Using gene therapy to manipulate the immune system in the fight against B-cell leukemias

Abstract

Introduction: Over 20 years ago, chimeric antigen receptors (CARs) were created to endow T cells with new antigen-specificity and create a therapy that could eradicate cancer and provide life-long protection against recurrence. Steady progress has led to significant improvements with CAR design and CAR T-cell production, allowing evaluation of CAR T cells in patients. The initial trials have targeted CD19, which is expressed on normal and malignant B cells.

Areas covered: We review data from trials for patients with chronic lymphocytic leukemia (CLL) and B-cell acute lymphoblastic leukemia (B-ALL). In addition, we discuss the on-target toxicities, B-cell aplasia and cytokine release syndrome (CRS), which is uniquely associated with T-cell immunotherapies.

Expert opinion: We compare the results when targeting the same antigen in CLL or B-ALL and speculate on reasons for outcome differences and future directions to enhance outcomes. Furthermore, the dramatic results targeting B-ALL require further analysis in Phase II trials, and we discuss important components of these future trials. We also suggest a management scheme for CRS. The next several years will be critical and may lead to the first clinical indication of a gene-engineered cell therapy for cancer.

Keywords:

• adoptive T-cell therapy
• B-cell acute lymphoblastic leukemia
• chimeric antigen receptors
• chronic lymphocytic leukemia
• gene therapy
• immunotherapy

Declaration of interest

This work has been funded by the American Society of Hematology/Harold Amos Fellowship. ML Davila is a member of the Scientific Advisory Board for Adaptive Biotechnologies (Seattle, WA, USA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.

Notes

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