Intratumoral Injection of Dendritic Cells Engineered to Secrete Interleukin-12 by Recombinant Adenovirus in Patients With Metastatic Gastrointestinal Carcinomas

Abstract

PurposeTo evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity.Patients and MethodsSeventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 × 106to 50 × 106cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals.ResultsFifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment.ConclusionIntratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes

“…Interleukin-12 is critical for therapeutic immunity against cancer (Mazzolini et al, 2003). Artificial enhancement of IL-12 production by DC strengthens elicited immunity and therapeutic potential (Melero et al, 1999;Mazzolini et al, 2005). Therefore, selective inhibition of IL-12 is likely to be suppressive for cellular immune responses.…”

IL-12 immunotherapy of Braf-induced papillary thyroid cancer in a mouse model

“…It has been successfully used in both preclinical 41 and clinical trials. [42][43][44] The commonly used methods include intratumoral injection of IL-12 plasmid DNA, 43 peritumoral injection of IL-12-producing autologous fibroblasts 42 or autologous tumor cells, 45 and intratumoral injection of dendritic cells secreting interleukin-12. 44 The response rate ranges from 6 to 89% depending on the tumor types and method of delivery.…”

“…[42][43][44] The commonly used methods include intratumoral injection of IL-12 plasmid DNA, 43 peritumoral injection of IL-12-producing autologous fibroblasts 42 or autologous tumor cells, 45 and intratumoral injection of dendritic cells secreting interleukin-12. 44 The response rate ranges from 6 to 89% depending on the tumor types and method of delivery. Intratumoral injection of IL-12 plasmid DNA in patients with advanced malignant melanoma, 43 and peritumoral injection of IL-12-producing autologous fibroblasts in patients with disseminated cancer 42 have achieved 89% (8/9) and 56% (5/9) response rate, respectively.…”

Cells as vehicles for therapeutic genes to treat liver diseases

“…7,17 In a recent clinical trial conducted in patients with advanced primary or metastatic liver cancer, monocyte-derived DCs engineered with adenoviral vector encoding IL-12 were injected directly into the tumor. 18 In this trial, 3 monthly doses of the transduced cells were administered, and it was expected that, after intratumoral injection, DCs would take up tumor antigens and migrate to regional lymph nodes to stimulate an antitumor T-cell response that would be facilitated by the in situ production of IL-12. In this trial, the observed antitumor effect was very poor.…”