Therapy Analysis - Anticancer drugs
Cancer vaccines
Cancer vaccines are an emerging type of biological cancer therapeutic. While cancer vaccines have been studied for several decades, advances in this field have been slower than for other forms of immunotherapy. There are a variety of types of cancer vaccines under investigation. They include tumour cell vaccines, which are composed of cancer cells removed during surgery. The cells are usually irradiated, as well as chemicallyand/ or genetically-modified to increase their immunogenicity. Once replaced, the immune system recognizes the antigens on these cells, then seeks out and attacks any other cells with that antigen. A distinct advantage of whole-cell vaccines over antigen-based vaccines is that not all cancer antigens have been found yet. Using the whole tumour cell may expose the immune system to a large number of cancer antigens, including some that have not yet been identified. However, this is still an investigative approach as the two cancer vaccines that are currently launched, Merck's Gardasil and GSK's Ceravix, both target the HPV virus known to cause many cervical cancers, rather than targeting the cancer itself.
Some promising newer versions of these vaccines use tumour cells that are fused to dendritic cells, in the hope of further stimulating the immune system. Dendritic cells are extremely efficacious antigen presenting cells that help the immune system to recognize cancer cells. Dendritic cell vaccines, like autologous cell vaccines, must be made individually for each patient. Once removed from a patient, dendritic cells are exposed to cancer antigens or are genetically modified to produce the antigens, so on return to the patient they are primed to stimulate the immune system to recognize these cancer antigens and act accordingly.
The highest stage dendritic cell vaccine in development is Sipuleucel-T (Provenge), which is awaiting approval in the US for the treatment of prostate cancer. In clinical trials, it has been shown to increase patient survival and time to disease progression. Preliminary data from a Phase III trial showed that sipuleucel-T caused a 21% improvement in median survival and 32% of patients were alive at 3yr compared with 21% of patients on placebo. A review by the Cellular, Tissue and Gene Therapies Advisory Panel found that there was 'substantial evidence' of efficacy in men with asymptomatic, metastatic AIPC, and that it was safe in the intended population, despite insignificant results in trials.
Tumour cell or antigen-based vaccines may be effective initially, but they often become less effective over time. Without any further stimulation, the immune system often returns to its pre-vaccinated state. In order to overcome this, a steady supply of antigens is required. DNA vaccines use the nucleic acid sequence of the tumour antigen to produce the cancer antigen proteins in vivo. The aim is for the immune system to attack not only the antigen presenting cells, but also tumour cells containing the same antigen. Vector-based and DNA vaccines are attractive because they are easier to manufacture than some other vaccines.
Not all cancer treatments using DNA are designed to target the immune system. DNA therapy can be used to treat cancer cells directly in an approach known as gene therapy. Multiple gene therapy strategies have been developed to treat a wide variety of cancers. These methods replace defective genes, add genes to induce apoptosis, or increase cell susceptibility to chemotherapy. Non-viral vectors such as liposomes that do not integrate into the genome, and viral vectors, such as retroviruses and adenoviruses, are used to deliver genes into patients.
Two-thirds of all gene therapy trials are for cancer and many of these are entering the advanced stages of clinical development (graph 3). There are also numerous Phase I and Phase II clinical trials for a wide range of cancers, being conducted at present. It remains to be seen what the long-term effects are of this type of treatment, including how long the therapeutic effects remain.
With the biotechnology revolution opening the door to a whole new class of drugs, certain issues also arose with these proteins and peptides, and these shortcomings were found to limit the potential of these novel drugs as therapeutic agents. Disadvantages include a susceptibility to degradation by proteolytic enzymes, rapid clearance by kidneys, generation of neutralizing antibodies to the foreign antigens introduced, as well as a short circulating half life and shelf life.
