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Front Immunol. 2023 Oct 30;14:1251593. doi: 10.3389/fimmu.2023.1251593. eCollection 2023.

ABSTRACT

INTRODUCTION: Allogeneic stem cell transplantation is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population.

METHODS: We report the results of a randomized controlled multi centre phase I/IIa study (MULTIVIR-01) using a newly developed T cell product with specificity for CMV and EBV derived from the allogeneic stem cell grafts used for transplantation. The study aimed at prevention and preemptive treatment of both viruses in patients after allogeneic stem cell transplantation targeting first infusion on day +30. Primary endpoints were acute transfusion reaction and acute-graft versus-host-disease after infusion of activated T cells.

RESULTS: Thirty-three patients were screened and 9 patients were treated with a total of 25 doses of the T cell product. We show that central manufacturing can be achieved successfully under study conditions and the product can be applied without major side effects. Overall survival, transplant related mortality, cumulative incidence of graft versus host disease and number of severe adverse events were not different between treatment and control groups. Expansion of CMV/EBV specific T cells was observed in a fraction of patients, but overall there was no difference in virus reactivation.

DISCUSSION: Our study results indicate peptide stimulated epitope specific T cells derived from stem cell grafts can be administered safely for prevention and preemptive treatment of reactivation without evidence for induction of acute graft versus host disease.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT02227641.

PMID:37965339 | PMC:PMC10642256 | DOI:10.3389/fimmu.2023.1251593

Curr Opin Allergy Clin Immunol. 2023 Nov 15. doi: 10.1097/ACI.0000000000000955. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This review aims to summarize the current best knowledge on the efficacy of COVID-19 vaccination in vulnerable patients affected by primary antibody deficiencies (PADs), both in patients previously infected and vaccine-immunized, focusing also on the durability, on the need for multiple booster doses and on the safety of anti-SARS-CoV-2 vaccines.

RECENT FINDINGS: Patients vaccinated for SARS-CoV2 have variable humoral response, still showing a tendency towards an increase in antibody titers, with factors such as booster doses, previous infections, age and specific genetic mutations influencing the outcome. Long-lasting cellular responses to SARS-CoV-2 vaccination instead, mostly of the T-cell type, have been observed. Overall, the duration of protection given by vaccinations is sufficient and increased upon further simulations. Furthermore, the safety profile in PID patients is excellent, with most adverse events being transient and mild and no major adverse event reported.

SUMMARY: Several studies have emphasized the benefit of vaccinating patients with PADs against the SARS-CoV-2 virus and the necessity of administering booster doses. This review, by gathering the most recent and significant data from the scientific literature, could be helpful in clinical practice in the management of disease prevention in patients affected by primary immunodeficiency and also serve as inspiration for further in-depth clinical research.

PMID:37962877 | DOI:10.1097/ACI.0000000000000955

Med Clin North Am. 2024 Jan;108(1):189-200. doi: 10.1016/j.mcna.2023.05.019. Epub 2023 Jul 11.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a disorder of impaired immune regulation resulting in hyperinflammation that is ultimately fatal if not treated. HLH is categorized into familial disease, caused by genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, and secondary disease, triggered by infections, malignancies, rheumatologic disorders, or immune deficiency. Adolescent and young adults with HLH represent a unique population with specific diagnostic challenges. Here we review the diagnostic criteria, possible etiologies, pathophysiology, and management of HLH with focus on the adolescent population.

PMID:37951650 | DOI:10.1016/j.mcna.2023.05.019

Cells. 2023 Nov 6;12(21):2581. doi: 10.3390/cells12212581.

ABSTRACT

While chimeric antigen receptor (CAR) T cell therapy has shown promising outcomes among patients with hematologic malignancies, it has also been associated with undesirable side-effects such as cytokine release syndrome (CRS). CRS is triggered by CAR T-cell-based activation of monocytes, which are stimulated via the CD40L-CD40R axis or via uptake of GM-CSF to secrete proinflammatory cytokines. Mouse models have been used to model CRS, but working with them is labor-intensive and they are not amenable to screening approaches. To overcome this challenge, we established two simple cell-based CRS in vitro models that entail the co-culturing of leukemic B cells with CD19-targeting CAR T cells and primary monocytes from the same donor. Upon antigen encounter, CAR T cells upregulated CD40L and released GM-CSF which in turn stimulated the monocytes to secrete IL-6. To endorse these models, we demonstrated that neutralizing antibodies or genetic disruption of the CD40L and/or CSF2 loci in CAR T cells using CRISPR-Cas technology significantly reduced IL-6 secretion by bystander monocytes without affecting the cytolytic activity of the engineered lymphocytes in vitro. Overall, our cell-based models were able to recapitulate CRS in vitro, allowing us to validate mitigation strategies based on antibodies or genome editing.

PMID:37947658 | DOI:10.3390/cells12212581

Clin Infect Dis. 2023 Nov 8:ciad676. doi: 10.1093/cid/ciad676. Online ahead of print.

ABSTRACT

BACKGROUND: There is currently no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). The purpose of this study is to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs.‏.

METHODS: A pre-and post-intervention study was conducted during February 2017-June 2019 at Siriraj Hospital (Bangkok, Thailand).‏ Five patients were invited to receive once weekly BTZ (1.‏3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/day) for 4 months.‏ The primary outcomes were the difference in antibody level at 8 and 48 weeks compared to baseline, and the incidence of serious adverse events (AEs).‏ The secondary outcome was the occurrence of opportunistic infections (OIs) throughout 72 weeks after starting BTZ.‏.

RESULTS: The median patient age was 46 years (range: 34-53).‏ All patients had 3-5 OIs prior to enrollment.‏ All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment.‏ There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.‏73 ± 0.‏72) or 48 weeks (3.‏74 ± 0.‏53) compared to baseline (3.‏84 ± 0.‏49) (p = 0.‏336 and p = 0.‏555, respectively).‏ However, after serum dilution, the antibody titer non-significantly decreased during 8-16 weeks after BTZ initiation (p = 0.‏345).‏ Ten OIs were observed during 24-72 weeks after BTZ initiation, and Mycobacterium abscessus was the most prevalent pathogen.‏.

CONCLUSIONS: Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and ten OIs were observed during 24-72 weeks of BTZ.‏ No serious AEs were observed.‏ Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells.‏.

PMID:37947190 | DOI:10.1093/cid/ciad676

J Allergy Clin Immunol Pract. 2023 Nov;11(11):3559-3560.e9. doi: 10.1016/j.jaip.2023.08.026.

NO ABSTRACT

PMID:37945212 | DOI:10.1016/j.jaip.2023.08.026

Clin Immunol. 2023 Nov 7:109837. doi: 10.1016/j.clim.2023.109837. Online ahead of print.

ABSTRACT

Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient’s manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.

PMID:37944684 | DOI:10.1016/j.clim.2023.109837

J Infect. 2023 Nov 7:S0163-4453(23)00554-6. doi: 10.1016/j.jinf.2023.11.001. Online ahead of print.

NO ABSTRACT

PMID:37944565 | DOI:10.1016/j.jinf.2023.11.001

Sci Rep. 2023 Nov 8;13(1):19386. doi: 10.1038/s41598-023-46332-4.

ABSTRACT

Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A.Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of Atm-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).

PMID:37938627 | DOI:10.1038/s41598-023-46332-4

J Clin Pharmacol. 2023 Nov;63 Suppl 2:S110-S116. doi: 10.1002/jcph.2368.

ABSTRACT

The current dosing strategy of immune globulin products for the treatment of primary immunodeficiency diseases (PIDDs) in the USA is based on total body weight (BW). The aim of our study was to assess the relationship between dose and trough level, and to determine whether an alternative dosing strategy should be considered for patients who are overweight or obese. We analyzed data in a total of 533 patients from 11 studies. We modeled the relationship between trough level and dose per week using a linear mixed model. We used an over-dispersed Poisson model to model the relationship between infection and trough level. In these analyses, we then combined the study-specific treatment effects using a random-effect or fixed-effect model. The mean administered dose per week was 9.77, 14.00, or 18.17 g in patients who were normal weight, overweight, or obese, respectively. Compared with a patient of normal weight, a 1 g increase in dose per week in a patient who was overweight was associated with a smaller increase in the trough level, 0.08 g/L less (95%CI -0.14 to -0.03 g/L), and a 1 g increase in dose per week in a patient who was obese was associated with a much smaller increase in trough level, 0.01 g/L less (95% CI -0.07 to 0.06 g/L). Last, for a 1 unit (g/L) increase in trough level, the expected number of infections remained the same, with a multiplicative factor of 1.01 (95%CI 0.98-1.04). Overall, we found no compelling evidence to justify a reconsideration of the current dosing strategy based on total BW for patients with PIDDs who are overweight or obese.

PMID:37942903 | DOI:10.1002/jcph.2368