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首页> 美国卫生研究院文献>other >Anti-Transgene Rejection Responses Contribute to Attenuated Persistence of Adoptively Transferred CD20/CD19-Specific Chimeric Antigen Receptor Re-directed T Cells in Humans
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Anti-Transgene Rejection Responses Contribute to Attenuated Persistence of Adoptively Transferred CD20/CD19-Specific Chimeric Antigen Receptor Re-directed T Cells in Humans

机译：抗转基因排斥反应有助于减弱持续转移的CD20 / CD19特异性嵌合抗原受体重新指导的人类中的T细胞

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Immunotherapeutic ablation of lymphoma is a conceptually attractive treatment strategy that is the subject of intense translational research. Cytotoxic T lymphocytes (CTL) that are genetically modified to express CD19- or CD20-specific, single-chain-antibody-derived chimeric antigen receptors (CARs) display HLA-independent antigen-specific recognition/killing of lymphoma targets. Here, we describe our initial experience in applying CAR-redirected autologous CTL adoptive therapy to patients with recurrent lymphoma. Using plasmid vector electrotransfer/drug selection systems, cloned and polyclonal CAR+ CTL were generated from autologous peripheral blood mononuclear cells and expanded in vitro to cell numbers sufficient for clinical use. In two FDA-authorized trials, patients with recurrent diffuse large cell lymphoma (DLCL) were treated with cloned CD8+ CTL expressing a CD20-specific CAR (along with NeoR) following autologous HSCT, while patients with refractory follicular lymphoma (FL) were treated with polyclonal T cell preparations expressing a CD19-specific CAR (along with HyTK, a fusion of hygromycin resistance and HSV-1 thymidine kinase suicide genes) and low-dose s.c. rhuIL-2. A total of fifteen infusions were administered (five at 108cells/m2, seven at 109cells/m2, three at 2×109cells/m2) to four patients. Overt toxicities attributable to CTL administration were not observed. However, detection of transferred CTL in the circulation, measured by Q-PCR, was short (24hrs-7d), and cellular anti-transgene immune rejection responses were detected in two patients. These studies reveal the primary barrier to therapeutic efficacy is limited persistence and provide the rationale to prospectively define T cell populations intrinsically programmed for survival following adoptive transfer and to modulate the immune status of recipients to prevent/delay anti-transgene rejection responses.

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