Cancer Vaccine - Hypothesized Problems

Hypothesized Problems

A vaccine against a particular virus is relatively easy to create. The virus is foreign to the body, and therefore will express antigens the immune system can recognize. Furthermore, there are usually only a few viable variants of the virus in question. It is very hard to develop vaccines for viruses that mutate constantly such as influenza or HIV.

A tumour can have many different types of cells in it, each with different cell-surface antigens. Furthermore, those cells are derived from the individual with cancer, and therefore display few if any antigens that are foreign to that individual. This makes it difficult for the immune system to distinguish the cancer cells from normal cells. Some scientists believe that Renal cancer and melanoma are the two cancers with most evidence of causing spontaneous and effective immune responses, possibly because they often display antigens that are recognized as foreign. Therefore, many attempts at developing cancer vaccines are directed against these tumors. However, given Dendreon's success in prostate cancer, a disease that never spontaneously regresses, cancers other than melanoma and renal cancer may be equally amenable to immune attack.

However, most clinical trials investigating a cancer vaccine have failed or had very modest responses by standardized oncologic assessment criteria described as the RECIST criteria. The precise reasons are unknown, but possible explanations include:

1) disease stage being treated was too advanced: it is difficult to get the immune system to fight bulky tumor deposits, because tumors actively suppress the immune system using a variety of mechanisms (e.g. secretion of cytokines that inhibit immune activity). The most suitable stage for a cancer vaccine is likely to be early disease, when the tumor volume is low, but the problem there is that clinical trials take upwards of five years and require high numbers of patients to reach measurable end points. The alternative is to target patients with minimal residual disease after de-bulking of the tumor by surgery, radiotherapy or (providing it does not in itself harm the immune system) chemotherapy.

2) escape loss variants (cancer vaccines that target just one tumor antigen are likely to be less effective. Tumors are highly heterogeneous and antigen expression differs markedly between tumors (even within deposits in the same patient). The most effective cancer vaccine is likely to raise an immune response against a broad range of tumor antigens to minimise the chance of the tumor being able to mutate and become resistant to the therapy.)

3) prior treatments (numerous clinical trials in the past have treated patients who have received numerous cycles of chemotherapy. Chemotherapy is often myelosuppressive and destroys the immune system. There is little point giving a cancer vaccine to a patient who is immune suppressed).

4) some tumors progress very rapidly and/or unpredictably, and they can literally outpace the immune system. It may take two to three months for an immune response to a vaccine to mature, but some cancers (e.g. advanced pancreatic) can produce marked clinical deterioration, or even death, within this timeframe.

5) many cancer vaccine clinical trials examine immune responses by patients as their primary goal. Correlations are then made, typically showing that the patients who made the strongest immune responses were the ones who lived the longest, and this is taken as evidence that the vaccine is working. The alternative explanation, however, is that the patients who made the best immune responses were the healthier patients with the better prognosis, and they would have survived longest in any event, even without the vaccine. In other words, the immune responses may simply be a simple reflection of a better health status, not an indication that the vaccine had any beneficial effects. As such, these immune 'false friends' may have tempted some to embark on expensive phase III trials without a solid rationale.