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 reached commercialization. Other current ACT [Adoptive Cell Therapies] such as CAR-T have recently been approved for the treatment of Acute lymphocytic Leukemia (ALL) in children and young adults, Large B-cell Lymphomas and pediatric B-cell Acute Lymphoblastic Leukemia, as well as Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL), and are now being studied for the treatment of Solid Tumors.

Provenge is an autologous cancer vaccine that works by stimulating the patient's own immune system to target prostate cancer cells. The manufacturing process for Provenge involves the collection of a patient's own T Cells by leukapheresis and the introduction into these cells in the laboratory, ("in vitro"), of a protein that functions as a prostate-cancer associated antigen. An antigen is a substance (usually a peptide or a protein) that causes the body to mount a specific immune response and that is capable of binding with the product (an antibody or T cell) of the immune response. When the laboratory altered cells are transfused back into the patient these cells interact with and activate the patient's own immune cells making them more able to fight against prostate cancer cells.

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.

CAR-T, like 'Provenge', is an autologous product. It is also derived from the patient's own T-cells, which are modified and grown "in vitro", and are then transfused back into the same patient, where now in their modified state they seek, attach to and kill the patient's tumor cells.

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 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 half a century in the fight against cancer, the so called "magic bullet" has not yet been found. This is perhaps not so surprising considering the complexity of cancer. In addition, the products were not always as pure or as 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 in fact 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, in recipients of to "targeted therapies" response rate appears to be about 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. Advances in cancer genetics should result in better selection of a specific treatment and honing of these treatments to each individual patient's cancer.  
       
  o Tumor cells mutate naturally and as a result of chemotherapy and radiation treatment, and therefore the target antigen on the tumor cell to which the therapy is aimed can change over time or as a result of treatment. If the target changes, then the mAbs, which target those specific antigens, could become 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), or after other therapies have failed. This means that they are typically used in cancer patients after the patient's own immune system is likely weakened by initial standard or other previously administered cancer therapy. Often, they may 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. However, that is often not possible because the treatment with certain immunotherapies (which take on average 3 months or longer) could lead to a delay in surgery and thereby become unacceptable as it may harm the patient.