Summary
Advanced colorectal cancer is a common disease with an high mortality rate. For four decades, pharmacological treatment of the advanced disease was based on the use of 5-fluorouracil alone or in combination with biomodulators such as folinic acid and intereferon alpha. In the last 5 years, response to therapy has been considerably ameliorated thanks to the discovery of new drugs such as oxaliplatin and CPT-11. These agents, in combination with 5-fluorouracil, according to various schedules of treatment, have reached a significant improvement of palliation, response rate and survival. Immunotherapy is an uprising modality of treatment for human cancer including colorectal carcinoma. Its rationale is based on the knowledge that tumour cells are genetically unstable and produce molecular structures which allow their recognition and destruction by the immune-surveillance system. Therefore, humoral as well as cellular compartments of the immune system can be utilized according to a “passive” strategy (e.g. monoclonal antibody administration and adoptive immunotherapy) or an “active” approach, by using different modalities of vaccine therapy. In this context, monoclonal antibodies (mAbs) and cancer vaccines are being tested for the treatment of advanced colorectal cancer. Due to their genetic instability and extraordinary adaptative potential, tumour cells may acquire resistance to the immune effectors and mAbs exactly as they do for cytotoxic drugs. To improve the results of both immunological and chemical modality of cancer treatment, an increasing number of authors is starting to combine chemo and immunotherapy in the attempt to circumvent the limitations of both strategies.
This report tries to review the possible rationale of the chemo-immunotherapy combination, illustrating preliminary results of preclinical and clinical studies.
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Ferlay J, Bray F, Pisani P, Parkin DM (2001) Cancer incidence, mortality and prevalence worldwide. In: GLOBOCAN 2000 version 1.0 IARC CancerBase No. 5. IARC Press, Lyon
Grem JL (1996) 5-Fluoropyrimidines. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy principles and practice, 2nd edn. Lippincot William & Wilkins, Philadelphia, pp 149–163
Francini G, Petrioli R, Lorenzini L, Mancini S, Armenio S, Tanzini G, Marsili S, Aquino A, Marzocca G, Civitelli S, Mariani L, De Sando D, Lorenzi M (1994) Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer. Gastroenterology 106:899–906
O'Connell MJ, Laurie JA, Kahn M, Fitzgibbons RJ Jr, Erlichman C, Shepherd L, Moertel CG, Kocha WI, Pazdur R, Wieand HS, Rubin J, Vukov AM, Donohue JH, Krook JE, Figueredo A (1998) Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16:295–300
Skibber JM, Minsky BD, Hoff PM (2001) Cancer of the Colon. In: De Vita V, Hellman S, Rosenberg SA (eds) Cancer principles and practice of oncology, 6th edn. Lippincott Williams & Wilkins, Philadelphia, pp 1216–1271
Von Hoff DD (1998) Promising new agents for treatment of patients with colorectal cancer. Semin Oncol 25:47–52
Salts LB, Locker PK, Pirotta N, Eltring GL, Miller LL (1999) Weekly irinotecan (CPT-11), leucovorin (LV), and Fluorouracil (FU) is superior to daily x 5 LV/FU in patients with previously untreated metastatic colorectal cancer. (“Abstract”). Proc Am Soc Clin Oncol 18:898
Fischel JL, Etienne MC, Formento P, Milano G (1998) Search for the optimal schedule for the oxaliplatin/5-fluorouracil association modulated or not by folinic acid: preclinical data. Clin Cancer Res 4:2529–2535
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30
Gill S, Loprinzi CL, Sargent DJ, Thomé SD, Alberts SR, Haller DG, Benedetti J, Francini G, Shepherd LE, Seitz JF, Labianca R, Chen W, Cha SS, Heldebrant MP, Goldberg RM (2004) Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22:1797–1806
Rosenberg SA (1992) Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer. J Clin Oncol 10:180–199
Wang RF, Rosenberg SA (1999) Human tumor antigens for cancer vaccine development. Immonol Rev 170:85–100
Thompson JA, Grunert F, Zimmermann W (1991) Carcinoembryonic antigen gene family: molecular biology and clinical perspectives. J Clin Lab Anal 5:344–366
Evans TR, Kaye SB (1999) Vaccine therapy for cancer—Fact or fiction? Q J M 92:299–307
Swartzberg L (2001) Clinical experience with edrecolomab: a monoclonal antibody therapy for colorectal carcinoma. Crit Rev Oncol Hematol 40:17–24
Fields AL, Keller AM, Schwartzberg L, Bernard S, Pazdur R, Kardinal C, Cohen J, Schultz J, Eisenberg P, Barber L, Edmundson S, Wissel P (2002) Edrecolomab (17-1A antibody) in combination with 5-Fluorouracil based chemotherapy in the adjuvant treatment of stage II colon cancer: results of a randomized North America phase III study. Proc Am Soc Clin Oncol 21:128a(abstract 508)
Punt CJ, Nagy A, Douillard JY, Figer A, Skovsgaard T, Monson J, Barone C, Fountzilas G, Riess H, Moylan E, Jones D, Dethling J, Colman J, Coward L, MacGregor S: Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 31;360(9334):671–677
Velders MP, van Rhijn CM, Oskam E, Fleuren GJ, Warnaar SO, Litvinov SV (1998) The impact of antigen density and antibody affinity on antibody-dependent cellular cytotoxicity: relevance for immunotherapy of carcinomas. Br J Cancer 78:478– 483
Pantel K, Braun S, Passlick B, Schlimok G (1996) Minimal residual epithelial cancer: diagnostic approaches and prognostic relevance. Prog Histochem Cytochem. 30(3):1–60
Veronese ML, O'Dwyer PJ (2004) Monoclonal antibodies in the treatment of colorectal cancer. Eur J Cancer 40:1292–1301
Alliot C, Spizzo G, Punt CJ (2003) Edrecolomab in the adjuvant treatment of colorectal carcinoma. Lancet 361:82–83
Haller DG: Update of clinical trials with edrecolomab (2001) a monoclonal antibody therapy for colorectal cancer. Semin Oncol 28(1 Suppl 1):25–30
Baselga J (2002) Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 7(Suppl 4):2–8
Hemming AW, Davis NL, Kluftinger A, Robinson B, Quenville NF, Liseman B, LeRiche J (1992) Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol 51:147–152
Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J, Fan Z (2000) Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cell lines do not involve the c-Jun N-terminal kinase activity. Br J Cancer 82:1991–1999
Mendelson J (2001) The epidermal growth factor receptors: a target for cancer therapy. Endocr Relat Cancer 8:3–9
Ciardiello F, Bianco R, Damiano V, De Lorenzo S, Pepe S, De Placido S, Fan Z, Mendelsohn J, Bianco AR, Tortora G (1999) Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5:909–916
Prewett MC, Hooper AT, Bassi R, Ellis LM, Waksal HW, Hicklin DJ (2002) Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Cancer Res 8:994–1003
Mendelson J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in biology and treatment of cancer. J Clin Oncol 21:2787–2799
Saltz L, Rubin M, Hochster H, Tchekmeydian NS, Waksal H, Needle A, LoBuglio A (2001) Cetuximab (IMC-C225) plus irinotecan (CPT-11) ia active in CPT-11 refractory colorectal cancver (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 20:3a(Abstr 7)
Lutz MP, Schoffski P, Folprecht G, Haag C, Seufferlein T, Beutel G, Marschner JP, Mueser M, Harstrick A, KöHne H (2001) A phase I/II study of cetuximab (C225) plus irinotecan (CPT-11) and 24 h infusional 5 F U/folinic acid (FA) in the treatment of metastatic colorectal cancer (MCRC) expressing the epidermal growth factor receptor (EGFR). Ann Oncol 13(Suppl 5):73(abstract 265PD)
Rosenberg AH, Loehrer PJ, Needle MN, Waksal H, Hollywood E, Ramos L, Saltz LB (2002) Erbitux (IMC-C225) plus weekly irinotecan (CPT-11), fluorouracil (5FU) and leucovorin (LV) in colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFr). Proc Am Soc Clin Oncol 21:135a (Abstr 536)
Van Laethem JL, Raoul JL, Mitry E, Brezault C, Husseini F, Cals L, Vedovato JC, Mueser MM, Rougier P (2003) Cetuximab (C225) in combination with bi-weekly irinotecan (CPT-11), infusional 5-fluorouracil (5-FU) and folinic acid (FA) in patients (pts) with metastatic colorectal cancer (CRC) expressing the epidermal growth factor receptor (EGFR). Preliminary safety and efficacy results. Proc Am Soc Clin Oncol 22:264 (Abstr 1058)
Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345
van den Eertwegh AJM, Baars A, Pinedo HM (2001) Adjuvant treatment of colorectal cancer: toward tumor-specific immunotherapies. Cancer Metastasis Rev 20:101–108
Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182–1186
Kabbinavar F, Schulz J, McCleod M, Patel T, Hamm J, Hecht J, Perrou B, Griffing S, Nelson B, Novotny W (2004) Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, prolongs progression-free survival in first line colorectal cancer in subjects who are not suitable candidates for first-line CPT-11. Proc Am Soc Clin Oncol 22:249(abstract 3516)
Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400
Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, Griffing S, Bergsland E (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65
Fernando NH, Hurwitz HI (2004) Targeted therapy of colorectal cancer: clinical experience with bevacizumab. Oncologist 9(Suppl 1):11–18
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron Ari, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med 350:2335– 2342
Meyerhardt JA, Mayer RJ (2005) Systemic therapy for colorectal cancer. New Engl J Med 352:476–487
Baselga J (2003) Skin as surrogate tissue for pharmacodynamic end points: is it deep enough? Clin Cancer Res 9:2389– 2390
Jung S, Schluesener HJ (1991) Human T lymphocytes recognize a peptide of single point-mutated oncogenic ras proteins. J Exp Med 173:273–276
Anderson KS, Alexander J, Wei M, Cresswell P (1993) Intracellular transport of class I MHC molecules in antigen processing mutant cell lines. J Immunol 151:3407–3419
Melero I, Nathan B, Lieping C (1997) Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumor antigens. Life Sci 60:2035–2041
Grabbe S, Beissert S, Schwarz T, Granstein RD (1995) Dendritic cells as initiators of tumor immune responses: a possible strategy for tumor immunotherapy? Immunol Today 16:117– 121
Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Ann Rev Immunol 9:271–296
Bell D, Young JW, Banchereau J (1999) Dendritic cells. Adv Immunol 72:255–324
Hanna MG, Peters LC (1978) Specific immunotherapy of established visceral micrometastases by BCG-tumor cell vaccine alone or as an adjunct to surgery. Cancer 42:2613–2625
Baars A, Buter J, Pinedo HM (2002) Making use of the primary tumor. BioEssay 25:79–86
Vermorken JB, Claessen AM, van Tinteren H, Gall HE, Ezinga R, Meijer S, Scheper RJ, Meijer CJ, Bloemena E, Ransom JH, Hanna MG Jr, Pinedo HM (1999) Active specific immunotherapy for stage II and stage III human colon cancer: a randomized trial. Lancet 353:345–350
Parmiani G, Colombo MP, Melani C, Arienti F (1997) Cytokine gene trasduction in the immunotherapy of cancer. Adv Pharmacol 40:259–307
Parmiani G, Rodolfo M, Melani C (2000) Immunological gene therapy with ex vivo gene modified tumor cells: a critique and a reappraisal. Hum Gene Ther 11:1269–1275
Waelti ER, Gluck R (1998) Delivery to cancer cells of antisense L-myc oligonucleotides incorporated in fusogenic, cationic-lipid-recostitued influenza-virus envelopes (cationic virosomes). Int J Cancer 77:728–733
Aarts WM, Schlom J, Hodge JW (2002) Vector based vaccine/cytokine combination therapy to enhance induction of immune response to a self- antigen and anti-tumor activity. Cancer Res 62:5770–5777
Harshyne LA, Watkins SC, Gambotto A, Barratt-Boyes SM (2001) Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J Immunol 166:3717–3723
Brigl M, Brenner MB (2004) CD1 antigen presentation and T cell function. Ann Rev Immunol 22:817–890
Nestle FO (2000) Dendritic cell vaccination for cancer therapy. Oncogene 19:6673–6679
Srivastava PK, Menoret A, Basu S, Binder RJ, McQUade KL (1998) Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 8:657– 665
Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70 and calreticulin. Immunity 14:303–313
Falk K, Rötzschke O, Stevanovic S, Rammensee HG (1991) Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351:290–296
Parker KC, Bednarek MA, Coligan JE (1994) Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 152:163–175
Robbins PF, Kawakami Y (1996) Human tumor antigens recognized by T cells. Curr Opin Immunol 8:628–636
Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, Schlom J (1995) Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia-CEA vaccine. J Natl Cancer Inst 87:982–990
Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E, Pedicano JE, Gehan E, Peck RA, Arlen P, Tsang KY, Schlom J (2000) Phase I study in advanced cancer patients of a diversified prime boost vaccination protocol using recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J Clin Oncol 18:3964–3973
Morse MA, Deng Y, Coleman D, Hull S, Kitrell-Fisher E, Nair S, Schlom J, Ryback ME, Lyerly HK (1999) A phase I study of active immunotherapy with carcinoembryonic antigen peptide(CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignacies expressing carcinoembryonic antigen. Clin Cancer Res 5:1331–1338
Kantor J, Irvine K, Abrams S, Kaufman H, DiPietro J, Schlom J (1992a) Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigen vaccinia virus vaccine. J Natl Cancer Inst 84:1084–1091
Kantor J, Irvine K, Abrams S Snoy P, Olsen R, Greiner J, Kaufman H, Eggensperger D, Schlom J (1992b) Immunogenicity and safety of a recombinant vaccinia virus vaccine expressing the carcinoembryonic antigen gene in a nonhuman primate. Cancer Res 52:6917–6925
Foon KA, John WJ, Chakraborty M, Serratt A, Garrison J, Flett M, Bhattacharya-Chatterjee M (1997) Clinical and immune responses in advanced colorectal cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. Clin Cancer Res 3:1267–1276
Kass E, Schlom J, Thompson J, Guadagni F, Graziano P, Greiner JW (1999) Induction of protective host immunity to carcinoembryonic antigen (CEA), a self antigen in CEA transgenic mice, by immunizing with a recombinant vaccinia-CEA virus. Cancer Res 59:676–683
Correale P, Walmsley K, Nieroda C, Zaremba S, Zhu M, Schlom J, Tsang KY (1997) In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen. J Natl Cancer Inst 89:293–300
Houbiers JG, Nijman HW, van der Burg SH, Drijfhout JW, Kenemens P, van de Velde CJ, Brand M, Momberg F, Kast WM, Melief CJM (1993) In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur J Immunol 23:2072–2077
Francini G, Scardino A, Kosmatopoulos K, Lemonnier KA, Capoccia G, Sabatino M, Pozzessere D, Petrioli R, Lozzi L, Neri P, Fanetti G, Cusi MG, Correale P (2002) High Affinity HLA-A(*)02.01 peptides from parathyroid-hormone related protein generate in vitro and in vivo antitumor CTL response without autoimmune side effects. J Immunol 169:4840– 4849
Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G (2002) Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol 46:33–57, 2003
Zinkernagel RM (2001) Immunity against solid tumors. Int J Cancer 93:1–5
Graziani G, Faraoni I, Grohmann U, Bianchi R, Binaglia L, Margison GP, Watson AJ, Orlando L, Bonmassar E, D'Atri S (1995) O6-alkylguanine-DNA alkyltransferase attenuates triazene-induced cytotoxicity and tumor cell immunogenicity in murine L1210 leukemia. Cancer Res 55:6231–6236
Heinzer H, Huland E, Huland H (2001) Systemic chemotherapy and chemoimmunotherapy for metastatic renal cell cancer. World J Urol 19:111–119
Elias L, Binder M, Mangalik A, Clark D, Morrinson B, Altobelli KK, Smith A (1999) Pilot trial of infusional 5-fluorouracil, interleukin-2, and subcutaneous interferon α for advanced renal cell carcinoma. Am J Clin Oncol 22:156–161
Lauro S, Bordin F, Trasatti L, Lanzetta G, Della Rocca C, Frati L (1999) Concurrent chemoimmunotherapy in metastatic clear cell sarcoma: a case report. Tumori 85:512–514
Lau WY, Leung TWT, Lai BS, Liew CT, Ho SKJW, Yu SCH, Tang AMY (2001) Preoperative systemic chemoimmunotherapy and sequential resection of unresectable hepatocellular carcinoma. Ann Surg 233:236–241
D'Atri S, Marini S, Tentori L, Tricarico M, Fuggetta MP, Bonmassar E (1991) Drug-mediated increase of susceptibility of human lung cancer to NK or LAK effector cells. Immunopharmacology 21:199–210
Correale P, Caraglia M, Fabrocini A, Guardasi R, Pepe S, Patella V, Marone G, Pinto A, Bianco AR, Tagliaferro P (1995) Bryostatin 1 enhances lymphokine activated killer sensitivity and modulates the beta 1 integrin profile of cultured human tumor cells. Anticancer Drugs 6:285–290
Correale P, Tagliaferri P, Celio L, Genuav G, Montagnani S, Bianco AR (1991) Verapamil upregulates sensitivity of human colon and breast cancer cells to LAK-cytotoxicity in vitro. Eur J Cancer 27:1393–1395
Tagliaferri P, Correale P, Mottola M, De Simone G, Montesarchio V, Matano E, Rea A, Morabito A, Famiani M, Ciardiello F, Tortora G, Caraglia M, Barile C, Palmieri G, Bianco AR (1996) High-dose recombinant interleukin-2/Verapamil combination in advanced cancer. Eur J Cancer 32:1436–1437
Frost P, Ng CP, Belldegrun A, Bonavida B (1997) Immunosensitization of prostate carcinoma cell lines for lymphocyte (CTL, TIL, LAK)-mediated apoptosis via the fas-fas-ligand pathway of cytotoxicity. Cell Immunol 180:70–83
Bergmann-Leitner ES, Abrams SI (2001) Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-specific CD8+ cytotoxic T lymphocytes. Cancer Immunol Immunother 50:445–455
Correale P, Aquino A, Pellegrini M, Micheli L, Cusi MG, Nencini C, Petrioli R, Prete SP, De Vecchis L, Turriziani M, Giorgi G, Bonmassar E, Francini G (2003) Treatment of colon and breast carcinoma cells with 5-fluorouracil enhances expression of carcinoembryonic antigen and susceptibility to HLA-A(*)02.01 restricted, CEA-peptide-specific cytotoxic T cells in vitro. Int J Cancer Apr 20;104(4):437–445
Correale P, Del Vecchio MT, Di Genova G, Savellini GG, La Placa M, Terrosi C, Vestri M, Urso R, Lemonnier F, Aquino A, Bonmassar E, Giorgi G, Francini G, Cusi MG (2005) 5-fluorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine. J Natl Cancer Inst 97:1437–1445
Bellone M (2000) Apoptosis, cross-presentation, and the fate of the antigen specific immune response. Apoptosis 5:307–314
Onier N, Hilpert S, Arnould L, Saint-Giorgio V, Davies JG, Jeannin JF, Jeannin JF (1999) Cure of colon cancer metastasis in rats with the new lipid A OM 174. Apoptosis of tumor cells and immunization of rats. Clin Exp Metastasis 17:299–306
Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, Rigo P, Green A (2002) Increased uptake of the apoptosis-imaging agent (99 m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 8:2766–2774
Markowicz S, Engleman EG (1990) Granulocyte-macrophage colony stimulating factor promotes differentiation and survival of human peripheral blood dendritic cells in vitro. J Clin Invest 85:955–961
Morgan DA, Ruscetti FW, Gallo R (1976) Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193:1007–1008
Correale P, Campoccia G, Tsang KY, Micheli L, Cusi MG, Sabatino M, Bruni G, Sestini S, Petrioli R, Pozzessere D, Marsili S, Fanetti G, Giorgi G, Francini G (2001) Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hrGM-CSF (molgramostim) and hr IL-2: results from a Phase Ib Clinical Trial. Eur J Cancer 37:892–902
Correale P, Cusi MG, Tsang KY, Del Vecchio MT, Marsili S, Placa ML, Intrivici C, Aquino A, Micheli L, Nencini C, Ferrari F, Giorgi G, Bonmassar E, Francini G (2005) 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. J Clin Oncol 23:8950–8958
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Correale, P., Cusi, M.G., Micheli, L. et al. Chemo-immunotherapy of colorectal carcinoma: preclinical rationale and clinical experience. Invest New Drugs 24, 99–110 (2006). https://doi.org/10.1007/s10637-006-5932-7
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DOI: https://doi.org/10.1007/s10637-006-5932-7