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Anti‐JCV TCR‐based chimeric immune receptors create functional designer T cells for PML therapy
Author(s) -
Junghans Richard Paul,
Yang Wen,
Bais Anthony,
Beaudoin Esther
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.859.5
Subject(s) - t cell receptor , cd3 , cd28 , natalizumab , t cell , chimeric antigen receptor , progressive multifocal leukoencephalopathy , jurkat cells , cancer research , immune system , biology , microbiology and biotechnology , immunology , multiple sclerosis , cd8
Progressive Multifocal Leukoencephalopathy (PML) is a lethal brain disease caused by JC polyomavirus (JCV) that arises in immunodepressed HIV+ patients and in rare individuals who are treated with natalizumab (Tysabri) for multiple sclerosis or Crohn's disease. Chimeric immune receptors (CIRs) are engineered from JCV specific TCR á and â chains cloned from a PML survivor and fused to the transmembrane (TM) and cytoplasmic (cyt) domains of CD3æ providing Signal 1. These form functional á/â chain heterodimers, induce retrovirally transduced expressor T cells to secrete cytokines and exhibit cytotoxicity against JCV+ cells. In further experiments, these TCR‐based CIRs were engineered to create 2nd generation products with added CD28, providing Signal 1+2, containing an extracellular (EC) region and TM and cyt domains of CD28 and cyt of CD3æ. The 2nd generation anti‐JCV designer T cells are intended to resist AICD and proliferate on antigen contact, with resistance to regulatory T cell and other suppressions, and function in the absence of CD4 T cell help. Here, we demonstrate that under the hypothesis of several variations of constructs with either CD28, CD3æ or hybrid TM domains that removal of the CD28 EC region is required for effective expression, heterodimerization and designer T cell function. These products are being prepared for clinical application in HIV+ or natilizumab treated PML patients.