Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia

From Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.)
New England Journal of Medicine (Impact Factor: 55.87). 03/2013; 368(16). DOI: 10.1056/NEJMoa1215134
Source: PubMed


Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

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    • "These T cells also activate the IRF7/IFNb pathway, which supports the anti-tumor activity of these T cells. Thus, CAR T cells can be engineered to different levels of potency, which may be useful to tackle a broad range of cancers, including solid tumors. in ALL (Brentjens et al., 2011; Davila et al., 2014; Grupp et al., 2013; Lee et al., 2015; Maude et al., 2014), reviewed in (Davila et al., 2012; Ramos et al., 2014). Here we model CD19 CAR therapy of ALL and evaluate CAR designs that differ structurally in their recruitment of CD28 and 4-1BB signaling with the aim of unraveling the subtlety of providing optimal costimulatory support to engineered T cells. "
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    ABSTRACT: T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
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    • "Patients' T cells, easily accessible in peripheral blood, can be genetically instructed to target tumors by transduction of receptors for antigen, utilizing either the physiological TCR (Ho et al., 2003; Stone and Kranz, 2013) or synthetic receptors now known as CARs (Sadelain et al., 2009). Both approaches have shown clinical successes, particularly in melanoma (Robbins et al., 2011), targeting NY- ESO1 (Chen et al., 1997), and in acute lymphoblastic leukemia, (Brentjens et al., 2013; Grupp et al., 2013; Davila et al., 2014; Lee et al., 2015; Maude et al., 2014), targeting CD19 (Brentjens et al., 2003). CARs are artificial, composite receptors for antigen that integrate principles of B cell and T cell antigen recognition (Figure 3A). "
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    • "The transferred cells may be ex vivo expanded tumor infiltrating lymphocytes (TIL) [2], transgenic T-cell receptor (TCR) T cells [3] [4], or chimeric antigen receptor (CAR) T cells [5e7]. In particular, CAR T cells have shown some promising activity with complete responses observed in patients with leukemia [8] [9] and neuroblastoma [10]. However, despite these encouraging early clinical data, factors that influence CAR T-cell persistence and anti-tumor activity still require optimization. "
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