Oncolytic Immunotherapy of Advanced Solid Tumors with a CD40L-Expressing Replicating Adenovirus: Assessment of Safety and Immunologic Responses in Patients

Abstract

The immunosuppressive environment of advanced tumors is a primary obstacle to the efficacy of immunostimulatory and vaccine approaches. Here, we report an approach to arm an oncolytic virus with CD40 ligand (CD40L) to stimulate beneficial immunologic responses in patients. A double-targeted chimeric adenovirus controlled by the hTERT promoter and expressing CD40L (CGTG-401) was constructed and nine patients with progressing advanced solid tumors refractory to standard therapies were treated intratumorally. No serious adverse events resulting in patient hospitalization occurred. Moderate or no increases in neutralizing antibodies were seen, suggesting effective Th1 immunologic effects. An assessment of the blood levels of virus indicated 17.5% of the samples (n ¼ 40) were positive at a low level early after treatment, but not thereafter. In contrast, high levels of virus, CD40L, and RANTES were documented locally at the tumor. Peripheral blood mononuclear cells were analyzed by IFN-g ELISPOT analysis and induction of both survivin-specific and adenovirus-specific T cells was seen. Antitumor T-cell responses were even more pronounced when assessed by intracellular cytokine staining after stimulation with tumor type-specific peptide pools. Of the evaluable patients, 83% displayed disease control at 3 months and in both cases in which treatment was continued the effect was sustained for at least 8 months. Injected and noninjected lesions responded identically. Together, these findings support further clinical evaluation of CGTG-401. Cancer Res; 72(7); 1621-31. Ó2012 AACR.

Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy

“…6 However, previous work has also revealed the ability of CD40L to induce APC activation not only CD40 C but also in CD40 ¡ tumors, suggesting the potential use of virus for tumor immunotherapy regardless of CD40 status. 6,7,52 This is in accordance with our study in which Ad3-hTERT-CMV-hCD40L (Figs. 3C-E) as well as virally produced hCD40L (Figs.…”

“…Unfortunately, adenovirus alone is not potent enough to initiate a powerful vaccine effect thus presenting the rationale for arming them with immunostimulatory molecules such as CD40L, a potent stimulator of dendritic cells (DCs). [4][5][6][7] There are more than 50 identified serotypes of adenoviruses. Serotype 5 adenoviruses (Ad5) are commonly used in gene therapy applications.…”

Use and Safety of Intratumoral Application of European Mistletoe (Viscum album L) Preparations in Oncology

“…1,2 Anticancer agents that have been applied via IT injection include chemotherapy agents (eg, vincristine), oncolytic viruses (eg, ONYX-015), immunomodulators (eg, agonistic CD40 monoclonal antibodies), and autologous immune cells (eg, dendritic cells). [2][3][4][5][6][7][8][9] Potential advantages of IT delivery of anticancer drugs include better anticancer effectiveness through achievement of high concentrations of anticancer agents within the tumor microenvironment and reduced systemic adverse drug reactions (ADRs) and drug resistance. 5,[10][11][12] In general, single-agent efficacy has been less than satisfying to date; however, promising results have been achieved using IT-administered targeted therapies, combined with conventional chemotherapy or radiation.…”

Dendritic cells serve as a “Trojan horse” for oncolytic adenovirus delivery in the treatment of mouse prostate cancer

“…The CD40-CD40 ligand (CD40L) interaction plays an important regulatory role aspects of in DC function such as T-lymphocyte activation and effector cytokine production [9] . Researchers have shown that arming an oncolytic virus with CD40L brings the tumor antigens to the DC surface by CD40L, thereby initiating more effective anti-tumor immunity [10] .…”