Immunotherapy is emerging as a potential treatment strategy for various human malignancies. Monoclonal antibody (MAb) therapy (MAb), a form of passive immunization, targets tumor specific antigens by eliciting a strong anti-tumor response. But MAb therapy also results in serious inflammatory reactions such as diarrhea and rashes. In a recent study, published in the Proceedings of the National Academy of Sciences, researchers at the Dana-Farber Cancer Institute, Massachusetts, have reported that a vaccine-antibody combination approach is effective in treating melanoma and ovarian cancer with far fewer side effects.
The study conducted by Stephen Hodi, MD, Clinical Director of the Melanoma Program at Dana-Farber Cancer Institute, Boston, Massachusetts, and his colleagues demonstrated that periodic injections of Ipilumimab (Medarex and Bristol-Myers Sqibb) reduced the incidence of tumor development in advanced melanoma and ovarian cancer patients who were previously vaccinated with GVAX® (Cell Genesys), an immunotherapy agent. Although, adverse effects were noticed in a few patients, the symptoms were not as severe as those experienced by patients receiving monoclonal antibody therapy alone. Examination of tumor biopsies from these patients established the presence of a high ratio of CD8+ T cells (also known as cytotoxic T cells, actively involved in destroying virally infected and tumor cells), compared to FoxP3+ regulatory T cells, a sub-group of T-cells that suppress immune response.
Ipilimumab (MDX-010) is a fully humanized antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a receptor molecule on T-cells that plays a critical role in regulating immune response. Ipilimumab, co-developed by Bristol-Myers Squibb and Medarex, is currently being investigated under three different clinical studies for metastatic melanoma: in combination with dacarbazine, as first-line treatment, and as a second line therapy, alone or in combination with a melanoma-peptide vaccine. It is also undergoing multiple Phase II clinical trials to iassess its potential activity in other types of cancer such as prostate, lung, pancreatic, bladder, breast, lymphoma and leukemia, and in combinational studies with chemotherapy, immunotherapy and vaccine agents.
GVAX immunotherapy is indicated in the treatment of various types of cancers, including prostrate cancer, leukemia, and pancreatic cancer. The vaccine comprises of irradiated autologous tumor cells, which are genetically modified to secrete an immune-stimulating cytokine, known as granulocyte-macrophage colony-stimulating factor (GM-CSF). Administration of these GM-CSF secreting cells greatly enhances the immune response to multiple tumor antigens on the cancerous cells, which may persist or recur following surgery, radiation therapy or chemotherapy treatment, and destroys them.
Earlier, Jaber and colleagues (Archives of Dermatology, 2007) had conducted a single-institution prospective study to analyze the safety and efficacy of anti CTLA-4 monoclonal antibody therapy as a single therapeutic agent for melanoma. The team administered anti-CTLA-4 antibodies to 63 patients with stage IV melanoma every 3 weeks, and studied the clinicopathologic features by physical examination, conventional histologic analysis, antibody staining, and complete blood cell counts. Results demonstrated an incidence of skin lesions in 14% of the patients administered with CTLA-4 antibodies, and extensive alopecia in one patient. A similar study conducted by Blansfield and colleagues (Journal of Immunotherapy, 2005) also reported that melanoma and renal cancer patients infused with anti-CTLA-4 antibodies suffered from grade III/IV autoimmune manifestations such as dermatitis, enterocolitis, hepatitis, uveitis, and a single case of hypophysitis.
The current study provides an insight into an effective vaccine-antibody therapeutic approach, which provokes a stronger immune response to tumor cells with lower dosage of MAb, and also targets immune suppressing anti-tumor regulatory T-cells. Considering the potential hazards of monoclonal antibody monotherapy, the new antibody-vaccine combination therapy could emerge as a potential winning strategy in cancer pharmacotherapy.
References
1. Hodi FS, Butler M, Oble DA, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proceedings of the National Academy of Sciences. Published online on 2008 Feb 19.
2. Vaccine-and-antibody treatment shows effectiveness and milder side effects in advanced melanoma and ovarian cancer patients. Press release. Dana-Farber Cancer Institute. Last accessed on March 01, 2008.
3. Jaber SH, Cowen EW, Haworth LR, et al. Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Archives of Dermatology. 2006 Feb; 142(2):166-72.
4. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. Journal of Immunotherapy. 2005 Nov-Dec;28(6):593-8.
