Extracorporal Cancer Immunotherapy
Development of Technique for Cancer Immunotherapy Based on the Complex Extracorporal Activation of Natural and Adoptive Immunity: Experimental and Clinical Studies
Tech Area / Field
- BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
3 Approved without Funding
Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- Cancer Research Center, Russia, Moscow
- Triumf International, L.L.C., USA, UT, Draper\nFachklinik "Leonardis" GmbH, Germany, Kornwestheim\nSYNERGY - Hematology-Oncology Medical Associates, Inc., USA, CA, Los-Angeles\nGerontology Research Center, USA, MD, Baltimore\nChiba Cancer Center, Japan, Chiba\nApplied Life Sciences, USA, HI, Captain Cook\nThe Cleveland Clinic Foundation / Lerner Research Institute, USA, OH, Cleveland\nInstituto de InvestigacionBiomedica y Desarollo Tecnologico, Spain, San Sebastian
The Project is dedicated to one of the most urgent problems of contemporary biology and medicine — to the development of approaches to the complex cancer immunotherapy based on extracorporal activation of natural and adoptive immunity.
Lately, two basic lines of cancer immunotherapy had been under development.
The first one connected with extracorporal activation of natural killers ( NK-cells) and lymphokine activated killers (LAK-cells) with the help of cytokines, such as interleukin-2 (IL-2), interferons (INFs) and prothymosin- ( ProT).
The second one is based on the usage of extracorporally cultured dendrite cells and fibrocytes as natural vectors for specific vaccination of cancer patients. Dendrite cells and fibrocytes are being the most effective antigen-presenting cells and extremely important for the development of adoptive immunity on the stage of specific recognition of foreign antigen and immune system activation. That type of antigen-representing cells had permanently manifested expression of B7 co-stimulator, molecules of the I-st and II-nd classes of the main histocompatibility complex (MHC) and adgesines ICAM-I, ICAM-3, LFA-3. Thus, initiation of surface structure, taking part in the formation of T-cell response is not needed. Permanent synthesis of molecules of I-st and II-nd classes of MHC in those cell type lead to the fast formation of immunogenic complexes with peptides of tumor associated antigens, easily assimilated through pinocytosis. The fact of the presence on the one and the same antigen-representing cell both of specific immunogen and non-specific co-stimulator creates the conditions for the span into action of two-signal system of specific T-cell selection, activation of the secretion of IL-2 which joins into the process of T-cell proliferation and differentiation. Deficiency of antitumor immunity is stipulated by many factors, in particular, weak recognition of autologic tumor cells on the account of secretion of vascular endothelial growth factor by the latter , which inhibits dendrite cell maturing. Usage of extracorporal therapy technique permitting to restore vasted functions of dendrite cells as the result of their activation in vivo by cytokines ( GM-CSF, G-CSF, IL-4, TNF-) in the presence of tumor antigen ensures effective vaccination in cancer patients. Synthetic peptides, recombinant tumor antigens or tumor lysates are to be used as antigens.
In the frames of the Project, it is proposed to join the means of adoptive immunotherapy through the stimulation of T-killer antitumor activity and bettering of tumor recognition creating autovaccines based on mature dendrite cells combined with chemotherapy and surgery. To obtain lymphocytes from cancer patients, an original technique of the shunting of direct thoracic duct draining worked out by the participants of the Project ( Russian patent No 321 858) would be used. That method ensures to obtain large volumes of lymthocytes without traditional expensive and exhausting (8-hours ) procedure of blood separation. Isolation of large scale of lymphocytes (upto 8 billion) enables to increase therapy efficacy and substantially low the IL-2 dose ( from 18 mln.ME/m2 to 0,5 mln.ME/m2,), and thus to minimize immunotherapy side effects and to decrease treatment price. To intensify the activation of antitumor immunity, it is proposed to study in the frames of the Project efficacy of complex application of cytokines ( IL-2, INFs,Pro T). A complex native preparation named Lymphokinin (Russian patent No 2048816) developed by the participants of the Project and successfully passed the I-st and II-nd stages of clinical trails would be used.
That approach is planned to be used, first of all, for the treatment of chemo-radio-resistant form of non-small cell lung cancer. Now the complex extracorporal immunotherapy of cancer diseases is not realized in practice.
The aim of the Project:
To develop the approaches to the complex immunotherapy of cancer based on extracorporal activation of natural and adopted immunity in experiment and in clinic.