We examined the response of patients who received intravenous infusions of autologous leukemia cells transduced ex vivo to express a recombinant CDI 54 (termed "Ad-CD154 gene-Rx"). We found such treatment could induce p53-dependent genes encoding pro-apoptotic proteins in non-transduced "bystander" CLL cells that lacked functional p53 via c-abl-kinase activafion of TAp7S. Activation of TAp7S could sensitize such drug-resistant CLL cells to the cytotoxic effects of drugs that ordinarily require functional p53. Ad-CD154 gene Rx also could induce auto antibodies to ROR1, which found absent on normal adult tissues, but expressed on CLL cells of virtually all cases, where it plays an apparent role in pathogenesis. We hypothesize that treatment of CLL patients with lenalidomide might mimic these effects of Ad-CDI 54 gene Rx. We also propose that ROR1could serve as an excellent target for development of novel therapies. Finally, ROR1 is one of several receptors for factors engaged in the cross talk between CLL cells and its microenvironment. CLL cells simulated by nurse like cells (NLC) found in the CLL microenvironment are induced to elaborate chemokines (CCLS and CCL4) that can recruit T cells and NLC-precursor cells to the microenvironment. Preliminary data suggest that the serum levels of CCL3/CCL4 might serve as surrogate markers of disease activity and possibly of early response to novel therapies intended to induce immune activation or cause disruption of the CLL microenvironment that are being investigated by the CRC. To take advantage of these observations we have the following specific aims: 1. Evaluate whether lenalidomide can induce anti-ROR1 auto antibodies and mimic the capacity of Ad-CDI 54 Gene Rx to enhance sensitivity of drug-resistant CLL cells to chemotherapy. Determine whether such effects are noted primarily in patients who are most likely to respond favorably to lenalidomide;2. Evaluate expression levels of CCLS and CCL4 in relation to disease progression or response to treatment strategies intended to induce immune activation or disrupt the CLL microenvironment;3. Evaluate strategies to target RORI with RORI vaccines, anti-ROR1 mAbs, T cells bearing ROR1-specific chimeric antigen receptors, or drug-laden liposomes that target ROR1.
The studies in this project could define novel and effective therapies for patients with drug-refractory CLL or CLL in general. These studies also might validate surrogate markers of aggressive disease and/or response to therapy with agents intended to induce immune activation or disruption of the CLL microenvironment that are being investigated by the CRC.
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|Fecteau, Jessie-F; Corral, Laura G; Ghia, Emanuela M et al. (2014) Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53. Blood 124:1637-44|
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