Chimeric Antigen Receptor (CAR) T-Cell Immunotherapy for Leukemia and Beyond

Sagar B. Kudchodkar, PhD, and Marcela V. Maus, MD, PhD | August 29, 2014

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy in which the patient’s own T cells are isolated in the laboratory, redirected with a synthetic receptor to recognize a particular antigen or protein, and reinfused into the patient. Clinical trials of CAR T cells directed to the CD19 antigen have shown impressive results in advanced B-cell malignancies at multiple academic centers over the last 3 years. We describe the technology of CAR T cells, findings at 5 academic centers, and toxicities associated with CAR T cell-treatment and their management. Although CAR T cells for B-cell malignancies are the most advanced in terms of clinical testing, CAR T cells are the basis of a new platform technology that is poised to be expanded to other hematologic and nonhematologic malignancies, especially as new targets are identified and manufacturing processes are streamlined.
 
  Cancer Cell

Introduction

Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy in which the patient’s own T cells are isolated in the lab, redirected with a synthetic receptor to recognize a particular antigen or protein, and re-infused into the patient (Figure). Over the last 5 years, at least 15 clinical trials of CAR T cell therapy have been published. A new wave of excitement surrounding CAR T cell therapy began in August 2011, when investigators from the University of Pennsylvania (Penn) published a report on 3 patients with refractory chronic lymphocytic leukemia (CLL) who had long-lasting remissions after a single dose of CAR T cells directed to CD19.1,2 Since then, the enthusiasm has only increased as investigators from the National Cancer Institute (NCI),3,4 Memorial Sloan Kettering Cancer Center (MSKCC),5 which allowed us to transition most of these patients to a standard- of-care allogeneic hematopoietic stem cell transplant (allo- SCT), and Penn6 have published impressive results in lymphoma and acute lymphoblastic leukemia (ALL). At large meetings, including those of the American Society of Hematology (ASH) and the American Association for Cancer Research (AACR), new sessions devoted to CAR T cell therapies have been organized and well attended, and all the major centers developing CAR T cells, including also Baylor College of Medicine, Fred Hutchinson Cancer Research Center, City of Hope National Medical Center, and MD Anderson Cancer Center, have discussed their latest results. Tellingly, what was considered a fringe field only 5 years ago has recently attracted investors, and several new partnerships and biotechnology companies have been formed around CAR T cell therapies (Table).

What Exactly Is a CAR-Modified T Cell?

CARs are synthetic molecules that minimally contain: (1) an antigen-binding region, typically derived from an antibody, (2) a transmembrane domain to anchor the CAR into the T cells, and (3) 1 or more intracellular T cell signaling domains.7 A CAR redirects T cell specificity to an antigen in a human leukocyte antigen (HLA)-independent fashion, and overcomes issues related to T cell tolerance. Thus far, CAR T cells directed against CD19 are the only ones that have achieved a clinical proof-of-concept and are in later stages of clinical development. However, CAR-modified T cells are a platform for a therapy that could be extended to other hematologic and nonhematologic tumors, provided the CAR is specific to the desired proteins on the surface of the tumor cell. The CAR can be introduced into the T cells by a variety of techniques, some of which permanently modify the genome of the T cell (integrating vectors) and have the potential for long-term effects, and some of which are transient (nonintegrating). Examples of integrating methods are retroviral, lentiviral, and transposase-based vectors; examples of nonintegrating methods are adenoviral vectors and plasmid or RNA electroporation. Each method carries unique benefits and concerns related to cost of development, safety, and the durability of CAR expression. The intracellular domains included in the CAR (ie, CD28-z or 4-1BB-z) can modulate T cell properties, such as their ability to survive and proliferate.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Publication Bottom Border
Border Publication
$emailPop$
x