Characterization and prediction of hematotoxicity in pediatric patients receiving tisagenlecuecel.

Hematotoxicity is the most frequent severe toxicity following chimeric antigen receptor (CAR) T therapy. However, limited data exist on risk factors and outcomes for hematotoxicity for children and young adults (CAYA) with B-acute lymphoblastic leukemia (B-ALL) treated with tisagenlecleucel. We conducted a multi-institutional study involving 326 CAYA, with 144 evaluable in an initial training cohort and 141 evaluable in a validation cohort, through the Pediatric Real World CAR Consortium to characterize the incidence and outcomes of prolonged severe neutropenia (PSN) and to develop a predictive risk score for PSN, tailored for use in this population.

Intravenous and intracranial GD2-CAR T cells for H3K27M diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. ). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models.

Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART).

Tisagenlecleucel utilisation and outcomes across refractory, first relapse and multiply relapsed B-cell acute lymphoblastic leukemia: a retrospective analysis of real-world patterns.

Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval.

HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL.

Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs.

Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia.

Purpose: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%.

Post-infusion CAR T cells identify patients resistant to CD19-CAR therapy.

Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4Helios CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated.

Disease Burden Affects Outcomes in Pediatric and Young Adult B-Cell Lymphoblastic Leukemia After Commercial Tisagenlecleucel: A Pediatric Real-World Chimeric Antigen Receptor Consortium Report.

Purpose: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel.

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report.

Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions.

Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy.

Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival.

Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells.

Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework.

Purpose: We evaluated the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines for internal consistency and compatibility with Bayesian statistical reasoning.

Methods: The ACMG/AMP criteria were translated into a naive Bayesian classifier, assuming four levels of evidence and exponentially scaled odds of pathogenicity. We tested this framework with a range of prior probabilities and odds of pathogenicity.

A research roadmap for next-generation sequencing informatics.

Next-generation sequencing technologies are fueling a wave of new diagnostic tests. Progress on a key set of nine research challenge areas will help generate the knowledge required to advance effectively these diagnostics to the clinic.

Ultrafast genome-wide scan for SNP-SNP interactions in common complex disease.

Long-range gene-gene interactions are biologically compelling models for disease genetics and can provide insights on relevant mechanisms and pathways. Despite considerable effort, rigorous interaction mapping in humans has remained prohibitively difficult due to computational and statistical limitations. We introduce a novel algorithmic approach to find long-range interactions in common diseases using a standard two-locus test that contrasts the linkage disequilibrium between SNPs in cases and controls.

Determinants of divergent adaptation and Dobzhansky-Muller interaction in experimental yeast populations.

Divergent adaptation can be associated with reproductive isolation in speciation [1]. We recently demonstrated the link between divergent adaptation and the onset of reproductive isolation in experimental populations of the yeast Saccharomyces cerevisiae evolved from a single progenitor in either a high-salt or a low-glucose environment [2]. Here, whole-genome resequencing and comparative genome hybridization of representatives of three populations revealed 17 mutations, six of which explained the adaptive increases in mitotic fitness.

Overlapping pools for high-throughput targeted resequencing.

Resequencing genomic DNA from pools of individuals is an effective strategy to detect new variants in targeted regions and compare them between cases and controls. There are numerous ways to assign individuals to the pools on which they are to be sequenced. The naïve, disjoint pooling scheme (many individuals to one pool) in predominant use today offers insight into allele frequencies, but does not offer the identity of an allele carrier.

Caenorhabditis elegans mutant allele identification by whole-genome sequencing.

Identification of the molecular lesion in Caenorhabditis elegans mutants isolated through forward genetic screens usually involves time-consuming genetic mapping. We used Illumina deep sequencing technology to sequence a complete, mutant C. elegans genome and thus pinpointed a single-nucleotide mutation in the genome that affects a neuronal cell fate decision.