3003 Background: Transduction of chronic lymphocytic leukemia (CLL) cells with replication-defective adenovirus (Ad) encoding a genetically engineered, membrane-stablized CD154 (ISF35) converts transduced, and “bystander” non-transduced, CLL cells into proficient antigen presenting cells that can induce immunity against autologous leukemia cells. Preclinical studies demonstrated that direct injection of Ad-ISF35 into lymphoma nodules can induce potent anti-lymphoma immune responses in test animals, capable of eradicating lethal tumors at distal sites and protect against recurrent disease upon subsequent re-challenge with syngeneic tumor. Methods: We conducted a phase I study on 15 patients to evaluate the safety of intranodal direct injection (IDI) of Ad-ISF35. Pts, ages 45–71 yrs, with rapidly progressive disease (median CLL doubling time of 3.7 months) each received a single ultrasound guided IDI of 1 to 30 x 1010 Ad-ISF35 viral particles in 4 different dose cohorts. Results: IDI of Ad-ISF35 was well-tolerated and effective in inducing systemic responses. Some pts had grade ≤ 2 injection-site erythema, pain and/or swelling, or flu-like symptoms. Some pts in the highest-dose cohorts had transient, asymptomatic grade 3/4 hypophosphatemia. No long-term (≥ 6 wk) adverse effects were observed. Although there was no evidence for dissemination of Ad-ISF35 beyond the injected lymph node, IDI of Ad-ISF35 induced blood CLL cells to express death receptors, pro-apoptotic proteins, and immune co-stimulatory molecules similar to those induced on “bystander” CLL cells co-cultured with Ad-ISF35 transduced cells in vitro. Importantly, IDI of Ad-ISF35 resulted in significant reductions in blood leukemia cell counts and a median reduction of 53.2% (range 25–75.4%) in the size of lymph nodes and/or spleen, which was durable (≥ 4 months) in 9 pts. Despite aggressive disease prior to treatment, the median treatment-free survival was 5.3 months and 3 pts have yet to require additional treatment after 1-year follow-up. Conclusions: Single IDI of Ad-ISF35 was safe and effective in inducing systemic biologic and clinical responses in pts with CLL. IDI of Ad-ISF35 might be effective in the treatment of CLL and related lymphomas. [Table: see text]
Phase I study of ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma