AdCD40L Immunogene Therapy for Bladder Carcinoma—The First Phase I/IIa Trial

Abstract

Purpose: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for highrisk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.Experimental Design: Patients with invasive bladder cancer scheduled for cystectomy or patients with T a tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.Results: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-γ increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.Conclusions: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies. Clin Cancer Res; 16(12); 3279-87. ©2010 AACR.

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

“…Thus, both CD40L and IFN-b confer negative effects on carcinoma growth by improving tumor cell immunogenicity (4,14,15) and triggering direct antiproliferative and proapoptotic properties (37)(38)(39)(40)(41). Both CD40L and type I IFNs also act on immune cells to augment Th1 cell responses, enhance expression of MHC class I molecules, and generate NK and T cellmediated cytotoxicity (reviewed in Refs.…”

“…The CD40 pathway holds promise for the immunotherapy of various types of cancer, including non-Hodgkin's lymphoma (44), chronic lymphocytic leukemia (45), and carcinoma (46,47), and CD40 agonists have recently entered clinical trials, with promising results (38,48). The aforementioned role of RelA as a master regulator of IFN-b, coupled with its previously described involvement in the CD40-mediated Ag transporter and immunoproteasome gene expression (15), suggests that NF-kB may make a positive contribution to CD40L therapy by controlling antitumor immunity.…”

Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer

“…We have previously shown that local adenoviral CD40L (AdCD40L) as well as CpG therapy can induce systemic antitumor responses in experimental bladder cancer (5,6). AdCD40L therapy has proven efficient and safe in both humans (7) and dogs (8). Consequently, we wanted to investigate whether local low-dose agonistic CD40 antibody injection could clear experimental bladder cancer.…”

CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma

“…[54][55][56] In human bladder cancer patients, an adenovirus expressing CD40L induced large T-cell infiltrates in the bladder wall. 57 …”