ABSTRACT
Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.
ABSTRACT
Naive CD4+ T cells can differentiate into different cell subsets after receiving antigen stimulation, which secrete corresponding characteristic cytokines and thereby exert biological effects in various diseases. Th22 cells, a novel subset of CD4+ T cells, are different from Th1, Th2, Th17, and Treg cell subsets, which have been discovered in recent years. They can express CCR4, CCR6, and CCR10 molecules and secrete IL-22, IL-13, and TNF-α. They are not able to secrete IL-17, IL-4, and interferon-γ (IFN-γ). IL-22 is considered as a major effector molecule of Th22 cells whose functions and mechanisms of regulating cell differentiation have been constantly improved. In this review, we provide an overview of the origin, differentiation of Th22 cells. Moreover, we also describe the interrelationships between Th22 cells and Th17, Th1, and Th2 cells. Additionally, the role of Th22 cells were discussed in human diseases with virus infection, which will provide novel insight for the prevention and treatment of viral infection in human.
ABSTRACT
Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.