Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule.

Abstract

New therapies for chronic lymphocytic leukemia (CLL) are needed, particularly those that can eradicate residual disease and elicit anti-CLL immune responses. CD40 ligation on CLL cells, which can be achieved using adenovirus encoding chimeric CD154 (Ad-ISF35), enhances their ability to function as antigen-presenting cells and increases their sensitivity to clearance by immune-effector mechanisms. In this study, we report the results of a first-in-man phase I trial of intranodal direct injection (IDI) of Ad-ISF35 in patients with CLL to evaluate toxicity, safety, and tolerability. Fifteen patients received a single IDI of 1 × 10(10) to 33 × 10(10) Ad-ISF35 viral particles (vp), with a defined maximum tolerated dose as 1 × 10(11) vp. Although the most common adverse events were transient grade 1 to 2 pain at the injection site and flu-like symptoms following IDI, some patients receiving the highest dose had transient, asymptomatic grade 3 to 4 hypophosphatemia, neutropenia, or transaminitis. Increased expression of death receptor, immune costimulatory molecules, and Ad-ISF35 vector DNA was detected in circulating CLL cells. Notably, we also observed preliminary clinical responses, including reductions in leukemia cell counts, lymphadenopathy, and splenomegaly. Six patients did not require additional therapy for more than 6 months, and three achieved a partial remission. In conclusion, Ad-ISF35 IDI was safely delivered in patients with CLLs and induced systemic biologic and clinical responses. These results provide the rationale for phase II studies in CLLs, lymphomas, and CD40-expressing solid tumors.

• Authors: Januario E Castro, Johanna Melo-Cardenas, Mauricio Urquiza, Juan S Barajas-Gamboa, Ramin S Pakbaz, Thomas J Kipps
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 12 Pg. 2937-48 (Jun 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22505652 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytokines
• Recombinant Fusion Proteins
• CD40 Ligand

Topics

• Adenoviridae (genetics)
• Aged
• Antibody Formation
• Antigen-Presenting Cells (immunology)
• CD40 Ligand (genetics, immunology)
• Cytokines (blood)
• Female
• Genetic Therapy
• Genetic Vectors
• Humans
• Immunotherapy
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, immunology, therapy)
• Male
• Middle Aged
• Recombinant Fusion Proteins (immunology)