T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors

Patel, S.; Москаленко, Марина; Tian, Tina; Smith, Douglas H.; McGuinness, Ryan; Chen, Lili; Winslow, Genine; Kashmiri, S. V. S.; Schlom, Jeffrey; Stanners, Clifford P.; Finer, Mitchell; McArthur, James G.

doi:10.1038/sj.cgt.7700213

Cited by 25 publications

(19 citation statements)

References 25 publications

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“…Bispecific immune receptors (BCIR) containing the z chain signaling subunit were generated that recognize the CEA and TAG-72 tumor antigens, or distinct epitopes in the HIV envelope (40). T cells expressing these chimeric receptors lysed cells expressing either one of the target antigens, thereby broadening the spectrum of target cells and reducing the potential of progression of disease due to antigen loss variants.…”

Section: T Lymphocytes With Grafted Recognition Specificity For Tumormentioning

confidence: 99%

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Uherek

Groner

Wels

2001

Journal of Hematotherapy & Stem Cell Research

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T lymphocytes recognize specific antigens through interaction of the T cell receptor (TCR) with short peptides presented by major histocompatibility complex (MHC) class I or II molecules. For initial activation and clonal expansion, naïve T cells are dependent on professional antigen-presenting cells (APCs) that provide additional co-stimulatory signals. TCR activation in the absence of co-stimulation can result in unresponsiveness and clonal anergy. To bypass immunization, different approaches for the derivation of cytotoxic effector cells with grafted recognition specificity have been developed. Chimeric antigen receptors have been constructed that consist of binding domains derived from natural ligands or antibodies specific for cell-surface antigens, genetically fused to effector molecules such as the TCR alpha and beta chains, or components of the TCR-associated CD3 complex. Upon antigen binding, such chimeric receptors link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. Since the first reports on chimeric antigen receptors, this concept has steadily been refined and the molecular design of chimeric receptors has been optimized. Aided by advances in recombinant antibody technology, chimeric antigen receptors targeted to a wide variety of antigens on the surface of cancer cells and of cells infected by human immunodeficiency virus (HIV) have been generated. In initial clinical studies, infusion of such cells into patients proved to be safe and transient therapeutic effects have been observed.

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Section: T Lymphocytes With Grafted Recognition Specificity For Tumormentioning

confidence: 99%

Chimeric Antigen Receptors for the Retargeting of Cytotoxic Effector Cells

Uherek

Groner

Wels

2001

Journal of Hematotherapy & Stem Cell Research

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“…[71][72][73][74][75][76][77][78][79][80] used measure of the viable HIV reservoir) and rectal HIV DNA (-0.5 log), and a trend toward less viral rebound, although no decrease in peripheral blood HIV DNA or rectal HIV RNA. 81 Long-term follow-up suggests that this approach was safe and results in long-lived cells with CAR DNA that persisted for more than a decade.…”

Section: Previous Trials Of Anti-hiv Carmentioning

confidence: 99%

Combining Cell and Gene Therapy in an Effort to Eradicate HIV

Wagner

2016

AIDS Patient Care and STDs

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More than 30 million people are infected with HIV, and HIV remains the fifth leading cause of disabilityadjusted life years worldwide. Antiretroviral therapy (ART) dramatically decreases mortality rate, but there are side effects, long-term toxicities, expenses, stigmas, and inconveniences associated with chronic treatment, and HIV-infected individuals on ART have an increased risk of malignancies, cardiovascular disease, neurologic disease, and shortened life expectancy. Therefore, a cure for HIV remains an important goal. Combining new cell and gene therapy technology is an exciting approach that appears promising in vitro. Animal testing and careful clinical trials will be needed to determine if these strategies are clinically useful.

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“…91 CAR has been introduced into T cells expressing endogenous ␣␤TCR that recognize allo- 92 or viral antigens. 41, [93][94][95] Triggering such TCRs in vivo can be used to numerically expand T cells to achieve an improved antitumor effect delivered by the CAR as was recently demonstrated by infusing bispecific T cells which recognized EBV-specific antigens via the endogenous ␣␤TCR and GD 2 on neuroblastoma cells by the introduced CAR. 41 Because T cells may require exogenous cytokines to sustain in vivo persistence, 96 investigators have enforced expression of cytokines that signal through the common ␥ cytokine receptor chain.…”

Section: Persistencementioning

confidence: 99%