Intratumoral injection of up to 3 x 10(12) viral particles of Ad.IL-12 to patients with advanced digestive malignancies is a feasible and well-tolerated procedure that exerts only mild antitumor effects.

Hypoxia‐inducible factor (HIF)‐1 and HIF‐2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF‐1α and HIF‐2α, are induced similarly by hypoxia, but their functional roles in cancer may be distinct and isoform‐specific. SW480 colon cancer cells with stable expression of siRNA to HIF‐1α or HIF‐2α or both were established. HIF‐1α‐deficient cells displayed lower rates of proliferation and migration, but HIF‐2α‐deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF‐1α deficiency inhibited overall tumor growth, whereas deficiency of HIF‐2α stimulated tumor growth. In human colon cancer tissues, expression of HIF‐1α and to a lesser extent, HIF‐2α, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF‐2α but not HIF‐1α was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF‐1α and HIF‐2α target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular, HIF‐1α promoted the growth of SW480 colon cancer cells but HIF‐2α appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform‐specific properties. © 2008 Wiley‐Liss, Inc.

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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.

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