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New HIV Immunotherapy - HIV-1-Specific Chimeric Antigen Receptors Based on Broadly-Neutralizing Antibodies
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"In summary, we have demonstrated that seven bnAbs varying in epitope specificity all have activity as single chain HIV-1 receptors in CARs. All constructs have the ability to recognize infected cells for proliferation, killing, and suppression of viral replication, although they may vary in their breadth of HIV-1 sequence diversity coverage. Additional studies will be necessary to understand and assay the properties important for transduced cell proliferation and function for in vivo immunotherapies based on bnAb CARs."
Jnl of Virology May 2016
Ayub Ali1 , Scott G. Kitchen1 , Irvin S.Y. Chen1,2 , Hwee L. Ng1 , Jerome A. Zack1,2 , Otto O. Yang1,2,3# 1 Department of Medicine, Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA 2 Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA 3 AIDS Healthcare Foundation, Los Angeles, California, USA
Although the use chimeric antigen receptors (CARs) based on single chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain, and was abandoned for lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (bnAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined bnAbs varying in binding sites and generated single chain antibody-based CARs. These included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log10 units) to transduced CD8+ T lymphocytes. Their antiviral activity was reproducible but varied according to the strain of virus. These findings indicated that bnAbs are excellent candidates for developing novel CARs to consider in the immunotherapeutic treatment of HIV-1.
IMPORTANCE While chimeric antigen receptors (CARs) using single chain antibodies as binding domains are growing in popularity for gene immunotherapy of cancers, the earliest human trials of CARs were for HIV-1 infection. However, those trials failed and the approach was abandoned for HIV-1. The only tested CAR against HIV-1 was based on using CD4 as the binding domain. The growing availability of HIV-1 broadly neutralizing antibodies (bnAbs) affords the opportunity to revisit gene immunotherapy for HIV-1 using novel CARs based on single chain antibodies. Here we construct and test a panel of seven novel CARs based on diverse bnAb types, and show that all are functional against HIV-1
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Immunotherapy Cancer Treatment Could Kill Cells Infected With HIV
Jul 18, 2016
HIV and cancer are both devastating, deadly diseases, but a recent study suggests the two conditions may have more in common than their ability to destroy the human body. According to the study, a new type of immunotherapy treatment originally developed for cancer patients may also be useful in the fight against HIV, the virus that causes AIDS. For the study, which is now published online in the peer-reviewed Journal of Virology, researchers from UCLA AIDS Institute and Center for AIDS Research discovered that an antibody used to combat cancer may also be useful in killing cells infected with HIV-1. When manipulated, these antibodies can be used to generate a specific type of cell called chimeric antigen receptors (CARs), which are essentially artificially created immune cells that are currently at the center of immunotherapy research.
Immunotherapy is a very popular route for cancer treatment and involves using the body's own immune system to fight off cancer. Although cancer does not inhibit immune system function, it is able to distinguish itself from immune system cells and destroy the body completely undisturbed. Chemotherapy and radiation have been the most popular routes for eliminating cancer from the body, and although both treatments often succeed in destroying cancer cells, they also destroy healthy cells along the way and have many devastating side effects.
Immunotherapy is a much less destructive way to eliminate cancer from the body. According to Cancer.org, immunotherapy usually involves either stimulating the immune system to work harder or smarter to attack cancer cells, or as in the case of CARS, it gives the immune system extra components, such as man-made immune system proteins, to better combat the cancer cells.
CARs are designed to produce receptors on their surface that target and kill specific cells containing either viruses or tumor proteins. For this study, however, the team realized that the immunotherapy treatment could not only destroy cancer cells, but also HIV-infected cells.
"We took new generation antibodies and engineered them as artificial T-cell receptors, to reprogram killer T cells to kill HIV-infected cells," said Dr. Otto Yang, the study's corresponding author, in a recent statement .
This is not the first time researchers have used artificial T-cell receptors to combat HIV, although past attempts have proved unsuccessful. However, the UCLA team believes that the discovery of new antibodies capable of creating CARS may be enough to turn the theory into a reality. However, Yang cautioned that what works in a test tube doesn't always work in a person so, while the therapy shows promise enough to move forward with research, it may be too soon to declare a "breakthrough" in HIV treatment just yet.
This is not the only way immunotherapy is being developed to help address HIV. Normally HIV-positive patients take a number of drugs, known as antiretroviral, to help keep their HIV virus levels low and prevent them from developing AIDS. However, a study released just last month described using a specific antibody to help HIV-positive patients maintain low viral levels without the need for a daily antiretroviral regimen. Although, like the CARs treatment, this therapy is also still in development, these studies combined with other new innovations in HIV research suggest that we may finally be on our way to winning the battle against this devastating disease.
Source: Alli A, Kitchen SG, Chen ISY, Nh H, Zack JA, Yang OO. HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies. Journal of Virology . 2016
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