Educating the Immune System to Kill Cancer Cells

     In one of the most exciting studies that I have seen lately, researchers have reported that a novel therapy has resulted in the complete remission of Chronic Lymphocytic Leukemia (CLL) in two patients. CLL is the most common form of leukemia in the Western hemisphere and there are over 10,000 new cases diagnosed annually in the United States. So far three patients have received the novel therapy and the details about one of the patients were reported in the New England Journal of Medicine and discussed in an article in the New York Times. 

     Our immune systems have several types of cells that work together to keep us healthy.  Two of the most important cells are the B cells and the T cells. CLL is a cancer that affects the B cell population. The main purpose of B cells is to produce antibodies to tag infectious agents so that the other cells of the immune system can then recognize and destroy them. T cells, on the other hand, can directly kill pathogens such as tumor cells or cells that have been infected with a virus by recognizing certain proteins on the surface of the pathogenic cells.  B cells express a unique protein on their surface that does not exist on any other cell in the human body.  The protein on the B cells is known as the CD19 protein. Researchers at the University of Pennsylvania thought that if they were able to ‘teach’ the T cells of CLL patients to recognize the CD19 protein on the cancerous B cells then maybe the T cells would destroy the cancerous cells. 

     The idea of genetically programming T cells was initially developed by Dr. Zelig Eshhar in Israel in the 1980’s.  Dr. Eshhar was able to add new genes to the genome of the T cells and create something called a ‘chimeric antigen receptor’ on the surface of the T cell which could then recognize the desired protein. 30 years later, the current study used this technology to create T cells that recognize the CD19 protein on the cancerous B cells. Surprisingly, the researchers used a disabled form of the Human Immunodeficiency Virus (HIV) to introduce the necessary genes to the T cells since HIV naturally targets T cells. 

     The patient described in the New England Journal of Medicine was first diagnosed with CLL in 1996 and had several clinical successes using chemotherapy treatments for more than 10 years.  By 2010, the patient had no options left and was enrolled in the Phase 1 clinical trial at the University of Pennsylvania. The researchers removed a billion of the patient’s T cells and then ‘educated’ them to attack the CD19 protein using the disabled HIV. Once all of the cells were educated, they were reintroduced into the patient over the course of three days.

     Fourteen days after the first infusion, the patient began to experience chills and a low grade fever which eventually exacerbated to a 102.5 ^oF fever. The patient was diagnosed with tumor lysis syndrome syndrome 22 days after the first infusion. Tumor lysis syndrome occurs when the cancerous cells are being destroyed at a very high rate. The symptoms of tumor lysis syndrome are caused primarily by two events. First, the molecules (known as cytokines) that are released by the T Cells to kill the cancerous cells cause flu-like symptoms. Secondly, the destroyed cancer cells themselves overwhelm the body with metabolic waste products.  The kidneys are especially wounded by the excessive amount of waste product.  Fortunately the patient was able to survive the tumor lysis syndrome and, ‘on day 23, there was no evidence of CLL in the bone marrow.’  By day 31, a CT scan showed that the patient’s lymph nodes were no longer enlarged.

     Overall, the doctors calculated that the HIV-educated T cells killed off TWO POUNDS of cancer cells.  The treatment also killed all healthy B cells so now the patient has to receive intravenous immune globulin regularly to supplement for the loss of antibody production, a condition known as hypogammaglobulinemia.  Fortunately, hypogammaglobulinemia is manageable clinically and so far the patient has not had any significant symptoms due to his lack of B cells and antibodies.

     While it seems as though this treatment could easily be applied to all cancers that is not necessarily the case. This treatment works for CLL because only B cells are involved in CLL and it is possible to survive without B cells. In liver or pancreatic cancer, the cancerous cells usually have most, if not all, of the same surface proteins as healthy cells and therefore if this treatment were to be used for the aforementioned cancers, it is possible that the entire organ could be attacked rather than just the tumor. Unfortunately, it is not possible to live without a liver or a pancreas.  Also, sometimes there are proteins that are expressed in multiple areas in the body.  If there was a protein on the cancerous pancreatic cells that was not found on healthy pancreatic cells it is possible that the protein might be expressed elsewhere in the body. It might be expressed in healthy colon cells or healthy heart cells. In this situation, the T cells educated to recognize the protein would attack the cancerous pancreatic cells and the healthy cells of the colon or the heart. There are many other possible dangers to consider as well when applying this treatment to other cancers.

    It is also important to remember that this novel therapy has only been used in three patients so far.  Two patients experienced a complete remission while one experienced a partial remission and then passed away. 

     According to Dr. June, the next step is to administer this treatment to a larger set of patients with randomization to determine if the treatment is as effective as it appears to be.  I know I will be eagerly awaiting the results.

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