Spike-directed vaccination elicits robust spike-specific T-cell response, including to mutant strains

Although most studies describing coronavirus disease 2019 vaccine responses have focused on antibodies, there is increasing evidence that T cells play a critical role. Here the authors evaluated T-cell responses in seronegative donors before and after vaccination to define responses to the severe acute respiratory syndrome coronavirus 2 reference strain as well as to mutations in the variant strains Alpha/B.1.1.7 and Beta/B.1.351. The authors observed enhanced T-cell responses to reference and variant spike strains post-vaccination

Secondary Graft Loss After Third-party "Off-The-Shelf" Antigen-Specific T cell Infusion

<p>Here, we describe a severe adverse event of virus-specific T cell (VST therapy) in an infant with severe combined immunodeficiency who received VSTs for treatment of CMV viremia post-transplant and developed secondary graft rejection at 1-month post-VST infusion associated with the expansion of VST donor-derived T cells. Deposited here are the bulk repertoire, single-cell gene expression and TCR, and flow cytometry data from the study.</p><p><strong>bulk_rep.zip contains tables of alpha/beta TCR sequences for post-infusion, VST donor, and VST product samples, and samples stimulated with neoepitope peptides. </strong></p><p><strong>VST_agg_wTCR_SS.rds is an R Data Serialization file containing a Seurat object of the processed 10X single-cell gene expression and TCR profiling for the post-infusion, VST donor, and VST product samples. TCR information is stored in the meta.data slot.</strong></p><p><strong>P0230D neoantigen expansions.acs, P0230D pentamers.acs, and P0230D_MLR.acs contain the flow cytometry data for the neoantigen and mixed lymphocyte reaction experiments.</strong></p&gt

Transcriptomic analysis reveals optimal cytokine combinations for SARS-CoV-2-specific T cell therapy products

Adoptive T cell immunotherapy has been used to restore immunity against multiple viral targets in immunocompromised patients after bone-marrow transplantation and has been proposed as a strategy for preventing coronavirus 2019 (COVID-19) in this population. Ideally, expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-virus-specific T cells (CSTs) should demonstrate marked cell expansion, T cell specificity, and CD8+ T cell skewing prior to adoptive transfer. However, current methodologies using IL-4 + IL-7 result in suboptimal specificity, especially in CD8 cells. Using a microexpansion platform, we screened various cytokine cocktails (IL-4 + IL-7, IL-15, IL-15 + IL-4, IL-15 + IL-6, and IL-15 + IL-7) for the most favorable culture conditions. IL-15 + IL-7 optimally balanced T cell expansion, polyfunctionality, and CD8+ T cell skewing of a final therapeutic T cell product. Additionally, the transcriptomes of CD4 and CD8 T cells cultured with IL-15 + IL-7 displayed the strongest induction of antiviral type I interferon (IFN) response genes. Subsequently, microexpansion results were successfully translated to a Good Manufacturing Practice (GMP)-applicable format where IL-15 + IL-7 outperformed IL-4 + IL-7 in specificity and expansion, especially in the desirable CD8 T cell compartment. These results demonstrate the functional implications of IL-15-, IL-4-, and IL-7-containing cocktails for therapeutic T cell expansion, which could have broad implication for cellular therapy, and pioneer the use of RNA sequencing (RNA-seq) to guide viral-specific T cell (VST) product manufacturing

Outcomes following posttransplant viral-specific T-cell therapy in patients with sickle cell disease

Hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative approach for sickle cell disease (SCD). With the risk of graft-versus-host disease (GVHD), especially in the HLA-mismatched donors, intense immunosuppression is required leading to an increased risk of viral infection. Post-HSCT, adoptive transfer of virus-specific T cell (VSTs) therapies have not been well-studied in SCD patients. Here, we report the outcomes of patients with SCD at a single-center who received VSTs post-transplant to prevent or treat virus infections. Thirteen patients who received HSCT from HLA-matched (n=9) or mismatched (n=4) donors for SCD were treated with a total of 15 VST products for the treatment or prophylaxis of multiple viruses (cytomegalovirus, ebstein barr virus, adenovirus, BK virus, human herpes virus 6 +/- human parainfluenza virus 3). Of the patients evaluated, 46.2% (n=6)) received VSTs as treatment of virus infection. Eighty percent of patients with active viremia (n=4/5) achieved remission of at least 1 target virus. Seven additional patients (53.8%) received VSTs prophylactically and 6/7 (85.7%) remained virus-free post-infusion. No immediate infusion-related toxicities occurred, and severe de novo acute GVHD occurred in only 2 (15.4%) patients. Given the good safety profile, high-rate of clinical responses and sustained remissions when administered with standard anti-viral treatments, the routine use of VSTs post-HSCT as prophylaxis or treatment may improve the overall safety of transplant for patients with SCD

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT