Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme.

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered.

INSPIRED Symposium Part 4A: Access to CAR T Cell Therapy in Unique Populations with B Cell Acute Lymphoblastic Leukemia.

The approval of tisagenlecleucel (tisa-cel) for use in children with B cell acute lymphoblastic leukemia (B-ALL) was based on the phase 2 ELIANA trial, a global registration study. However, the ELIANA trial excluded specific subsets of patients facing unique challenges and did not include a sufficient number of patients to adequately evaluate outcomes in rare subpopulations. Since the commercialization of tisa-cel, data have become available that support therapeutic indications beyond the specific cohorts previously eligible for chimeric antigen receptor (CAR) T cells targeted to CD19 (CD19 CAR-T) therapy on the registration clinical trial.

CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy.

Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.

In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature.

Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.

We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells.

Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study.

Background: Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia.

Clinically Applicable Assessment of Tisagenlecleucel CAR T Cell Treatment by Digital Droplet PCR for Copy Number Variant Assessment.

Chimeric antigen receptor (CAR) T cell therapy is an innovative immunotherapy for treating cancers in both children and adults with proven utility in numerous clinical trials. Significantly, some CAR T cell therapies have now been approved by relevant national regulatory bodies across numerous countries for clinical therapeutic use outside of clinical trials. One such recently licensed product is tisagenlecleucel, a CAR T therapy approved for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) using autologous T cells from the patient.

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study.

Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral.

Rare Sequences Make Sense of CAR T-cell Therapy Outcomes.

In this issue, Pulsipher and colleagues used next-generation sequencing to detect leukemia-specific sequences following tisagenlecleucel therapy of acute lymphoblastic leukemia. A challenge for the field currently is to identify which patients will have therapy failure and to do so early enough to allow planning for further treatment, for example, stem cell transplantation. Detection of disease below the standard detection level for this technique (less than one per million cells) at day 28 was associated with poorer outcomes and potentially therefore could be used to identify those that might benefit from adjunctive therapies.

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial.

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear.

Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.

Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence.

Activity of blinatumomab in lymphoblastic leukemia with impaired T-cell immunity due to congenital immunodeficiency.

Blinatumomab, a single-chain, bispecific, T-cell-engaging antibody targeting CD19, is effective in B-precursor acute lymphoblastic leukemia (BCP-ALL), even in the context of chemotherapy-related partial T-cell immunodeficiency. We report 2 patients with BCP-ALL and congenital T-cell immunodeficiency, who obtained an excellent response to blinatumomab. The first, a 6-year-old girl with Schimke immuno-osseous dysplasia (SIOD) and combined immunodeficiency disorder (CID) obtained a minimum residual disease-negative (MRD-) remission of high hyperdiploid BCP-ALL with blinatumomab.

Congenital acute myeloid leukemia: challenges and lessons. A 15-year experience from the UK.

Congenital Acute Myeloid leukemia (CAML) is a rare leukemia diagnosed within the first 28 days of life. Dismal survival rates of approximately 25% at two years from diagnosis have not improved despite multiple treatment protocols, and there lacks international consensus for optimal management of these vulnerable patients. We report a retrospective analysis of our fifteen-year experience from a large UK tertiary pediatric center, focusing on treatment modalities and outcomes, including late therapeutic toxicities.

CAR-T cell therapy in paediatric acute lymphoblastic leukaemia - past, present and future.

Over the last decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment modality for relapsed/refractory B-cell malignancies in both children and adults. As an adoptive immune therapy, CAR-T cells have the potential to overcome disease that is resistant to chemo- and radiotherapy as well as represent a viable option for those who have already reached toxicity ceilings with standard therapies. CD19-directed CAR-T cell products have been licensed for use in paediatric B-cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant or in second or later relapse.