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.
OBJECTIVE
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.


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+CD25T-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.


CONCLUSIONS
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.
Correale
Pierpaolo
P
Section of Medical Oncology, Department of Human Pathology and Oncology, Siena University School of Medicine, Viale Bracci 11, 53100 Siena, Italy.
Cusi
Maria Grazia
MG
Tsang
Kwong Yok
KY
Del Vecchio
Maria Teresa
MT
Marsili
Stefania
S
Placa
Marco La
ML
Intrivici
Chiara
C
Aquino
Angelo
A
Micheli
Lucia
L
Nencini
Cristina
C
Ferrari
Francesco
F
Giorgi
Giorgio
G
Bonmassar
Enzo
E
Francini
Guido
G
D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D013940:Thymidylate Synthase / Q000276:immunology; D016896:Treatment Outcome; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; D002272:Carcinoembryonic Antigen; D007376:Interleukin-2; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013940:Thymidylate Synthase; D002955:Leucovorin; D005472:Fluorouracil; D000093542:Gemcitabine