Biologics
Biologic Therapies that are currently available on the market, include Vaccines, cytokines, monoclonal antibodies, cell specific therapies, hematopoietic growth factors, and adoptive gene transfer, which is in its earliest stages still, after great difficulties.
Vaccines have been sought after for centuries, as scientists have tried to duplicate the results seen with infectious diseases in cancer. Composition of these vaccines mainly depends on obtaining a source of antigen, through autologous cells, allogeneic cells, killed or attenuated virus', and/or small peptides. Adjuvants are added to these vaccines, and include bacterial products or synthetic foreign substances that elicit the innate immune system to converge on the antigen source and ingulf it in associated with 'known' foreign substances (adjuvant). These cells, antigen presenting cells (APC), become activated and present the antigen to T cells forming an adaptive response. A stabilizing agent is always included within vaccines.
Overall, vaccines have had little effect in treating cancer. They may however, have a strong ability to provide preventative measures to people, as with the new cervical cancer vaccine. A few patients with cancer have had dramatic responses to vaccines. This is only seen in a few cancer settings, but points to there being a potential for much more effective vaccines. This will follow our knowledge of the immune system, and run parallel with the technologies for adoptive gene transfer, which are lagging begin.
Cytokines, small molecules which mediate signalling and transmit 'hormonal-like' instructions over very short distances, have become a major target recently for drug development. Interleukin-2 has become approved for the treatment of metastatic malignant melanoma and renal cell carcinoma. This cytokine is secreted from activated T cells, and propagates T cell proliferation and differentiation.
Interferon
Interferon is another cytokine which has been approved as adjuvant treatment in malignant melanoma. I has also been approved for the treatment of patients with other cancers, such as renal cell carcinoma, leukemia, and lymphomas, but has largely been replaced by more suitable drugs for these cancers.
The theory behind the development of monoclonal antibodies, was that cancer cells produce tumor-specific proteins, known to the immune system as pieces of protein, termed antigens. Attempt to find a tumor specific antigen, however, has yielded few results, as most proteins made by tumors are also produced by normal cells. Drug companies have sought to produce a monoclonal antibody against antigens that are overexpressed and/or restricted and/or blood vessels of cancer cells.
The new idea that saved monoclonal antibodies is to target substances that are overexpressed by the tumor cells. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20 – 25% of breast cancers. Therefore, a company developed Trastuzumab. is a humanized monoclonal antibody directed against HER2 which improves overall survival in ladies with HER2 positive breast cancer.
Monoclonal antibodies where Target substances that stimulate the growth of the blood vessels that supply tumors. Vascular Endothelial Growth Factor, well known as VEGF, is produced by endothelial cells of blood vessels in reaction to a low oxygen supply. The low oxygen state stimulates the growth of blood vessels in normal tissues, however, as by cancer cells. Bevacizumab (Avastin) is a monoclonal antibody directed against VEFG which improves overall survival of patients with certain forms of cancer, such as colorectal cancer.
Another strategy is to target antigens that are restricted to the tissues found only where the disease arises from. CD20 is a protein expressed on the surface of B lymphocytes constitutively. Rituximab is a monocloanl antibody developed to be directed against CD20. Rituximab has been shown to improve survival overall in B cell specific lymphoma patients. However, interestingly, Rituximab can produce dramatic responses in patients with other B cell mediated diseases, such as rheumatoid arthritis. Combined with common chemotherapy regimens, like CHOP, rituximab works synergistically to increase remission rates and time disease free.
Furthermore, targeting T cell surface molecules, similar to B cells, is another strategy that has been used. MDX-010 is a human IgG1 monoclonal antibody. MDX-010 is produced by the company Medarex Inc. Phase II studies have treated 220 patients with metastatic melanoma, and responses have been promising. Responses including complete responses, however, these positive responses also correlate with autoimmune complications.
Studies Targeting CTLA-4 on human T cell lymphocytes. Ticilimumab is a human monoclonal antibody produced by the pharmaceutical giant, Pfizer. Phase I/II studies have treated 58 patients most with metastatic melanoma. Responses included complete remissions have been seen. Similar to MDX-010, responses correlate with autoimmune complications. An international phase II study has just been completed but the results are not yet available.
Growth factors can also be used. These include Epoetin alpha and darbepoetin which reduce transfusion rates in nephrology, oncology and surgery. Palifermin reduces mucositis in stem cell transplantation and oncology. Thrombopoietin analogues improve platelet counts in immune thrombocytopenia and oncology. Filgrastim and pegylated filgrastim reduce infection rates in oncology.