies did not prevent changes detected at the tumor masses: increased infiltration and changes in the quality of immune cells per unit of tumor volume, and a less protumoral and more inflammatory profile of the tumor microenvironment. We believe that the model described here will enable the study of crucial events related to the immune responses affecting both the medicinal product and the tumor.

Parasitic Hematuria: Six Cases in a Row in a Single Centre in Spain.

Most cases of urogenital parasitosis are registered in Africa. However, migration movements and travellers moving from developed to developing countries are responsible for leading to an increased incidence of genitourinary infections caused by parasites in the western world including Spain having serious economic and health implications. The importance of its early detection and treatment also results from its potential risk for infertility, susceptibility for HIV infection and the development of bladder cancer. The most common presentation symptom is terminal haematuria, and when diagnosed, praziquantel is the treatment of choice. We report a series of 6 cases of urinary schistosomiasis that happened in a single centre in Spain and reminds the importance of having the infection in mind in certain cases of haematuria study.