CAR therapy for hematological cancers: can success seen in the treatment of B-cell acute lymphoblastic leukemia be applied to other hematological malignancies?

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From: Immunotherapy(Vol. 7, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 13,468 words
Lexile Measure: 1630L

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Author(s): Hollie J Pegram aff1 , Eric L Smith aff1 , Sarwish Rafiq aff1 , Renier J Brentjens [*] aff1 aff2 aff3

Keywords:

autologous T-cell infusion; B-cell malignancies; CAR; chimeric antigen receptor; immunotherapy; T cells

Background

Chimeric antigen receptors (CARs) can be used to redirect T-cell specificity. CARs consist of an extracellular antigen recognition domain that is usually comprised the single chain variable fragment (scFv), derived from a monoclonal antibody (mAb). This is linked to intracellular signaling domains that provide activation (signal 1) and costimulation (signal 2) to the T cells. For activating T cells through a CAR, signal 1 is usually provided by the CD3ζ signaling domain, as in normal T-cell stimulation through the T-cell receptor (TCR). To provide costimulation (signal 2), there are several options, including but not limited to CD28, 4-1BB and/or OX40 signaling domains. The costimulatory signaling moieties as well as combinations of costimulatory signaling domains have been extensively reviewed elsewhere and will not be covered here [1 ].

An important part of CAR design is choosing an optimal tumor-associated antigen (TAA) to target. Ideally, the target antigen should only be expressed on tumor cells and not on normal cells, to ensure that there is no 'on-target-off-tumor' activity that could result in toxicity. In the best possible situation, the target antigen is a molecule that is necessary for the survival of the tumor cell. This will reduce the risk of immune editing and tumor escape variant outgrowth. However, these criteria are rarely completely fulfilled. For example, the most extensively investigated CAR in the clinical setting targets CD19, which is expressed on most B-cell malignancies, but also expressed on normal B cells. Therefore, CAR-mediated tumor destruction is accompanied by CAR-mediated destruction of normal B cells, resulting in B-cell aplasia. For these patients, this is an acceptable 'on-target off-tumor' toxicity and can be managed with infusions of immunoglobulin. In contrast, a clinical trial investigating a CAR specific for ERBB2 for the treatment of ERBB2+ colon cancer resulted in a serious adverse event when the CAR T cells recognized low levels of ERBB2 on lung epithelial cells [2 ]. Unfortunately, this patient died as a result of this 'on-target, off- tumor' toxicity. Therefore, identifying an appropriate TAA is key to effective CAR T-cell therapy of cancer.

CD19-targeted CAR design

To date, CARs specific for CD19 have been the most successfully used in the clinical setting. Patient derived T cells modified to express CD19-targeted CARs have been used for the treatment of B-cell malignancies. A variety of CD19-targeted CARs have been used clinically, summarized here and in Table 1. Investigators at Memorial Sloan Kettering Cancer Center (MSKCC) have treated patients with a CD19-targeted CAR that utilizes the SJ25C1 scFv and the CD3ζ activation and CD28 costimulation signaling domains. The National Cancer Institute (NCI), Baylor College of Medicine and MD Anderson Center similarly used a CAR that contained the CD3ζ and CD28 signaling domains linked to a different CD19-specific scFv, FMC63 [ 3 ]. The University of Pennsylvania (UPenn) and Fred Hutchinson Cancer Research Center...

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Gale Document Number: GALE|A417580383