Chemo-immunotherapy of colorectal carcinoma: preclinical rationale and clinical experience
ABSTRACT 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.
- SourceAvailable from: Yuji Naito
[Show abstract] [Hide abstract]
- "However, there have been few studies combining immunotherapy and chemotherapy in cancer, mostly because it has been widely assumed that chemotherapy is immunosuppressive and would negate the potential benefits of immunotherapy. Recent evidence indicates that cytotoxic anticancer agents also affect the immune system, contributing to tumor regression.(1,7–9) In this study, we examined the effects of anticancer agents on PBMCs to provide a foundation for a rational approach to chemotherapy that would enable the effective use of adjunctive immunotherapy. "
ABSTRACT: We investigated the effects of anticancer agents on peripheral blood mononuclear cells for the purpose of providing data to support new translational chemoimmunotherapy regimens. Peripheral-blood mononuclear cells were treated with one of four anticancer agents (5-fluorouracil, irinotecan, cisplatin, and gemcitabine) for 2 h, after which cell viability was determined. For assessment of effects of each drug on proliferation and cytokine production, cells were stimulated with phytohemagglutinin for 48 h. As a result, the anticancer agents did not affect cell viability. Cell proliferation was unaffected by 5-fluorouracil and irinotecan but inhibited by cisplatin and gemcitabine. Treatment with gemcitabine enhanced the production of IFN-γ and decreased the number of regulatory T cells. gemcitabine treatment increased IFN-γ production among CD4 T cells but not among CD8 T cells. The results indicated that GEM had immunoregulatory properties that might support immune response against cancer. This finding has implications for designing chemoimmunotherapy strategies.Journal of Clinical Biochemistry and Nutrition 01/2013; 52(1):64-71. DOI:10.3164/jcbn.12-60 · 2.29 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Colorectal cancer remains the second leading cause of cancer-related mortality in the United States. Although surgical resection is still the primary treatment for colorectal cancer, in recent years, there has been a remarkable progress in the development of new therapies to treat colorectal cancer. Response rates have increased substantially and new immunotherapeutic approaches are shedding new light in the battle against the disease. This review will focus on the current immunotherapeutic approaches being developed and will discuss clinical data for some of these new treatments.Cancer biology & therapy 02/2007; 6(1):11-7. DOI:10.4161/cbt.6.1.3672 · 3.63 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: GOLFIG chemoimmunotherapy regimen proved to be a safe and very active chemoimmunotherapy regimen in advanced colon cancer patients. We have thus investigated the immunobiological feedback to the treatment and its possible correlation with the clinical outcome of these patients. This clinical and immunologic study involved 46 patients, 27 males and 19 females, enrolled in the GOLFIG-1 phase II trial who received gemcitabine (1,000 mg/m(2) on days 1 and 15), oxaliplatin (85 mg/m(2) on days 2 and 16), levofolinic acid (100 mg/m(2) on days 1, 2, 15, and 16), and 5-fluorouracil (400 mg/m(2) as a bolus, and 800 mg/m(2) as a 24-hour infusion on days 1, 2, 15, and 16) followed by s.c. granulocyte macrophage colony-stimulating factor (100 mug, on days 3-7) and interleukin 2 (0.5 x 10(6) IU twice a day on days 8-14 and 17-29). The regimen was confirmed to be safe and very active in pretreated patients with metastatic colorectal cancer. A subgroup analysis of these patients revealed a prolonged time to progression and survival in six patients who developed late signs of autoimmunity. A multivariate analysis validated the occurrence of autoimmunity signs as an independent predictor of favorable outcome. A parallel immunologic study detected in the peripheral blood mononuclear cells of these patients a progressive increase in lymphocyte and eosinophil counts, amplification in central memory, a marked depletion of immunosuppressive regulatory T cells, and activation of colon cancer-specific cytotoxic T cells. Our results suggest that immunity feedback to GOLFIG regimen and its antitumor activity are tightly correlated.Clinical Cancer Research 08/2008; 14(13):4192-9. DOI:10.1158/1078-0432.CCR-07-5278 · 8.19 Impact Factor