Abstract #3613: Phase I study of direct intranodal injection of adenovirus encoding recombinant CD40-ligand (Ad-ISF35) in patients with chronic lymphocytic leukemia

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Chronic lymphocytic leukemia (CLL) is a malignancy of inept antigen presenting B cells (APC) that possibly re-circulate between the blood, marrow, and secondary lymphoid compartments. Studies indicate that transduction of CLL cells ex vivo with the gene encoding the CD40-ligand (CD154) can convert transduced and non-transduced \#8220;bystander\#8221; CLL cells into proficient APC capable of eliciting immune responses against leukemia-associated antigens. In a recent study, patients received infusions of autologous CLL cells transduced ex vivo with a replication-defective adenovirus encoding ISF35 (Ad-ISF35), a recombinant CD154 engineered to have enhanced membrane stability and activity in effecting CD40-ligation. This treatment was well tolerated, did not have dose-limiting toxicity and elicited anti-leukemia effects. Because of these results, and preclinical studies demonstrating systemic anti-lymphoma activity upon direct injection of Ad-ISF35 into growing tumors, we conducted a first-in-man phase I clinical study, evaluating the safety of direct intranodal injections of Ad-ISF35 in patients with CLL. Fifteen patients, ages 45-71 years (10 male and 5 female), with progressive CLL participated in a dose-escalation study involving 4 single dose cohorts (1x10e10, 3x10e10, 1x10e11, or 3x10e11 Ad-ISF35 viral particles). Intranodal injection of Ad-ISF35 was well tolerated. Adverse events included injection site erythema, pain and/or swelling and \#8220;flu like symptoms\#8221;. Two of 6 patients in the 1x10e11 cohort and 3 of 3 patients in the 3x10e11 cohort developed asymptomatic and transient Grade 3 or 4 neutropenia or hypophosphatemia.Although we did not detect systemic distribution of Ad-ISF35 following treatment, injection of Ad-ISF35 into a single lymph node resulted in systemic anti-leukemia effects. Treated patients experienced reductions in CLL blood counts, lymph nodes and spleen size. This activity was durable in 9 patients with leukemia cell counts below pre-treatment levels for up to 4 months. Reductions in the lymph node size were observed in the majority of patients with a median reduction from base line of 56.4% (25.8-72.7%) and median duration of 6 months (range 2.7-12.4 months). Four of 15 treated patients have not required additional anti-leukemia treatment over a median follow-up period of 9 months. We also observed a systemic \#8220;bystander\#8221; effect in the non-transduced CLL cells found in the blood, thus supporting a model for continuous leukemia-cell re-circulation between blood and lymph node compartments. These changes included up-regulation of death receptors, immune co-stimulatory molecules, and pro-apoptotic proteins. Collectively, these studies indicate that direct intranodal injection of Ad-ISF35 is feasible, well tolerated, and has clinical activity in patients with CLL and possibly other B cell malignancies. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3613.