Overcoming Tumor Immune Evasion Strategies in Hodgkin's Lymphoma

$0P01FY2002CANIH

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Paper 38819365 Paper 38659815 Paper 36653070 Paper 36574622 Paper 36518078 Paper 36122411 Paper 35821636 Paper 35325065 Paper 34323938 Paper 33742099 Paper 33738181 Paper 33571680 Paper 33536140 Paper 33434061 Paper 33148882 Paper 32145203 Paper 31779709 Paper 31558475 Paper 31135527 Paper 31005599 Paper 30936089 Paper 30891427 Paper 30850208 Paper 30619856 Paper 30396848 Paper 30318742 Paper 30262660 Paper 29880586 Paper 29851933 Paper 29747685 Paper 29727246 Paper 29315015 Paper 29301109 Paper 29273500 Paper 29079582 Paper 28978471 Paper 28974431 Paper 28939089 Paper 28856237 Paper 28830878 Paper 28801306 Paper 28783452 Paper 28676343 Paper 28642356 Paper 28602436 Paper 28550199 Paper 28183713 Paper 28129132 Paper 28129119 Paper 27913506 Paper 27897332 Paper 27783956 Paper 27687136 Paper 27626039 Paper 27473568 Paper 27427982 Paper 27313973 Paper 27261481 Paper 27207801 Paper 27183388 Paper 27019998 Paper 26920464 Paper 26708005 Paper 26639404 Paper 26428384 Paper 26332003 Paper 26321144 Paper 26250410 Paper 26240290 Paper 26160910 Paper 26072403 Paper 26056165 Paper 26015959 Paper 25977584 Paper 25947952 Paper 25940712 Paper 25849134 Paper 25734008 Paper 25691731 Paper 25572477 Paper 25505959 Paper 25440610 Paper 25415440 Paper 25386934 Paper 25245583 Paper 25186558 Paper 25159713 Paper 25082406 Paper 25060519 Paper 25049328 Paper 24964991 Paper 24924183 Paper 24876563 Paper 24787977 Paper 24782509 Paper 24753538 Paper 24732709 Paper 24714353 Paper 24667962 Paper 24667955

Abstract

DESCRIPTION (provided by applicant): The malignant B-lineage Reed-Sternberg (H-RS) cells in about half of all cases of Hodgkin lymphoma express Epstein-Barr virus (EBV) antigens, rendering this tumor highly attractive for cytotoxic T-lymphocyte (CTL) immunotherapy. However, these tumor-associated viral antigens are either subdominant (LMP1 and LMP2) or not presented to the immune system (EBNAI and BARFO). The H-RS cells also express molecules that are inhibitory to CTL, such as TGF-beta, the chemoattractant TARC and Fas-ligand that can comprise immunotherapy even when immune epitopes are effectively presented to CTLs. The studies proposed here seek to overcome these immune evasion tactics by redirecting immune responses to the LMP2 viral antigen, using LMP2a-transduced dendritic cells, and by genetically modifying CTLs in vitro so that they will resist the inhibitory effects of TGF-beta and Fas ligand. The latter aim will rely on a transgenic dominant-negative TGF-beta type 2 receptor expressed on CTLs and the adenoviral RID protein, which should render CTLs resistant to inhibition by TGF-beta and killing through Fas ligand-receptor interactions. Our preliminary studies suggest that there may be few T helper epitopes in LMP2. Since persistence in vivo is dependent on the availability of help, we will also explore the possibility that EBNA1, expressed as a retrogen in dendritic cells (using technology developed in project 4) will reactivate EBNA1-specific CD4+ T cells that can provide cognate help for LMP2-specific CTL as well as broaden the cytotoxic repertoire of the tumor specific CTL by reactivating CD4+ EBNA1-specific CTL. The hypotheses underlying these aims will be tested both in vitro and in vivo (Phase l/ll trials in patients with post-transplant or relapsed EBV-positive Hodgkin Lymphoma). Upon successful completion of the project, we will have learned whether our experimental modifications are safe in patients and whether they will render CTLs resistant to several of the immune evasion strategies commonly used by tumor cells.

View original record on NIH RePORTER →