Limitations of Current Immunotherapies

Currently, the most common forms of immunotherapy are mAbs (monoclonal antibodies), which are commercially available, and cancer vaccines, with the first approved cancer vaccine, Provenge, for prostate cancer.  Provenge is the first immunotherapy "success story" that has reached commercialization.

Provenge is an autologous  cancer vaccine and works by stimulating the patient's own immune system to target prostate cancer cells. The process of making Provenge involves the introduction of a patient's immune cells to a protein that functions as a prostate-cancer associated antigen.  An antigen is a substance that causes the body to mount an immune response to the specific antigen (usually a peptide or a protein). This process activates the patient's own immune cells against prostate cancer cells, which express the same antigen(s) to help the immune system better fight the disease.

Provenge represents an important clinical success and has shown very positive results, however, it is very hard to produce in large quantities.  It is an autologous vaccine, meaning one patient - one vaccine (prepared from the patient's own cancer cells), which does not readily lend itself to commercial scale production and world-wide distribution.

Most of the other existing immunotherapies have been designed to be 'targeted' to specific antigens on cancer cells. As a result of the interaction of the targeted antigen with a passively administered mAb or the antibody produced by the body in response to a vaccine, a cascade of events generally leads to tumor cell death.

Targeted cancer immunotherapies, like monoclonal antibodies and certain vaccines, are aimed at finding a so called "magic bullet" - a cancer treatment which can destroy only the cancer cells and spare the healthy cells.

This approach has not been as successful as expected. After global efforts and more than 40 years of work in the fight against cancer, the "magic bullet" has not yet been found. This is perhaps not so surprising considering the complexity of a disease such as cancer. In addition, the products were not always as pure or specific as they initially were thought to be and were generally more toxic when given systemically, especially when given in high doses. More recently, the FDA has requested that some of these therapies exhibit a "Black-Box" Warning Label - due to the level of toxicity of some of these treatments.

  o The major challenge with targeted therapies: they can be "too targeted"; the targets can differ among different patients, and the targets can change when cancer cells mutate;  
  o Not all antigens are the same: All cancers may "look" the same, but they are not. Not all patients' cancers may express the same antigen against which a specific monoclonal antibody or cancer vaccine is targeted.  In general, response rates to "targeted therapies" appear to be around 20 to 30 percent. To optimize this type of therapy, it will be necessary to identify each subgroup of patients with a specific cancer and develop therapies targeted to, or directed specifically at, their individual cancers.  
  o Tumor cells mutate as a result of chemotherapy and radiation treatment, and therefore, the target antigens on the tumor cells at which the therapy is aimed also can be changed. If the target changes, then the mAbs or cancer vaccines which target those specific antigens (targets) can become less effective or ineffective.  
  o The second major limitation of current immunotherapies is that they often are administered to patients late in the cancer therapy cycle, when the patient's immune system is already weakened.  
  o Most immunotherapies have historically been used late in the disease treatment process, for example: after radiation, chemotherapy, or surgery (i.e., after the current standard cancer therapy as that is defined and recommended according to NCCN guidelines). This means that they are typically used in cancer patients after the patient's own immune system is likely weakened by initial standard cancer therapy. Often, they can be used too late in the disease process to be effective in treating the cancer.  
  o Experts in the cancer field generally have now come to recognize that, in order to achieve a meaningful immunotherapeutic effect when treating cancer, immunotherapy should be used as treatment early in the disease process. It should be used before any potential effect on the immune system that might be caused by radiation, chemotherapy and surgery, and before the cancer has possibly become "tolerated" by the affected individual's immune system.