The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer - PubMed (original) (raw)

The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer

Daniel W Lee et al. Clin Cancer Res. 2012.

Erratum in

Abstract

Improved outcomes for children with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, gene therapy, and cell-processing technologies have paved the way for clinical applications of chimeric antigen receptor-based therapies. This is a new form of targeted immunotherapy that merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity, potential for expansion, and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B-cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. In pediatric oncology, CD19 and GD2 are compelling antigens that have already been identified for targeting pre-B acute lymphoblastic leukemia and neuroblastoma, respectively, with this approach, but it is likely that other antigens expressed in a variety of childhood cancers will also soon be targeted using this therapy. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of childhood cancer.

©2012 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1

Current CAR design allows for MHC-independent antigen recognition and incorporates costimulatory signal (s) endowing the transduced T cell with potent cytotoxic activity. In contrast to the TCR, which recognizes peptide in the context of MHC and provides signal 1, CARs interact in an MHC-independent manner. All CARs must provide signal 1 in the form of the TCR z activating subunit (first-generation), but the addition of one (second-generation) or 2 (third-generation) costimulatory signals (CD28, 4-1BB, or OX40) provides the CAR-transduced T cell with both signals 1 and 2, leading to full activation, proliferation, and cytotoxicity.

Figure 2

Figure 2

General schema for the preparation, transduction, and infusion of CAR-modified T cells. A, apheresed T cells from a patient or an allogeneic donor are activated. Three accepted methods are illustrated: (i) stimulation with the activating CD3 antibody, OKT3, in the presence of IL-2; (ii) stimulation with anti-CD3– and anti-CD28–coated paramagnetic beads in the presence of IL-2; and (iii) stimulation with aAPC (expressing 4-1BBL and an Fc receptor) with OKT3 and IL-2. Activated cells are then transduced with the CAR using a retro- or lentiviral platform. Because the CAR is integrated into the T-cell genome, all daughter cells that are generated (a mix of CD4+ [Th1/Th2/TH17/Treg] and CD8+ T cells) during this expansion also express the CAR. CAR T cells are then infused into the patient after preparative chemotherapy. B, generation of CAR-expressing T cells generally results in a several-hundred-fold expansion over 14 days. Such extensive proliferation may generate predominantly TEFF cells, which have cytotoxic capabilities but limited proliferative potential compared with T-effector and TCM cells. C, less intense stimulation and/or modulation of stimulation methods may produce more naïve T cells or T–central memory cells, which have an increased likelihood of persistence.

Figure 3

Figure 3

Lymphodepleting preparatory regimens can enhance the efficacy of adoptive cell therapy. Proposed mechanisms include (i) a reduction in endogenous lymphocytes, leading to accumulation of IL-7 and IL-15 (homeostatic cytokines that support cell expansion and persistence); (ii) a transient reduction in the number and frequency of Tregs, thereby diminishing suppression; and (iii) induction of gut damage, which can lead to the systemic release of bacterial byproducts [e.g., lipopolysaccharide (LPS)] that activate the innate immune system.

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