Chemo-immunotherapy of colorectal carcinoma: Preclinical rationale and clinical experience

Center of Oncopharmacological Research, Faculty of Medicine, University of Siena, Italy.
Investigational New Drugs (Impact Factor: 2.92). 04/2006; 24(2):99-110. DOI: 10.1007/s10637-006-5932-7
Source: PubMed


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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    • "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. "
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    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 · 2.19 Impact Factor
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    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 · 3.07 Impact Factor
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    ABSTRACT: Adoptive cell therapy using cytotoxic CD8+ T lymphocytes (CTL) has shown promising results in recent clinical trials for cancer patients. Although significant advances have been achieved in this field, there are still many issues that need to be addressed before wide application of adoptive cellular immunotherapy as an adjuvant or mainstream therapy for various cancers. Difficulties related to the ex vivo generation of large number of effective antigen-specific CTLs, their in vivo tracking and short term survival following adoptive transfer are among the barriers decelerating the clinical use of this approach. In this review, we focus on recent developments in adoptive cell therapy using CD8 T cells and discuss the hurdles that need to be overcome. In addition, current status of adoptive cell transfer using other T cell populations for cancer immunotherapy that may circumvent some of the problems related to current protocols of using CTL is also discussed.
    Current Cancer Therapy Reviews 02/2008; 4(1):1-13. DOI:10.2174/157339408783565475
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