The viral vectors used to insert genes into the cells are one major cause of the problems associated with gene therapy. Firstly, a virus, being a foreign invader, is seen by the immune system as something that needs to be attacked. This can either over-stimulate the immune system, which can inadvertently damage host cells. Secondly, the gene may not be properly inserted into the cells 100% of the time. This could cause mutations, which could subsequently cause a normal cell to develop into a cancerous cell.
Acute B cell lymphoblastic leukemia is a cancer that is typically found in children, but can also be seen in adults as an aggressive, difficult to treat cancer. Even if the cancer is successfully treated and the adult patient enters remission, acute B cell lymphoblastic leukemia has a high rate of relapse. When this occurs, the relapsed cancer is normally resistant to the chemotherapeutic drugs used previously, making the cancer more difficult to treat, and the prognosis is very bad. Recently, researchers treated 5 patients with relapsed, chemotherapy-resistant acute B cell lymphoblastic leukemia with gene therapy. In this therapy, genes were inserted into the patients’ T cells, a type of white blood cell that fights infection and cancer. The inserted genes helped the T cells more efficiently target and kill the cancerous cells. The T cells were engineered to target and attack a protein called CD19, which is found on the surface of the cancerous B cells. In addition, the T cells also received costimulatory molecules to allow them to be more easily activated in the host. The T cells were then injected back into the patients.
The gene therapy was mostly well tolerated in the patients. High levels of cytokines, proteins produced by T cells to fight infections that can be dangerous to the host in very high quantities, were found in the patients. However, this effect was short lived and easily treated with steroids, and did not stop the therapy. Researchers noted rapid decreases in tumor volume, and by the end of the treatment, the patients had no detectable cancer. After receiving the gene therapy and removing most of the cancer cells, the patients were eligible for bone marrow transplants to help completely cure the cancer. All of the patients had remission of the cancer after receiving the gene therapy. Four of the 5 patients received follow up bone marrow transplants, and three have been free of cancer for up to 24 months.
The fifth patient had a relapse of acute B cell lymphoblastic leukemia, which the researchers attributed to a lack of CD19-specific T cells. This result suggested multiple treatments with the engineered T cells could be more beneficial than single treatments. This is not an uncommon occurrence with gene therapy. Techniques to insert genes permanently into cells have not been well developed yet. In addition, cells that receive the gene may not propagate well in the host, which would require multiple treatments to maintain therapeutic efficacy. Unfortunately, repeated rounds of gene therapy are not always effective. Because the new gene is introduced using a virus, an immune response may be developed against the virus. This means that when the virus is introduced into the host again, it may be rapidly attacked and destroyed by the immune system.
While the concept of gene therapy offers hope for many, and clinical studies have given promising results, it is clear that science still has a long way to go until safe, effective gene therapy is readily available. However, data obtained from the trial described above prove that we are heading in the right direction.