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Active Immunotherapy

       
  ° Cancer Vaccines  
   
     
> Limitations of Cancer Vaccines  
     
 
  ° Cellular Therapies  
   
     
> Limitations of Cellular Therapies  
     
 
  ° Adjuvants  
   
     
> Limitations of Adjuvant Immunotherapies  
     
 

Cancer Vaccines

Preventative vaccines are vaccines that protect against infectious diseases caused by viruses such as the influenza virus or other microbial agents such as bacteria and parasites. These vaccines are given to a person before he/she is infected with the virus and who is normally free of the targeted disease. Therapeutic vaccines are vaccines that are given as a method to treat a disease after the disease is detected or has advanced. In recent years, scientists have been attempting to develop therapeutic vaccines for cancer. The first successful prostate cancer vaccine called Provenge was approved in 2010 by the US FDA. Since that time a number of cancer vaccines have been developed and some have been approved for use. Therapeutic cancer vaccines are designed to treat cancer by boosting/activating the immune system to fight against the cancer.

Cancer vaccines are active immunotherapies because they are meant to trigger the patient's own immune system to respond. Cancer vaccines are targeted because they do not just boost the immune system in general, but because they cause the immune system to attack the cancer cells, honing in on one or more specific tumor antigens.

  o Examples of Cancer vaccines include: Tumor cell vaccines, Antigen Vaccines, Dendritic cell vaccines (Provenge), Anti-idiotype vaccines, DNA vaccines, Vector-based vaccines.  

Cancer vaccines may contain cancer cells, parts of cells, or purified tumor-specific antigens and are designed to increase the targeted immune response against cancer cells already present in the patient. A cancer vaccine may be combined with other substances called adjuvants or cells that help boost the immune response even further.

Cancer vaccines generally fall into two main categories: a) cell-based cancer vaccines, which are created using cells from the patient's own cancer that have been presented to and cultured with the patient's own immune system cells (autologous cell vaccines). These activated immune cells from the patient are delivered back to the same patient (usually via infusion) with other proteins (e.g., IL-2) to further facilitate immune activation of these tumor antigen primed immune cells; and b) vector-based cancer vaccines in which an engineered virus, or other vector, is used to introduce cancer specific proteins and other molecules to the patient (or to cells isolated from the patient - such as in ACT [Adoptive Cell Therapies] e.g., CAR-T) in order to stimulate the patient's immune system to recognize the tumor cells and fight the patient's own cancer.

Both approaches are designed to stimulate the patient's own immune system to attack tumor cells.

       
   
  Limitations of Cancer Vaccines:
 
   
       
  o Today, most cancer vaccines are targeted; i.e. made against a specific tumor cell antigenic target. The limitations of targeted vaccines are very similar to the limitations of other targeted therapies like mAbs; i.e. not all patients' antigens are the same and tumor cells and their antigens mutate. In other words, when the targets change, the targeted vaccine becomes less effective - or ineffective.  
       
  o Not all antigens are the same; All cancers may "look" the same, but they are not. Not all patients' cancers may express the antigen against which a specific vaccine is targeted. Response rates in general to "targeted therapies" appear to be around 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 cancer.  
       
  o Tumor cells mutate as a result of chemotherapy and radiation treatment, and during the natural progression of the cancer. Therefore, the target antigens on the tumor cells at which the therapy is aimed, also changes. If the target changes, then the vaccines, which target those specific antigens, become ineffective.  
       
 
   
  Other vaccine limitations:
 
   
       
  o

Autologous vaccine therapy (a vaccine derived from the patient's own tumor and customized for the same patient) presents many manufacturing challenges.

 
       
  o Autologous therapy is very costly and requires patient to visit the hospital or clinic usually for multiple procedures and multiple visits since the treatments are not able to be mass produced.  
       
  o Many cancer vaccines are poorly immunogenic (i.e., they do not elicit an immune response on their own) and require the use of adjuvants to elicit an effective immune response. The addition of adjuvants may increase immunogenicity of the vaccine, but may also cause increased toxicity and cost.  
       
  o The increased antigenicity of the patient’s own cellular derived materials used to produce autologous cancer vaccines may cause auto-reactivity and the subsequent development of an autoimmune disease.  
       
  o Patients treated with genetically engineered vaccines may produce neutralizing antibodies, and or cellular therapies (Treg) which could cause subsequent therapies with the same product to become ineffective.  
 
       
       

Cellular therapies

Cellular therapies are usually single cell type agents derived from the cancer patient which are modified in the laboratory to become more adept at recognizing and killing the patient's own tumor, e.g., CAR-T (Chimeric Antigen Receptor T-cell) therapy. This type of active immunotherapy is designed to boost specific parts of the immune system to cause tumor cell death. Vaccines, in contrast, attempt to get the body's immune system to react to specific antigens. (ACS)

  o Examples of Cellular Therapies include: Lymphocyte activated killer cells therapy, tumor infiltrating lymphocyte (TIL) with IL-2, suppressor regulatory T cell, Modified T-cell Receptor (TCR) and CAR-T therapy.  
       
   
  Limitations of Cellular Therapies:
 
   
       
  o Not all tumor infiltrating lymphocytes grow well enough in culture to generate the quantity of cells that would be required to produce a useful anti-tumor effect when they are infused back into the patient.  
       
  o Not all tumor infiltrating lymphocytes can be made, in culture, to become more adept at killing the tumor upon return to the patient.  
       
  o The infusion back into a cancer patient of billions of cells that have been grown or modified genetically "in vitro" is not completely without risk and may be associated with immediate and delayed hypersensitivity reactions that can be life threatening. In addition, the manufacturing process under which these cells are grown and infusions are prepared must be carried out under strict aseptic conditions with extraordinary rigid quality control. If the conditions under which these infusions have been prepared are faulty, these infusions may possibly result in life-threatening consequences.  
       
  o Autologous therapy is cumbersome and does not easily lend itself to the commercial scale mass production techniques necessary to reach the multitude of cancer patients world-wide.  
       
  o Autologous therapy; a one-patient-one-therapy, is also usually very costly.  
 
       
       

Adjuvant Immunotherapies

An adjuvant is any material which when injected together with an antigenic protein or other substance (like a mAb or cancer vaccine) increases or boosts the immune response to the particular substance (antigenic parts of the vaccine).

  o Examples include:  BCG, KLH, IFA, QS21, Detox, DNP, FCA, GM-CSF.  

The only adjuvant currently used in approved drug products for human use is Alum.  Alum pre-disposes the formation of antibodies and directs the immune response away from a cellular immune response, which is generally thought to be necessary by the scientific community for an anti-cancer immune response.

Immune Check-Point Inhibitor Immunotherapies

Immune Check-Point Inhibitors are designed to interfere with the tumor's ability to inhibit the cells of the immune response from attacking the tumor. The US-FDA has recently approved a number of Immune Check-Point Inhibitors for the treatment of patients with cancer whose tumors express PD-L1.

 

  • Techentriq - (Atezolizumab) was approved for metastatic uretheliial carcinoma.
  • Bavencio (Avelumab) and Imfinzi (Durvalumab) have been approved by the FDA for treating bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer.
  • KEYTRUDA - (Pembrolizumab), has been approved for metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.
  • Opdivo (Nivolumab). has been approved for Melanoma (skin cancer), non-small cell lung cancer, kidney cancer, bladder cancer, Hodgkin lymphoma, and recurrent-metastatic head and neck cancer.
  • YERVORY - Iplimumab, is a monoclonoal antibody that is a check point inhibitor which targets the CTLA-4 protein on T cells. CTLA-4 acts as a type of an "Off Switch" that keeps the immune system "in check" inhibiting the regulatory cells such that they stop working. By inhibiting CTLA-4 Iplimumab boosts the patient's own anti-tumor immune response allowing it to mount an attack against the tumor. Iplimumab has been approved to treat melanoma of the skin.

 

       
   
  Limitations of Adjuvant And Check-Point Inhibitor Immunotherapies:
 
   
       
  o Adjuvants have their own associated toxicities.  
       
  o Many adjuvants can only be administered once or twice to humans.  
       
  o Many adjuvants can only be administered per-cutaneously (injected into the skin or muscle), and cannot be infused.
       
  o Immune Check-Point Inhibitors
  • Because iplilimumab affects the immune system, it may cause serious and at times life-threatening side effects in the recipients of this therapy. 
  • These Drugs can cause the immune system to attack some normal cells and organs of the body that can lead to serious and life-threatening side effects with serious problems noted in the lungs, liver, intestine, kidneys, and in hormone-making glands or other organs. 
  • Not all treated individuals respond to Check-point inhibitor therapy, in fact it is estimated that only a fraction (about 30-40%) of recipients exhibit a measurable/assessable response.