Originally published as JCO Early Release 10.1200/JCO.2005.12.147 on August 1 2005

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Chemo-Immunotherapy of Metastatic Colorectal Carcinoma With Gemcitabine Plus FOLFOX 4 Followed by Subcutaneous Granulocyte Macrophage Colony-Stimulating Factor and Interleukin-2 Induces Strong Immunologic and Antitumor Activity in Metastatic Colon Cancer Patients

Pierpaolo Correale, Maria Grazia Cusi, Kwong Yok Tsang, Maria Teresa Del Vecchio, Stefania Marsili, Marco La Placa, Chiara Intrivici, Angelo Aquino, Lucia Micheli, Cristina Nencini, Francesco Ferrari, Giorgio Giorgi, Enzo Bonmassar, Guido Francini

From the Section of Medical Oncology; Section of Pathology, Department of Human Pathology and Oncology; Section of Virology, Department of Molecular Biology; Giorgio Segre Department of Pharmacology; Department of Imaging and Radiology; Interdepartmental Oncopharmacological Centre, Siena University School of Medicine, Siena; Medical Oncology and Pharmacology Section, Department of Neuroscience, Tor Vergata University, Rome, Italy; and the Experimental Oncology Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD

Address reprint requests to Prof. Guido Francini, Director of the Oncology Section, Department of Human Pathology and Oncology, Siena University School of Medicine, Viale Bracci 11, 53100 Siena, Italy; e-mail: francini{at}unisi.it.

PURPOSE: Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen–specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy.

MATERIALS AND METHODS: We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 males and 13 females with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement.

RESULTS: The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMCs) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4⁺CD25_T-reg⁺). A cytofluorimetric study of the PBMCs of five HLA-A()02.01⁺ patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes.

CONCLUSION: The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.

Supported by a grant from the Italian Ministry of University and Technology (MIUR-2004).

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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