Genotype-Phenotype Correlations in Chronic Granulomatous Disease: Insights From a Large National Cohort.

Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic Granulomatous Disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the NADPH oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyper-inflammatory manifestations. We report a multi-center cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2,918 patients suffering from frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD, 56 of Jewish ancestry, 48 of Arabic ancestry and 6 non-Jewish/non-Arabic. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyper-inflammatory manifestations are described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39/110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multi-professional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management and prevention.

Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

SLP76 Mutation Associated with Combined Immunodeficiency and EBV-Related Lymphoma.

Increased susceptibility to develop severe forms of Epstein-Barr virus (EBV) infection in early age is a significant hallmark of an underlying primary immunodeficiency (PID). Here, we present immunologic and genetic evaluations of a 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and proliferation. A diagnosis of diffuse large B cell lymphoma was made and the immunological workup was suggestive of T cell immunodeficiency. Unfortunately, the patient succumbed to EBV-related lymphoma. Whole-exome sequencing revealed a novel homozygous mutation, c.991del.C; p. Q331Sfs*6 in the SLP76 gene. The SLP76 protein, a TCR signaling molecule, was recently linked to a human disease of the immune system. In order to examine the effect of this new SLP76 mutation on T cell signaling, a SLP76-deficient Jurkat-derived T cell line was transduced either with wild-type (WT), or with the specific SLP76 mutant, or with a mock vector. Downstream TCR signaling events, including ERK1/2 phosphorylation, CD69 expression, and Ca2 + mobilization, were reduced in cells harboring the reported mutation, linking this novel mutation to the expected immunological outcome. SLP76 deficiency should be added to the growing list of monogenetic diseases that predispose affected individuals to acquire severe and uncontrolled EBV infections and to develop substantial complications. This case further links mutations in the SLP76 gene to a significant human immunodeficiency and extends its clinical phenotype.

Combined Immunodeficiency Caused by a Novel Nonsense Mutation in LCK.

Mutations affecting T-cell receptor (TCR) signaling typically cause combined immunodeficiency (CID) due to varying degrees of disturbed T-cell homeostasis and differentiation. Here, we describe two cousins with CID due to a novel nonsense mutation in LCK and investigate the effect of this novel nonsense mutation on TCR signaling, T-cell function, and differentiation. Patients underwent clinical, genetic, and immunological investigations. The effect was addressed in primary cells and LCK-deficient T-cell lines after expression of mutated LCK. RESULTS: Both patients primarily presented with infections in early infancy. The LCK mutation led to reduced expression of a truncated LCK protein lacking a substantial part of the kinase domain and two critical regulatory tyrosine residues. T cells were oligoclonal, and especially naïve CD4 and CD8 T-cell counts were reduced, but regulatory and memory including circulating follicular helper T cells were less severely affected. A diagnostic hallmark of this immunodeficiency is the reduced surface expression of CD4. Despite severely impaired TCR signaling mTOR activation was partially preserved in patients' T cells. LCK-deficient T-cell lines reconstituted with mutant LCK corroborated partially preserved signaling. Despite detectable differentiation of memory and effector T cells, their function was severely disturbed. NK cell cytotoxicity was unaffected. Residual TCR signaling in LCK deficiency allows for reduced, but detectable T-cell differentiation, while T-cell function is severely disturbed. Our findings expand the previous report on one single patient on the central role of LCK in human T-cell development and function.

Clinically Complex LRBA Deficiency Due to a Founder Allele in the Georgian Jewish Population.

Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin's disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.

Development and manufacture of novel locally produced anti-BCMA CAR T cells for the treatment of relapsed/refractory multiple myeloma: results from a phase I clinical trial.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti- BCMA CAR T-cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1: 150x106 CAR T cells, n=6; cohort 2: 450x106 CAR T cells, n=7; cohort 3: 800x106 CAR T cells, n=7) in 20 heavily pre-treated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS nor neurotoxicity of any grade were observed. No dose-limiting toxicities were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR), and very good partial response rates were 75%, 50%, and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR, and 57% minimal residual disease negativity in the high-dose cohort 3. Across all cohorts, the median overall survival (OS) was 308 days (range 25-466+), with an estimated OS of 55% as of June 27th (data cut-off). The median progression-free survival was 160 days, with 6 subjects remaining progression free at the time of data cut-off. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These encouraging data support the decentralization of CAR T production in an academic setting, ensuring sufficient CAR T supply to satisfy the increasing local demand. Clinicaltrials.gov NCT04720313.

Response rates of extra-nodal diffuse large B cell lymphoma to anti-CD19-CAR T cells: A real word retrospective multicenter study.

Chimeric antigen receptor T-cells (CAR-T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR-T cell therapy in patients with extra-nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR-T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)-only and 12 of 126 (10%) showed no disease assessed by PET-CT. There were no significant differences in CAR-T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8-13.6] vs. 14.1 [95% CI: 10-18.1] months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5-18.2] vs. 18.4 [95% CI 14.8-22.1] months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9-15.5] vs. 4.28 months [95% CI 0.6-7.9], p = .010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4-19.6] vs. 8.7 months [95% CI 4.6-12.8], p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.

Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48-16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure (BMF); none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p = .002 for acute and p = .004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n = 20) to other donors (n = 21), including survival rates (p = .1), time to engraftment (p = .69 and p = .14 for neutrophil and platelet engraftment time, respectively), chimerism status (p = .36 and p = .83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p = 1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identifies factors that may significantly affect transplant outcomes such as graft source and chimerism status.

High rate of adenovirus detection in gastrointestinal biopsies of symptomatic stem cell transplant recipients.

OBJECTIVES: The gastrointestinal (GI) tract is a major human adenovirus (HAdV) replication site in patients undergoing hematopoietic stem cell transplantation (HSCT), yet the prevalence and correlates of HAdV GI infection in this setting have remained poorly recognized, especially among adult HSCT recipients. DESIGN OR METHODS: We retrospectively studied the prevalence and risk factors of HAdV GI-tissue infection in HSCT recipients (73 adults and 15 children) with GI symptoms who underwent GI-tissue biopsy between January-2012 and December-2017. The presence of HAdV in the GI tissues was determined by real-time PCR. RESULTS: HAdV GI-tissue infection was detected in 21 (23.9%) patients, with similar infection rates identified in adults and children. GI-tissue detection was more common at late (>100 days) compared to early times post-transplantation (50% vs. 12.9%, p < .001). The presence of bloody diarrhea, Arab ethnicity (p = .014) and concurrent cytomegalovirus GI-tissue detection (p = .025) were significantly correlated with HAdV GI-tissue infection, while chronic graft versus host disease was of borderline association (p = .055). CONCLUSIONS: Our findings reveal a high rate and new clinical-demographic correlates of HAdV GI-tissue infection in adult and pediatric HSCT recipients with GI symptoms. The findings highlight the need for future prospective studies to assess the relatedness of HAdV infection to the GI symptoms, and the prevalence, impact, and treatment of HAdV GI infection in HSCT recipients.

Vedolizumab for pediatric patients with gastrointestinal acute graft-versus-host-disease.

Vedolizumab, an anti-α4ß7 integrin monoclonal antibody, impairs homing of T-cells to the gastrointestinal (GI) endothelium and acts as a gut-selective anti-inflammatory agent. Recent reports of the efficacy of vedolizumab in treating lower GI acute graft-versus-host disease (aGVHD) are promising, but experience in children is scarce. We present a cohort of 13 pediatric patients who were treated with vedolizumab for GI aGVHD. Ten of the patients were treated for steroid-refractory disease, out of which, six suffered from severe (stage 3 or 4) GI disease before the first dose of vedolizumab. In the other three patients, vedolizumab was introduced early in the disease course. Median time between GI GVHD onset to vedolizumab treatment was 23 days (range 7-59 days), with a median of 3 doses (range 1-5) per patient. GI GVHD staging was evaluated at various time points after the first vedolizumab dose, showing improvement in nine of the 13 patients. After a median follow-up time of 13 months (range 6-34 months), eight patients completely recovered, two had ongoing chronic colitis, and three patients died. During the vedolizumab treatment period, 38 infectious episodes were noted, most of them GI related. The unique activity profile of vedolizumab makes it an appealing treatment option for lower GI aGVHD, but caution for concurrent infections is warranted.

A mutation in POLR3E impairs antiviral immune response and RNA polymerase III.

RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Modulate Apoptosis, TNF Alpha and Interferon Gamma Response Gene mRNA Expression in T Lymphocytes.

Recent studies have highlighted the therapeutic potential of small extracellular bodies derived from mesenchymal stem cells (MSC-sEVs) for various diseases, notably through their ability to alter T-cell differentiation and function. The current study aimed to explore immunomodulatory pathway alterations within T cells through mRNA sequencing of activated T cells cocultured with bone marrow-derived MSC-sEVs. mRNA profiling of activated human T cells cocultured with MSC-sEVs or vehicle control was performed using the QIAGEN Illumina sequencing platform. Pathway networks and biological functions of the differentially expressed genes were analyzed using Ingenuity pathway analysis (IPA)® software, KEGG pathway, GSEA and STRING database. A total of 364 differentially expressed genes were identified in sEV-treated T cells. Canonical pathway analysis highlighted the RhoA signaling pathway. Cellular development, movement, growth and proliferation, cell-to-cell interaction and inflammatory response-related gene expression were altered. KEGG enrichment pathway analysis underscored the apoptosis pathway. GSEA identified enrichment in downregulated genes associated with TNF alpha and interferon gamma response, and upregulated genes related to apoptosis and migration of lymphocytes and T-cell differentiation gene sets. Our findings provide valuable insights into the mechanisms by which MSC-sEVs implement immunomodulatory effects on activated T cells. These findings may contribute to the development of MSC-sEV-based therapies.

[STEM CELL TRANSPLANTATIONS FOR PATIENTS WITH FANCONI ANEMIA: AN ISRAELI TERTIARY CENTER EXPERIENCE].

INTRODUCTION: Fanconi anemia (FA) is a rare genetic syndrome characterized by increased chromosomal breakage, congenital anomalies, bone marrow failure and an increased tendency to develop malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure and the hematologic malignancies these patients develop. Given the sensitivity of FA patients to chemotherapy and radiation, as to the clinical symptoms of graft versus host disease (GvHD), HSCT in these patients is challenging. Since the mid-nineties, HSCT for FA patients is performed in our center by using the fludarabine based reduced-intensity protocol. AIMS: To summarize the results of HSCT for patients with FA using a fludarabine based reduced-intensity conditioning regimen at the Hadassah Medical Center. METHODS: This retrospective research is based on the collection and analysis of clinical and laboratory data from the medical records of patients. RESULTS: Since June 1996 up till February 2020, 39 patients with FA underwent 43 HSCTs with a fludarabine based protocol at the Hadassah Medical Center. Four patients required a second transplant due to primary engraftment failure. Nine patients (23%) suffered from acute GvHD, four of them severe. Eight patients (20%) developed chronic GvHD, two with an extensive and debilitating disease. Thirty-three (85%) of the patients survived and six died, five shortly after the transplant, and one twenty years later from malignancy. CONCLUSIONS: Our results show high survival rates with low rates of engraftment failure and reasonable rates of GvHD. DISCUSSION: As of today, there is an effective and safe treatment for patients with FA who require HSCT by using a fludarabine-based reduced-intensity conditioning regimen, with high survival rates and few complications.

[SURVIVAL OF PEDIATRIC PATIENTS WITH NON-MALIGNANT DISEASES REQUIRING HOSPITALIZATION IN THE INTENSIVE CARE UNIT FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION AND RISK FACTORS FOR MORTALITY].

INTRODUCTION: Although Hematopoietic Stem Cell Transplantation (HSCT) is the only curative option for children with certain non-malignant disorders, a proportion of these children are admitted to the Pediatric Intensive Care Unit (PICU) due to treatment related life-threatening complications. AIMS: To analyze risk factors for ICU hospitalizations, morbidity and mortality in children with genetic diseases who have undergone HSCT and were admitted to intensive care units. METHODS: This retrospective study is based on the collection and analysis of clinical and laboratory data from the medical records of patients from the departments of Bone Marrow Transplantations and Intensive Care, from 2 hospitals, Hadassah and Rambam Medical Centers. RESULTS: Over the course of 15 years (2005-2019), 463 HSCT were performed for pediatric patients with non-malignant diseases, 68 of them (15%) required hospitalization in Intensive Care Units (ICU), 41% of the patients survived. The PICU mortality rate has decreased over the last years. Factors found to have a significant negative impact on PICU survival were severe neutropenia at admission to ICU, mechanical ventilation, inotropic support, and Multi Organ Failure (MOF). CONCLUSIONS: Our results showed low incidence of ICU admissions and relatively high survival rate for pediatric patients with non-malignant disorders post HSCT, comparing with literature data.

Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ≥18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma.

Chimeric antigen receptor (CAR) T-cell based immunotherapy has become a promising treatment mainly for hematological malignancies. Following the major success of CD19-targeted CAR, new potential targets for other malignancies are required. As such, B-cell maturation antigen (BCMA) is an attractive tumor-associated antigen to be targeted in multiple myeloma (MM). Herein, we aimed at assessing the function and optimal configuration of different BCMA-specific CAR, based on the same targeting moiety but with a different hinge and co-stimulatory domain. We compared their function to that of a previously characterized BCMA-CAR used in clinical trials. All constructs were expressed at high levels by primary human T cells and could trigger cytokine production and cytotoxicity upon co-culture with multiple myeloma targets. Nonetheless, critical differences were observed in off-target activation, exhaustion, and activation marker expression and in vivo antitumoral activity mediated by these different constructs. Interestingly, we noted that CD8-based hinge, combined with a 4-1BB intracellular domain, proved superior compared to IgG4-connecting regions, and/or a CD28-signaling moiety respectively. Overall, this study emphasizes the influence of CAR primary structure on its function and led to the identification of a highly efficient BCMA-specific CAR, namely H8BB, which displayed superior anti-tumoral activity both in vitro and long-term in vivo efficacy.

Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study.

Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

Social determinants of health and primary immunodeficiency.

OBJECTIVE: Inborn errors of immunity (IEI) are rare genetic conditions affecting the immune system. The rate of IEI and their presentation, course, and treatment are all affected by a multitude of social determinants, eventually affecting prognosis. This review summarizes the current knowledge of the social determinants affecting infectious susceptibility, genetic predisposition, diagnosis, and treatment of IEI. DATA SOURCES: PubMed. STUDY SELECTIONS: Search terms included "consanguinity," "social determinants," and "founder effect." Further studies were selected based on relevant citations. RESULTS: Changes in climate and human behavior have modulated the spread of disease vectors and infectious organisms. Consanguinity increases the rate of autosomal recessive conditions, changes the distribution, and affects the severity of IEI. Access to sophisticated genetic and immunologic diagnostic modalities affects genetic counseling and timely diagnosis. Effective genetic counseling should address to the patient's genetic background and ethical code. Access to appropriate and timely treatment of immunodeficiencies is scarce in some regions of the world. CONCLUSION: High consanguinity rate and reduced access to prophylactic measures increase the burden of immunodeficiencies in many low- and medium-income countries. Furthermore, poor access to diagnostic and treatment modalities in these regions adversely affects patients' prognosis. Increased awareness among health care professionals and the public and increased collaboration with Western countries aid in diagnosis of these conditions. Further advancements require improved public funding to the prevention, diagnosis, and treatment of IEI.

Survival of pediatric patients requiring admission in the intensive care unit post hematopoietic stem cell transplantation: Prognostic factors associated with mortality.

BACKGROUND: Although hematopoietic stem cell transplantation (HSCT) is the only curative option for some children with malignant and nonmalignant disorders, the procedure itself carries a high risk of complications. A proportion of children undergoing HSCT develop severe transplant-related complications requiring hospitalization in the pediatric intensive care unit (PICU). METHODS: A retrospective cohort study included 793 children with malignant and nonmalignant diseases that underwent 963 HSCTs in two large pediatric hospitals over 15 years. Ninety-one patients needed 105 (11%) PICU admissions. The objective of the study was to analyze the risk factors associated with morbidity and mortality in children post HSCT who were admitted to the PICU. RESULTS: Survival rate of a single PICU hospitalization was 43%. Long-term survival rate (classified as 1 year and 3 years) was 29.1% and 14.9% among PICU hospitalized patients compared with 74.6% and 53.3% among patients who had undergone HSCT and did not require PICU hospitalization. Factors found to have a significant negative association with PICU survival were respiratory failure as indication for PICU admission, neutropenia, graft-versus-host disease, mechanical ventilation, inotropic support, need for dialysis, and multiple-organ failure (MOF) with more than one systemic intensive intervention. The strongest prognostic factors associated with mortality were MOF (p < .001) and the need for inotropic support (p = .004). CONCLUSIONS: Neutropenia was found to be negatively associated with survival, suggesting non-engraftment and late engraftment are important risk factors for HSCT patients hospitalized in PICU. MOF and inotropic support were found to be the main negatively associated predictive factors with survival.