Chimeric antigen receptor T cell therapy for pediatric and young adult B cell acute lymphoblastic leukemia

Abstract

Introduction: Though 85% of children and young adults with acute lymphoblastic leukemia (ALL) are cured, until recently, the prognosis of relapsed or refractory disease has been dismal. The advent of chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory ALL. The most well-studied, successful CARs are autologous, murine-based anti-CD19 CARs, but new constructs are currently under clinical investigation.

Areas covered: This review describes the history and design of CAR T cells, clinical trial outcomes of anti-CD19 and newer CARs, treatment-related toxicities including cytokine release syndrome and neurotoxicity, and issues with resistance and relapse. A search of PubMed and clinicaltrials.gov spanning from 2012-present was used to select original reports investigating the use of CAR T in pediatric patients.

Expert opinion: CD19-targeted CARs have demonstrated remarkable response rates and produced durable remissions in very high-risk pediatric patient populations. The therapies, however, are limited by unique treatment-related toxicities and considerable rates of antigen-positive and antigen-negative relapses. Current research efforts focused on elucidating mechanisms of resistance/relapse and on developing strategies to prevent and treat relapse are critical to optimizing the use of CAR-T. In addition, ongoing trials testing CARs earlier in therapy and for new indications are key to informing their widespread usage.

Keywords: Acute lymphoblastic leukemia; adoptive T cell therapy; car T cell; cd19; chimeric antigen receptor; cytokine release syndrome; immunotherapy; tisagenlecleucel.

Figure 1:. Autologous chimeric antigen receptor T-cell generation

For autologous CAR-T cell generation, peripheral blood mononuclear cells are collected from a patient by leukapheresis. T-cells are then transduced with a viral vector containing genetic information that encodes the receptor of interest. The CAR-Ts are expanded ex-vivo and then infused into the patient. Once infused, the CAR-Ts survey for the antigen of interest and are activated upon engagement with the target.