Infectious Diseases
Viral infections can be life threatening in patients who are immune-compromised because they cannot mount an effective immune response. Approaches to protection from infection using gene therapy include T cell-based immunotherapy, stem-cell based therapy, genetic vaccines, and other approaches to genetic blockade of infection. The rationale for use of gene therapy is that most common viral or fungal infections are only life threatening in patients who are immune-compromised because they cannot mount an effective immune response to the virus. Common causes of inadequate immune responses to viral infections include the Human Immunodeficiency Virus (HIV) which compromises function of immune cells and the necessary immunosuppressive drugs given to patients with an organ or bone marrow transplant. Both HIV infection and treatments used in transplant patients can cripple the immune response of its victims by killing the helper T cells (CD4+) that help amplify an effective Cytotoxic T Lymphocyte (CTL) immune response against the virally infected cells. Such patients can succumb to life threatening infections caused by Cytomegalovirus (CMV) , Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Epstein Barr Virus (EBV), Adenovirus (Ad), Human Herpes Virus type 6 (HHV6), and BK virus. In addition, fungal infections such as candida and aspergilus can be a particular problem in patients with immunodeficiency. Inability to control certain virus infections, such as EBV, HBV, and human papillomavirus, can also increase the risk for cancers. For example, transplant recipients can develop lymphoproliferative disease caused by EBV, a common virus in humans normally causing mononucleosis. Gene and cell therapies are being developed to treat these viral infections.
T Cell Based Approaches. Several approaches that enhance function of T cells with gene transfer using T cells given to patients are in phase I human clinical trials for treatment of HIV, HCV, and EBV infections. For example, T cells are engineered with a novel T cell receptor that recognizes HIV-infected cells. These engineered T cells will be infused into patients to presumably seek, find, and kill HIV-infected cells. The trial is testing the safety of these cells and ultimately the hypothesis that these cells can slow or halt the progression of the disease. In a second example, T cells are engineered to produce a material such as an antiviral RNA [See Proc Natl Acad Sci 103: 17323-7, 2006] or an enzyme (zinc finger nuclease) [See Nature Biotech 26: 808-16, 2008] that blocks virus infection. Theoretically, these engineered T cells should not be susceptible to HIV-induced lysis and will help patients maintain a sufficient level of T cells for immune functions.
Cell therapy approaches that transfer abundant T cells specific for several viruses have completed phase I. Some of the therapies are in phase II clinical trials for treatment of transplant patients who have an unrelenting viral infection. The objectives are to gather safety data, feasibility and efficacy data on the transfer of the T cells. As noted, allogeneic hematopoietic stem cell transplant patients are at risk for persistent Adenoviral, CMV, or EBV infections despite standard therapy, and T cells that can kill cells infected with these viruses are being administered to these patients. The patients receive donor-derived T cell lines which are highly virus-specific with minimal alloreactivity, thus minimizing the possibility of graft versus host disease and optimizing the potency and long term presence of the transferred cells. The results of a phase I trial are very encouraging: the majority of patients with an active CMV, EBV or Adenovirus infection resolved their disease symptoms. The expansion of the viral-specific T cells occurred as the patients began improving [Nature Med. 12:1160-1166. (2006)]. As the lead scientist, Ann Leen, Ph.D. says, “translating basic immunology into a product that affects patients directly is very satisfying.” To address questions of long-term efficacy, safety, and practicality,Heslop and colleagues recently reviewed data from 114 patients who had received infusions of EBV-specificCTLs to preventor treat EBV+ lymphoproliferative disease (LPD) arising afterhematopoietic stem cell transplantation. Toxicity was minimal,and none of the 101 patients who received CTL prophylaxisdeveloped EBV+ LPD, while 11 of 13 patients treated with CTLsfor biopsy-proven or probable LPD achieved sustained completeremissions. [Blood 115:925-935, 2010]. Development of additional therapies, refinement of these reagents, and further testing are ongoing.
Stem-cell Based Approaches. Genetic manipulation of the blood progenitor cell or progenitors of T cells, using genes known to block replication and infection of viruses such as HIV, have also undergone testing in HIV/AIDS patients using bone marrow transplantation. If successful, this method would allow a patient to make T cells that are resistant to HIV infection. This approach remains early in its development and is limited by our understanding of how to establish safe and durable engraftment of modified progenitor cells [See Science Transl Med 2: 1-8, 2010] .
Genetic Vaccines. Vaccines which use gene transfer techniques include DNA vaccines, recombinant viral vaccines, and RNA-based dendritic cell vaccines. Each of these introduce viral encoded sequences for immunologically important anatigens which could contribute to immunity. Although no genetic vaccine has been approved for human use, this is an active area in which several vaccines against infections agents are being tested in humans.
Other Approaches. Use of genetic vectors for rapid introduction of protective proteins have been shown to be feasible in animal models. For example, use of Adenovirus-encoded antibody to anthrax toxin has been shown to be protective in a mouse model [See Human Gene Therapy 14: 1673-82, 2003].
For more information on clinical trials relating to HIV, Epstein Bar Virus, Cytomegalovirus, hepatitis, or other virus infections, please visit ClinicalTrials.gov.
For general information on these infections, visit the Centers for Disease Control and Prevention website.
Please visit the National Institute of Diabetes and Digestive and Kidney Diseases website for more information on Hepatitis B and C.
Be sure to consult your physician before making any medical decisions.