The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL

Abstract

Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2–3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10–15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse. Despite our increased understanding of risk factors and disease predictors, treatment strategies for patients with relapsed or refractory (r/r) disease, including variations of chemotherapy and stem cell transplant, remain ineffective for many patients. To improve outcomes of patients with r/r disease, immunotherapies targeting specific B cell antigens are being developed. Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy recently approved by the US Food and Drug Administration for patients with refractory leukemia or those with second or later relapse. In this treatment strategy, a patient’s own T cells are transduced to express an anti-CD19 CAR that, when reintroduced into the patient, directs specific binding and killing of CD19+ B cells. In a phase 2, single-arm, multicenter, global study, tisagenlecleucel resulted in a remission rate of 81% in pediatric and adolescent patients with r/r B cell ALL. This review article summarizes four typical cases of pediatric and adolescent r/r B-cell ALL, focusing on the patient’s journey from initial diagnosis to treatment with CAR T cell therapy.

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

“…However, more recent evidence from first clinical studies or off-label use, suggest that CAR-T-cells may represent an efficient option for treating CNS leukemia. Independent reports including small patient numbers showed sustained complete remission after CD19 CAR-T cell treatment in ALL patients with refractory disease and CNS involvement and/or isolated CNS disease [103,106,107]. Furthermore, the neurotoxic profile of CAR-T cells in patients with CNS involvement was limited and reversible [103,106,107] and, most importantly, did not differ from patients without CNS disease.…”

“…Their application spectrum includes diffuse large B cell lymphoma (DLBCL) and relapsed/refractory BCP-ALL. CAR-T-cells have shown impressive response rates in adult and pediatric patients [103,104]. Due to concerns regarding neurotoxicity, initial clinical studies with CD19 CAR-T cells strictly excluded patients with CNS involvement [105].…”

Critical illness epidemiology and mortality risk in pediatric oncology

“…As a result, pediatric oncologists tend to advocate for more aggressive PICU support. It is not uncommon now, for intensivists to be faced with oncology patients who survive longer, but who are of increasing complexity, including HSCT for expanded indications and the use of newer immunotherapies such as chimeric antigen receptor T‐cell (CAR T‐cell) therapy 11 …”

Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy

“…The current CAR-T cell therapies approved for the treatment of hematological malignancies require genetic engineering of patient-derived T cells. There are issues related to the manufacturing processes and quantity of these T cells in a fraction of pediatric or intensively treated patients, especially due to the heavy lymphocytotoxic chemotherapies the patients often receive 1,25 . Additionally, an increasing amount of data supports that greater clinical efficacy of the CAR-T cell therapy is determined by intrinsic factors of the T cells, such as poly-functionality and memory-like phenotypes 4,6,26 .…”