Cancer is an abnormal growth of cells the proximate cause of which is an imbalance in cell proliferation and death breaking-through the normal physiological checks and balances system and the ultimate cause of which are one or more of a variety of gene alterations. These alterations can be structural, e.g., mutations, insertions, deletions, amplifications, fusions and translocations, or functional (heritable changes without changes in nucleotide sequence). No single genomic change is found in all cancers and multiple changes (heterogeneity) are commonly found in each cancer generally independent of histology. In healthy adults, the immune system may recognize and kill the cancer cells or allow a non-detrimental host-cancer equilibrium; unfortunately, cancer cells can sometimes escape 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 (or otherwise altered) 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 patients own immune system to enhance the immune response to cancer cells, (ii) activate the patients own immune system (T cells or Natural Killer cells) to kill cancer cells, or (iii) to directly find and kill the cancer cells. Moreover, genetic approaches to modify cellular activity further alter endogenous immune responsiveness against cancer.
Currently, multiple promising clinical trials using these gene and cell based approaches are ongoing in Phase I through Phase III testing in patients with a variety of different types of cancer.
Cancer is a process in which cells 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, loss of normal tissue function and can acquire an even greater propensity to shed. Multiple cumulative genetic and/or epigenetic changes are needed to cause cancer. Those genes on which the maintenance of the cancer process depends are called driver genes which, unlike passenger genes, are key targets although non-driver genes can also contribute to cancer growth.
A number of gene therapy strategies are being evaluated in patients with cancer and these include manipulating cells to gain or lose function. For example, half of all cancers have a mutated p53 protein that 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. 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 patients own immune system to recognize and kill these cancer cells. Another immune modulating alternative entering the clinic is the use of RNA interference (RNAi) silencing of endogenous cancer intracellular immune suppressor proteins, e.g., TGF beta, as a component of immunotherapy.
Along this line, gene silencing has been designed to inhibit the expression of specific genes which are activated or over expressed in cancer cells and can drive tumor growth (with particular attention to presumptive driver genes), blood vessel formation, seeding of tumor cells to other tissues, and allow for resistance to chemotherapy. Several such genes, termed oncogenes, are often expressed continuously at high concentrations in cancer cells and express proteins that increase cell growth and/or division. Alternatively, tumor growth requires new blood vessel formation to survive, a process known as angiogenesis, which is mediated by an array of interacting proteins. A number of approaches to gene silencing have been or are being explored in the clinic including anti-sense oligonucleotides (ASO), short interfering RNA (siRNA) and short hairpin RNA (shRNA) that target post-transcription mRNA, and bi-functional shRNA which has both post-transcriptional silencing and translation-inhibitory effects.
Furthermore, tumor cells can loose intercellular cohesion, enter the bloodstream and seed other tissues, enabled by epithelial-mesenchymal transition, where they can undergo mesenchymal-epithelial transition and grow at the newly seeded site; 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. Mesenchymal stem cells, which have cancer-trophic migratory properties, are being engineered to express anti-proliferative, anti-EMT, and anti-angiogenic agents.
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. For example, an expanding number of human viruses such as measles virus, vesticular stomatitis virus, reovirus, adenovirus, and herpes simplex virus (HSV) can be genetically modified to grow in tumor cells with consequent cell kill, but very poorly in normal cells thereby establishing a therapeutic advantage. . 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. In addition, oncolytic viruses can be genetically modified (i.e. GM-CSF DNA transfer)so as to enhance immunogenicity (e.g., HSV). The combination of selective oncolytic cell death with release of danger-associated molecular-patterns and tumor-associated antigens with heightened immunogenicity has been shown both enhanced local and spatially additive effects. 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 to convert a nontoxic prodrug into a toxic drug. Examples of suicide enzymes and their prodrugs include HSV thymidine kinase (ganciclovir), Escherichia 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. Significantly, prior pilot studies suggested 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.
Most of 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 cancer progression is an evolutionary process and results in large part from an immune-evasive adaptive response to the cancer microenvironment affecting both the afferent and efferent arms of the immune response arc. This results in inhibition of the ability of a patients 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 host-cancer immune interaction and as a consequence, to improve the immune systems 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 patients 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 function and number of cells for therapy.
Clinical trials of cell therapy for many different cancers are currently ongoing. 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 patients own immune cells, typically T cells. 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 a variety of cancer types using T cells genetically modified to express tumor specific CARs are ongoing, some of which are showing promising results.
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