Patients treated with autologous CLL cells transduced with an adenovirus encoding murine CD154 (Ad-[unreadable] CD154) experienced acute declines in leukemia cell counts and lymph node size and long-term desirable[unreadable] effects, including increased numbers of leukemia-reactive T cells, generation of anti-CLL antibodies, and[unreadable] apparent slowing or halting of disease progression. Treated patients had changes in bystander nontransfected[unreadable] CLL cells, reflecting activation by CD154 in vivo. We found that CD154-activation induced a[unreadable] programmed series of events in CLL cells, which initially were transiently protected and then sensitized to[unreadable] apoptosis induced by ligation of induced extrinsic death receptors (e.g. CD95 and DR5), cytotoxic drugs, or[unreadable] novel agents that inhibit the inhibitor of apoptosis (IAP) proteins (see project 2). Sensitivity to these agents[unreadable] appears associated with the capacity of CD154-activation to induce expression of the pro-apoptotic molecule[unreadable] Bid through a p53-independent, c-Abl-dependent mechanism, which apparently involves the alpha isoform of[unreadable] p73. This raises the exciting prospect that Ad-CD154 gene therapy may circumvent the dependency on p53[unreadable] of anti-leukemia drugs, while inducing anti-leukemia cellular and antibody immune responses. The latter[unreadable] already have allowed us to identify a novel CLL-associated antigen, Ror1, which potentially could be used in[unreadable] assays to monitor the activity of Ad-CD154 gene therapy or in vaccines for immune therapy of this disease.[unreadable] For future clinical studies, we developed a "humanized" CD154 (designated ISF35) that can be stably[unreadable] expressed at high-levels on the CLL plasma membrane. This project has the following specific aims: (1)[unreadable] Continue ongoing analyses of the mechanism(s) responsible for the acute fall in leukemia-cell counts[unreadable] observed in patients treated with autologous Ad-CD154-transduced, or ISF35-transduced, CLL cells; (2)[unreadable] Examine cellular immune responses against a newly-identified CLL-associated antigen, Ror1; (3) Evaluate[unreadable] the specificity and biologic activity of anti-leukemia antibodies induced by Ad-CD154 gene therapy, with[unreadable] special emphasis on anti-Rorl autoantibodies. (4) Develop the E mu-TCL1 mouse model generated in Project[unreadable] 1 to evaluate parameters intended to maximize the activity of Ad-CD154 gene therapy, either alone or in[unreadable] combination with anti-leukemia drugs or immune-based treatment strategies.[unreadable]
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