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Novel Personalized Immunotherapy Treatments

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Argos Therapeutics and Université de Montréal today announced the presentation of new information on Argos’process for developing dendritic cell-based immunotherapies for HIV.

Results from the study demonstrate that loading monocyte-derived dendritic cells with combinations of HIV antigen RNA stimulates the expansion of HIV-specific T cells, which attack and kill HIV-infected cells.

Argos’ immunotherapies are generated by the Company’s Arcelis™ technology, which is a platform for creating autologous, RNA-loaded dendritic cell-based therapies perfectly matched to each patient’s unique virus. These data were presented in an oral poster discussion August 5, 2008 at the XVII International AIDS Conference in Mexico City.

“A key step in the durable control of HIV infection requires enhancing the development of memory immune responses and the stimulation of potent cytotoxic T cells through therapeutic vaccination,” said Charles Nicolette, Ph.D., Chief Scientific Officer of Argos. “Working with our colleagues at the Université de Montréal, we have shown that Argos’ approach of transfecting dendritic cells with autologous, HIV-specific antigens effectively activates dendritic cells and enhances the HIV-specific T cell response. We believe that these results support our methods of developing potent immunotherapies that help patients’ immune systems more effectively fight HIV infection.”

The inability of the immune system to effectively mount a response against HIV may be caused by a defect in the maturation of T cell memory. To explore this hypothesis, researchers from Dr. Rafick-Pierre Sékaly’s laboratory at the Université de Montréal and Argos tested whether modified dendritic cells, derived from monocytes of HIV-infected individuals, could correct the defective maturation of HIV-specific CD8 T-cells responsible for virus eradication. To potentially improve the magnitude and quality of the anti-HIV T-cell response, maturing dendritic cells were transfected with mRNA-encoding autologous HIV sequences combined with mRNA encoding immune modulatory molecules. These modified dendritic cells were then tested for their ability to expand and mature T cell responses in vitro.

The results of these recent assessments, presented for the first time at the International AIDS Conference in Mexico, show that this novel product induces greater proliferation, maturation and differentiation of HIV-specific CD8 cells in vitro. These properties, especially expanding memory cells, required for long term protection against pathogens, may represent an improvement worthy of future of clinical development.

“We believe that this improvement may represent a significant step forward,” said Dr. Sékaly, professor of immunology at the Université de Montréal. “The fact that we can stimulate a specific, long-term immune response gives us great hope that, with additional development, we will be able to give people infected with HIV a new option to battle the virus.”

The abstract, titled, “The co-transfection of monocyte derived dendritic cells (DC) by different combinations of HIV antigen RNA and molecular adjuvant RNA enhanced the response of HIV-specific CD8+ T cells,” was authored by Oleg Yegorov, Bader Yassine-Diab, Tom Baumgartner, Harris Carpenter, Irina Tcherepanova, Don Healey, Charles Nicolette, and Rafick-Pierre Sékaly.

This work was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. N01-AI-60019.

About the Arcelis™ Technology

Arcelis is Argos’ proprietary technology for personalizing RNA-loaded dendritic cell immunotherapies for HIV, other infectious diseases, and cancer. This platform is based on optimizing a patient’s own (autologous) dendritic cells to trigger a pathogen- or tumor-specific immune response. To address the challenge of the unique genetic profile of each patient’s disease and the genetic mutations of that disease, Argos loads the autologous dendritic cells with a sample of messenger RNA (“mRNA”) isolated from their disease. Through this process, dendritic cells can potentially prime immune responses to the entire antigenic repertoire, resulting in an immunotherapeutic that is customized to the patient’s specific disease. The development of the Arcelis platform is part of Argos’ broad collaboration with Kirin Pharma Company, Ltd.

PLoS ONE. 2008 Jan 30;3(1):e1489.
Multiplex RT-PCR amplification of HIV genes to create a completely autologous DC-based immunotherapy for the treatment of HIV infection.
Tcherepanova I, Harris J, Starr A, Cleveland J, Ketteringham H, Calderhead D, Horvatinovich J, Healey D, Nicolette CA.
Research and Development Department, Argos Therapeutics, Inc., Durham, North Carolina, USA. itcherepanova@argostherapeutics.com

BACKGROUND: Effective therapy for HIV-infected individuals remains an unmet medical need. Promising clinical trials with dendritic cell (DC)-based immunotherapy consisting of autologous DC loaded with autologous virus have been reported, however, these approaches depend on large numbers of HIV virions to generate sufficient doses for even limited treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: The present study describes a novel approach for RT-PCR amplification of HIV antigens. Previously, RT-PCR amplification of autologous viral sequences has been confounded by the high mutation rate of the virus which results in unreliable primer-template binding. To resolve this problem we developed a multiplex RT-PCR strategy that allows reliable strain-independent amplification of highly polymorphic target antigens from any patient and requires neither viral sequence data nor custom-designed PCR primers for each individual. We demonstrate the application of our RT-PCR process to amplify translationally-competent RNA encoding regions of Gag, Vpr, Rev and Nef. The products amplified using this method represent a complex mixture of autologous antigens encoded by viral quasispecies. We further demonstrate that DCs electroporated with in vitro-transcribed HIV RNAs are capable of stimulating poly-antigen-specific CD8+ T cell responses in vitro. CONCLUSION/SIGNIFICANCE: This study describes a strategy to overcome patient to patient viral diversity enabling strain-independent RT-PCR amplification of RNAs encoding sequence divergent quasispecies of Gag, Vpr, Rev and Nef from small volumes of infectious plasma. The approach allows creation of a completely autologous therapy that does not require advance knowledge of the HIV genomic sequences, does not have yield limitations and has no intact virus in the final product. The simultaneous use of autologous viral antigens and DCs may provoke broad patient-specific immune responses that could potentially induce effective control of viral loads in the absence of conventional antiretroviral drug therapy.

Written by huehueteotl

August 7, 2008 at 7:38 am

Posted in HIV

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