Gene Therapy in Cancer Treatment: Present and Future

What are genes?

Our bodies contain cells and each cell contains a nucleus. The nucleus consists of DNA (deoxyribonucleic acid), the genetic material inherited from our parents. Genes are made up of a few hundred to a few million pieces of DNA. Genes, in our body, contain instructions in the form of coded messages on how to make proteins.

Proteins are the molecules that control most of our life functions. Genes instruct cells on how to work and control our growth and development. Our body structure, how we look, and how our body works are decided by our genes. Genes also play an important role in repairing the damaged cells and tissues.

How does cancer develop?

A random change in a gene is known as a mutation. Cells which contain mutated genes start to grow uncontrollably and abnormally, which eventually leads to the formation of cancer. These mutations may result due to lifestyle factors such as smoking, environmental exposure, or they can be inherited.

What is gene therapy?

Gene therapy is a form of treatment that utilizes genes to treat illness. The researchers around the world are conducting studies to test different ways by which gene therapy can help treat cancer:

• Replacement of missing or non-functional genes by adding functioning copies of the same gene to the cell
• Stopping the function of oncogenes (mutated genes that cause cancer)
• Inserting genes into cancer cells that trigger the body to attack the cancer cells as foreign bodies
• Inserting genes into cancer cells to make them more susceptible to chemotherapy, radiation therapy or hormonal therapies
• Creating suicide genes that can enter into cancer cells and cause them to self-destruct
• Using genes to protect healthy cells in the body from the side effects of cancer therapy so that high doses of chemotherapy or radiation therapy can be used

How is gene therapy conducted?

It is very hard to inject genes into tiny cells and hence, gene therapy uses a "carrier" or a "vector" for this purpose. The vectors usually used are viruses. These viruses are genetically changed to carry human DNA. Such viruses used as vectors are typically those that cause the common cold. The only difference is that they are deactivated so that they do not cause any harm to the patient.

Current Clinical Trials in Gene Therapy For Cancer Treatment

A number of clinical trials conducted so far have shown promising results for the treatment of a wide variety of cancers such as lung cancer, pancreatic cancer, prostate cancer, and malignant melanoma. The FDA has approved gene therapies for the treatment of patients with certain types of cancers. Current clinical trials include Rexin-G gene for pancreatic cancer, p53 gene for head and neck cancer, the MDA-7 gene for melanoma, and TNF-α for pancreatic cancer. The Rexin-G gene (for pancreatic cancer) is a cytocidal cyclin C1 construct that gets accumulated preferentially in the cancer cells and blocks the action of cyclin G1 thus causing cell death. The trial for this gene therapy is in Phase III.

The clinical trial (currently in Phase III) of p53 gene for head and neck cancer involves the transfer of p53 gene through a replication inactivated adenovirus into cancer cells to inhibit cell growth and cause cell death. The MDA-7 (for melanoma) is a tumor-suppressing molecule, which is introduced into the melanoma cells in the body. The over expression of MDA-7 inhibits the cellular division and growth and induces cell death. The trial for this gene therapy is in Phase II.

Types of Gene Therapies: Present and Future Perspectives

Gene Transfer Treatment

This is the most widely used method of gene therapy. It involves the insertion of a foreign gene into the cancer cells through the use of viral vectors. These viruses usually belong to a group of viruses called as adenovirus. Many adenovirus vectors have been developed for use in cancer treatment and have shown a significant therapeutic impact.

The drug Gendicine, the first commercially approved gene therapy treatment, is a recombinant adenovirus which contains the tumor-suppressing gene p53. Delivery of this drug to cancer cells helps p53 to over express itself and restores its activity in cells with dysfunctional copies of this gene.

Gene transfer can be used to complement traditional treatment methods and create a more advanced and personalized approach to cancer treatment. Current gene transfer trials have shown promising results in improving the survival rates of cancers such as glioblastoma and pancreatic cancer. New delivery methods can help this form of gene therapy achieve the goal of cancer treatment

Immunotherapy

This type of gene therapy involves the modification of the immune system of the patient to strengthen the body's response to cancer cells. This treatment boosts the immune system to better target and destructs the cancer cells. One particular approach of immunotherapy is a cancer vaccine which tries to cure cancer by delivering material into the body that trains the immune system to recognize and attack cancer cells.

The vaccine is made by culturing tumor cells from the patient's body and modifying them genetically through the addition of genes that produce antigenic and immune-boosting proteins. When such vaccines are injected into the patient's body, it increases the activity of several immune cells and proteins. This creates a stronger anti-cancer immune response.

Example of such a vaccine, currently being tested in the clinical trial is GVAX, which targets advanced pancreatic cancer. It is currently in Phase II trials and recent reports indicate that patients with pancreatic adenocarcinoma, who were administered GVAX vaccine, had higher survival rates as compared to patients treated with standard chemotherapy. Another vaccine such as GM.CD40L has been also very successful in the treatment of malignant melanoma. It is currently in Phase II trial.

As is the case with any cancer monotherapy, cancer vaccines would prove to be more effective if used as an adjuvant therapy to other cancer therapies. With a modest immune response, they might prove more useful and beneficial when used as an adjuvant with chemotherapy to eliminate the rest of the cancer cells.

The initial phases of clinical trials for cancer vaccines are almost under completion. Most likely, they will be a part of effective cancer treatment regimen soon.

Oncolytic virotherapy

This therapy uses genetically engineered viral particles to target cancer cells. Such viruses do not grow or replicate in normal and healthy cells and are selective in destroying cancer cells. Oncorine (ONYX-015) is an oncolytic virus which has been used in nasopharyngeal cancer.

It is in Phase III trials and the response achieved is 80 percent, double the survival rate in patients who were given standard chemotherapy. ONYX-015 is an adenovirus that has been engineered to lack E1B protein. Without this protein, the virus is not able to replicate in cells with a normal p53 pathway. Cancer cells are often deficient in p53 pathway because of mutations. Thus, ONYX-015 can replicate in these cells and destroy them.

Oncolytic viro therapy is at a nascent stage and a lot of improvement can be done in the area of treatment vectors. Once this form of treatment matures and advances, it can be very beneficial. This is due to its selective nature of the minimum impact on healthy cells.

Direct gene editing

This technique involves the precise modification of DNA sequences. CRISPR/Cas9 is one of the fastest-growing areas of research in the field of gene therapy. This CRISPR/Cas9 construct has been modified and engineered to specifically target and cut the E6 oncogene of human papillomavirus (HPV) in cervical cancer cells. The results showed a substantial decrease in the viral load and restoration of normal cancer destroying genes.

Although the CRISPR/Cas9 construct is rapidly developing, a number of ethical, moral and legal controversies are arising due to the ability to modify the genetic content of human beings. These issues need to be addressed by the regulatory bodies before further progress in this area be made.

Future of Gene Therapy

Gene therapy is quite an innovative technology which is developing and advancing at a rapid pace. The use of gene therapies to create new medical procedures which when used alone or in combination with the currently available treatment (such as chemotherapy) will be able to target cancer and make it a manageable disease. However, the main problems being faced with the clinical application of gene therapy is the delivery of the genes to the target cells and the control of the expression of the gene which has been delivered.

A number of new methods to deliver genes such as cDNA complexed to liposomes, retroviral, and pseudo typed retroviral vectors are being developed; the gene-delivery system is at an early stage. However, a number of advancements and breakthroughs are being made in gene therapy. It will soon become a clinically realistic approach in cancer treatment.

With the advancement in genetic screening and identification of the molecular basis of the disease, it might become possible to identify individuals at risk, vaccinate them against the disease, thus helping in early diagnosis and treatment.

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