A Review of Clinical Outcomes of CAR T-Cell Therapies for B-Acute Lymphoblastic Leukemia

Abstract

Introduction: Treatment of relapsed and refractory (R/R) B acute lymphoblastic leukemia (B-ALL) represents an unmet medical need in children and adults. Adoptive T cells engineered to express a chimeric antigen receptor (CAR-T) is emerging as an effective technique for treating these patients. Areas covered: Efficacy and safety of CAR-T therapy in R/R B-ALL patients. Expert opinion: CD19 CAR-T infusion induce high CR rates in patients with poor prognosis and few therapeutic options, while real-life data demonstrate similar results with an interestingly lower incidence of grade 3/4 toxicity. Nevertheless, despite impressive in-depth responses, more than half of patients will experience a relapse. Therefore, rather than using CAR-T cell therapy as a stand-alone option, consolidation with allogeneic stem-cell transplant (Allo-SCT) after CAR-T treatment might increase long-term outcome. Moreover, CD19 is one target, but several other targets are being examined, such as CD20 and CD22 and dual-targeting CARs or combination therapy. Another issue is the time consuming process of CAR-T engineering. New platforms have shortened the CAR-T cell manufacturing process, and studies are underway to evaluate the effectiveness. Another way to mitigate waiting is the development of allogeneic “off the shelf” therapy. In conclusion, CD19-targeted CAR-modified T-cell therapy has shown unprecedented results in patients without curative options. Future work focusing on target identification, toxicity management and reducing manufacturing time will broaden the clinical applicability and bring this exciting therapy to more patients, with longer-term remissions without additional Allo-SCT.

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

“…This set of patients usually receives additional chemotherapy cycles and possibly hematopoietic progenitor transplants, which are frequently ineffective [12]. It is in this group of highly treated patients that a good rate of response to CAR T therapy has been observed [13]. Clinical trials have shown that CAR T-cells are able to expand in vivo, eliminate leukemia burden, and persist in the patient for as long as two years [6,[14][15][16].…”

Engineering of an Avidity-Optimized CD19-Specific Parallel Chimeric Antigen Receptor That Delivers Dual CD28 and 4-1BB Co-Stimulation

“…We focused on CARs that contain a CD28+CD3z endodomain since CD19 expression is most commonly retained at the time of disease relapse, following infusion of these cells (16)(17)(18). To generate a panel of scFvs with varying ability to bind CD19, CDR3 of the V H domain within the CD19-specific FMC63 scFv was subjected to alanine scanning mutagenesis (Figure 1A).…”

“…Moreover, greater than 50% of patients who receive CD19-specific CAR T-cell immunotherapy ultimately develop progressive disease (15). Relapse in which CD19 expression is maintained is the most common scenarioparticularly with CD28-containing 2G CARs -and this has been linked to limited persistence of CAR T-cells (16)(17)(18). Given the need for more potent and durable CAR T-cell strategies to target CD19, we set out here to develop CD19-targeted pCARs in order to test their potential utility in models of B-cell malignancy.…”

The fist experience of using locally manufactured CAR-T cells in patients with relapsed/refractory acute lymphoblastic leukemia in Belarus

“…На аутопсии пациента Б-к в костном мозге обнаружено небольшое количество бластов в состоянии некробиоза, несмотря на то, что он умер на 10-е сутки от введения CAR-T-клеток. Высокую антилейкемическую активность CAR-T-клеток отмечают многие исследователи [9,10] даже после неудачной терапии ОЛЛ блинатумомабом [8].…”