Cancer Gene and Cell Therapy
Cancer is an abnormal, uncontrolled growth of cells due to gene mutations and can arise in most cells. No single mutation is found in all cancers. In healthy adults, the immune system may recognize and kill the cancer cells; unfortunately, cancer cells can sometimes evade the immune system resulting in expansion and spread of these cancer cells leading to serious life threatening disease. Approaches to cancer gene therapy include three main strategies: the insertion of a normal gene into cancer cells to replace a mutated gene, genetic modification to silence a mutated gene, and genetic approaches to directly kill the cancer cells.
Furthermore, approaches to cellular cancer therapy currently largely involve the infusion of immune cells designed to either (i) replace most of the patient’s own immune system to enhance the immune response to cancer cells, (ii) activate the patient’s own immune system (T cells or Natural Killer cells) to kill cancer cells, or (iii) to directly find and kill the cancer cells. Currently multiple promising clinical trials using these gene and cell based approaches are ongoing in patients with a variety of different types of cancer. The strategies, associated challenges, and clinical trial progress are summarized here.
Gene Therapy Strategies to Correct or Eliminate Cancer Cells
Cancer causes cells to grow aberrantly. The growth of cancer cells leads to damage of normal tissues, causing loss of function and often pain. Many types of tumors shed cells that migrate to other distant sites in the body, establish a base there, and grow continuously. These secondary cancer sites, called metastases, cause local destruction and loss of normal tissue function. Multiple cumulative mutations are needed to cause cancer. While similar mutations are found in many cancers, no single mutation is found in all cancers.
A number of gene therapy strategies are being evaluated in humans with cancer and these include manipulating cells to gain or lose function. For example, half of all cancers have a mutated p53 protein which interferes with the ability of tumor cells to self destruct by a process called apoptosis. To this end, investigators are currently testing in clinical trials the ability to genetically introduce a normal p53 gene into these cancer cells. Introduction of a normal p53 gene renders the tumor cells more sensitive to standard chemotherapy and radiation treatments compared to tumor cells expressing the abnormal protein. Furthermore, other tumor suppressor genes are being placed in gene cassettes for expression in tumor cells which can similarly render them more sensitive to apoptosis, or the process of programmed cell death. Alternatively, other investigators are utilizing gene therapy approaches to induce expression of immune stimulating proteins called cytokines which in turn may increase the ability of the patient’s own the immune system to recognize and kill these cancer cells.
Another therapeutic approach, termed gene silencing, is designed to inhibit the expression of specific genes which are activated or over expressed in cancer cells and can drive tumor growth, blood vessel formation, seeding of tumor cells to other tissues, and allow for resistance to chemotherapy. Several such proteins, termed oncogenes, increase cell division and are often expressed continuously at high concentrations in cancer cells. Alternatively, as a tumor grows, it requires new blood vessel formation to survive by a process known as angiogenesis, which is mediated by a different set of proteins.
Furthermore, tumor cells have the capacity to travel through the blood and seed other tissues where they can grow in a process termed transition, once again mediated by a different set of genes. Finally, scientists have identified genes in tumor cells which allow for these tumor cells to escape killing by chemotherapy. Therefore, an alternative gene therapy approach for cancer is to target one or more of these genes in order to suppress or silence their expression resulting in an inability of these tumor cells to either maintain cell growth, inhibit metastases, impair blood vessel formation, or reverse drug resistance.
Alternatively, gene therapy approaches may be designed to directly kill tumor cells using tumor-killing viruses, or through the introduction of genes termed suicide genes into the tumor cells. Scientists have generated viruses, termed oncolytic viruses, which grow selectively in tumor cells as compared to normal cells. Tumor cells, but not normal cells, infected with these viruses are then selectively killed by the virus. Oncolytic viruses spread deep into tumors to deliver a genetic payload that destroys cancerous cells. Several viruses with oncolytic properties are naturally occurring animal viruses (Newcastle Disease Virus) or are based on an animal virus such as vaccinia virus (cow pox virus or the small pox vaccine). A few human viruses such as coxsackie virus A21 are similarly being tested for these properties. Human viruses such as measles virus, vesticular stomatitis virus, reovirus, adenovirus, and herpes simplex virus (HSV) are genetically modified to grow in tumor cells, but very poorly in normal cells. Currently, multiple clinical trials are recruiting patients to test oncolytic viruses for the treatment of various types of cancers.
Suicide genes encode enzymes that are produced in tumor cells and can convert a nontoxic prodrug into a toxic drug. Examples of suicide enzymes and their prodrugs include HSV thymidine kinase (ganciclovir), Eschericoli coli purine nucleoside phosphorylase (fludarabine phosphate), cytosine deaminase (5-fluorocytosine), cytochrome p450 (cyclophosphamide), cytochrome p450 reductase (tirapazamine), carboxypeptidase (CMDA), and a fusion protein with cytosine deaminase linked to mutant thymidine kinase. For example, the efficacy of an oncolytic adenovirus which expresses the fused cytosine deaminase linked to mutant thymidine kinase is currently being investigated in a phase II/III trial for the treatment of prostate cancer. Significantly, prior pilot studies indicated that the treatment of the prostate cancer cells with the suicide genes introduced by the oncolytic virus increased cancer cell sensitivity to radiation and chemotherapy.
Cellular Immune Therapy of Cancer
All the above approaches have the limitation that they require delivery of a "corrective" gene to every cancer cell, a demanding task. An alternative is to harness the immune system which may have an ability to actively seek out cancer cells. In healthy adults, the immune system recognizes and kills precancerous cells as well early cancer cells, but as the cancer progresses the immune system can become overwhelmed. In fact, many cancers have an ongoing ability to further inhibit the ability of a patient’s immune system to target and eradicate the tumor cells. To this end, investigators are developing and testing several cell therapy strategies to correct impairment of the patient’s immune system and as a consequence, to improve the immune system’s ability to eliminate cancer.
Cell therapy for cancer refers to one or more of 3 different approaches: (i) Therapy with cells that give rise to a new immune system which may be better able to recognize and kill tumor cells through the infusion of hematopoietic stem cells derived from either umbilical cord blood, peripheral blood, or bone marrow cells, (ii) Therapy with immune cells such as dendritic cells which are designed to activate the patient’s own resident immune cells (e.g. T cells) to kill tumor cells, and (iii) Direct infusion of immune cells such as T cells and NK cells which are prepared to find, recognize, and kill cancer cells directly. In all three cases, therapeutic cells are harvested and prepared in the laboratory prior to infusion into the patient. Immune cells including dendritic cells, T cells, and NK cells, can be selected for desired properties and grown to high numbers in the laboratory prior to infusion. Challenges with these cellular therapies include the ability of investigators to generate sufficient numbers of cells for therapy without damaging the ability of these cells to participate in clearance of the tumor. For example, it can be a challenge at times to identify and select immune cells that can efficiently find and then kill the tumor cells in the patient while maintaining these qualities until the cancer cells are fully eliminated. Clinical trials of cell therapy for many different cancers are currently ongoing with promising results.
More recently, scientists have developed novel cancer therapies by combining both gene and cell therapies. Specifically, investigators have developed genes which encode for artificial receptors, which , when expressed by immune cells, allow these cells to specifically recognize cancer cells thereby increasing the ability of these gene modified immune cells to kill cancer cells in the patient. One example of this approach, which is currently being studied at multiple centers, is the gene transfer of a class of novel artificial receptors called “chimeric antigen receptors” or CARs for short, into a patient’s own immune cells, typically T cells, in the laboratory. The resulting genetically modified T cells which express the CAR gene are now able to recognize and kill tumor cells. Significantly, scientists have developed a large number of CARs which recognize different molecules on different types of cancer cells. For this reason, investigators believe that this approach may hold promise in the future for patients many different types of cancer. To this end, multiple pilot clinical trials for multiple cancers using T cells genetically modified to express tumor specific CARs are in currently enrolling patients and these too show promising results.
For more information on cancer, please visit the following websites:
American Brain Tumor Association
Alliance for Cancer Gene Therapy
Brain Tumor Funding Collaborative
Be sure to consult your physician before making any medical decisions.