Background: The role of humoral immunity has been well established in reducing infection risk and facilitating viral clearance in patients with COVID-19. However, the relationship between specific antibody responses and severity of COVID-19 is less well understood. Methods: To address this question and identify gaps in knowledge, we utilized the methodology of a scoping review to interrogate risk of infection and clinical outcomes of COVID-19 in patients with iatrogenic and inborn humoral immunodeficiency states based on existing literature. Results: Among patients with iatrogenic B-cell depletion, particularly with agents targeting CD20, our analysis found increased risk of severe COVID-19 and death across a range of underlying disease states. Among patients with humoral inborn errors of immunity with COVID-19, our synthesis found that patients with dysregulated humoral immunity, predominantly common variable immunodeficiency (CVID), may be more susceptible to severe COVID-19 than patients with humoral immunodeficiency states due to X-linked agammaglobulinemia and other miscellaneous forms of humoral immunodeficiency. There were insufficient data to appraise the risk of COVID-19 infection in both populations of patients. Conclusions: Our work identifies potentially significant predictors of COVID-19 severity in patients with humoral immunodeficiency states and highlights the need for larger studies to control for clinical and biologic confounders of disease severity.
Cancer outcomes with chemotherapy are inferior in patients of minority racial/ethnic groups and those with obesity. Chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for relapsed/refractory hematologic malignancies, but whether its benefits extend commensurately to racial/ethnic minorities and patients with obesity is poorly understood. With a primary focus on patients with B-cell acute lymphoblastic leukemia (B-ALL), we retrospectively evaluated the impact of demographics and obesity on CAR T-cell therapy outcomes in adult and pediatric patients with hematologic malignancies treated with CAR T-cell therapy across five phase I clinical trials at the National Cancer Institute (NCI) from 2012 to 2021. Among 139 B-ALL CAR T-cell infusions, 28.8% of patients were Hispanic, 3.6% were Black, and 29.5% were overweight/obese. No significant associations were found between race, ethnicity, or body-mass index (BMI) and complete remission rates, neurotoxicity, or overall survival. Hispanic patients were more likely to experience severe cytokine release syndrome compared to white non-Hispanic patients even after adjusting for leukemia disease burden and age (odds ratio 4.5, p = 0.001). A descriptive analysis of patients with multiple myeloma (n=24) and NHL (n=23) displayed a similar pattern to the B-ALL cohort. Our findings suggest CAR T-cell therapy may provide substantial benefit across a range of demographics characteristics, including for those populations who are at higher risk for chemotherapy resistance and relapse. However, toxicity profiles may vary. Therefore, efforts to improve access to CAR therapy for underrepresented populations and elucidate mechanisms of differential toxicity among demographic groups should be prioritized.
The role of humoral immunity has been well established in reducing infection risk and facilitating viral clearance in patients with COVID-19. However, the relationship between specific antibody responses and severity of COVID-19 is less well understood. To address this question and identify gaps in knowledge, we utilized the methodology of a scoping review to interrogate risk of infection and clinical outcomes of COVID-19 in patients with iatrogenic and inborn humoral immunodeficiency states based on existing literature. Among patients with iatrogenic B cell depletion, particularly with agents targeting CD20, our analysis found increased risk of severe COVID-19 and death across a range of underlying disease states. Among patients with humoral inborn errors of immunity with COVID-19, our synthesis found that patients with dysregulated humoral immunity, predominantly common variable immunodeficiency (CVID), may be more susceptible to severe COVID-19 than patients with humoral immunodeficiency states due to X-linked agammaglobulinemia and other miscellaneous form of humoral immunodeficiency. There were insufficient data to appraise the risk of COVID-19 infection in both populations of patients. Our work identifies potentially significant predictors of COVID-19 severity in patients with humoral immunodeficiency states and highlights the need for larger studies to identify clinical and biologic confounders of disease severity.
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a highly effective treatment option for patients with relapsed/refractory large B cell lymphoma (r/r LBCL). However, widespread use is deterred by development of clinically significant acute inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), that induce significant morbidity and require close monitoring. Identification of host biochemical signatures that predict the severity and time-to-onset of CRS and ICANS may assist patient stratification to enable timely mitigation strategies. Here, we report pre-treatment host metabolites that are associated with CRS and ICANS induced by Axicabtagene Ciloleucel or Tisagenlecleucel therapy. Both untargeted metabolomics analysis and validation using targeted assays revealed significant association between the abundance of specific pre-treatment biochemical entities and an increased risk and/or onset of clinically significant CRS (q<.1) and ICANS (q<.25). Higher pre-treatment levels of plasma glucose, and lower levels of cholesterol and glutamate were associated with faster onset of CRS. On the other hand, low baseline levels of amino acids proline and glycine and secondary bile acid isoursodeoxycholate were significantly correlated with clinically significant CRS. Lower concentration of the amino acid hydroxyproline was associated with higher grade and faster onset of ICANS, whereas low glutamine was negatively correlated with faster development of ICANS. Overall, our data indicate that the pre-treatment host metabolome has biomarker potential in determining the risk of clinically significant CRS and ICANS, and may be useful in risk stratification of patients prior to anti-CD19 CAR T-cell therapy.
This letter to the editor considers outcomes for underrepresented populations across early phase pediatric oncology clinical trials, considering barriers to equitable representation of minorities in clinical trials.
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune disorder most commonly characterized by defective lymphocyte apoptosis. ALPS patients classically present with chronic non-malignant lymphadenopathy and/or splenomegaly and typically exhibit defects in FAS signaling. We identified an ALPS-like patient with normal FAS-mediated apoptosis. Whole exome sequencing identified a de novo nonsense mutation in one allele of the NF-κB subunit RELA/p65. NF-κB is a ubiquitous and rapid-acting family of transcription factors whose signaling has been implicated in numerous physiological processes including inflammatory responses, innate immunity, lymphocyte homeostasis, lymphoid organogenesis, and immune tolerance. We found the patient mutation resulted in reduced expression of p65; enhanced T cell effector responses; reduced FOXP3 expression and iTreg formation; and an over-representation of p65:p50 heterodimers in CD4+ T cells compared to normal controls. These observations, coupled with the previously demonstrated importance of NF-κB in establishing and maintaining lymphocyte homeostasis and immune tolerance, lead us to posit RELA/p65 haploinsufficiency as a novel cause of ALPS-like disease.
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