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Description: The trial is designed to determine the response of the immune system of patients with CML to a vaccine made from their own tumor. Researchers believe that this particular vaccine, which is made from purified heat shock proteins taken from each patient's tumor, alerts the body's immune system to recognize and attack invading cancer. To be considered potentially eligible for this study you must have CML in the chronic phase.
Length/Duration: Vaccinations will be administered weekly for eight weeks. One clinic follow up visit will be scheduled two weeks after the final vaccination.
Rational for immunotherapy of CML
Conceptually,CML in chronic phase is the best model for immunological intervention. It is a disease as a result of chromosomal translocation, which generates a true tumor-specific antigen. Patients in chronic phase have relatively preserved immune function for a prolonged period of time. Studies have indeed shown that peptides spanning the junctional region of both the bcr/abl and abl/bcr fusion proteins can bind to major histocompatibility complex (MHC) class I molecules (Berke et al. 2000). Vaccination of patients with bcr/abl breakpoint fusion peptides generates specific immune responses (Pinilla-Ibarz et al. 2000). In addition, for patients relapsed after bone marrow or stem cell transplant, donor lymphocyte infusion is effective in inducing a majority of them into remission. The role of donor lymphocyte infusion has proven the original concept of graft versus leukemia effect and the effectiveness of immunotherapy, in practice, towards CML (Dazzi et al. 1999). More recently, it was found that the presence of cytotoxic T lymphocytes (CTL) against HLA-A2-restricted myeloid-specific antigen proteinase 3 correlates significantly with cytogenetic remission of CML treated either with IFN or stem cell transplant (Molldrem et al. 2000), which provides strong evidence for a role of T cell immunity in clearing malignant cells.
Current proposal and hypothesis:
Based on the established roles of HSPs in T cell immunity and a large body of preclinical and clinical safety data, we propose to initiate a pilot study to test the feasibility of immunization with autologous tumor-derived HSP70 in the treatment of CML in chronic phase. This study will facilitate more clinical trials in the future, testing the ultimate hypothesis that the combination of the cytostatic therapy such as IFN and STI571, with specific immunomodulator such as HSP70 offers the best chance of eradication of CML. A total of 10 eligible patients will be enrolled in the study. All eligible patients will undergo aphaeresis to collect peripheral blood mononuclear cells. The autologous HSP70 is then purified using the standard protocol. After passing the established sterility testing, the patients are immunized intradermally with 50 micrograms HSP70 for a total of 8 injections in 2 months. They may receive their standard therapy during this time. In addition to collecting the feasibility and toxicity data, the development of anti-tumor immunity will be measured by,
1. an increase in peripheral blood of IFN-gamma producing CD8+ T-lymphocytes which are reactive to the autologous bcr/abl positive peripheral mononuclear cells
2. an increase of PR-1 specific CTLs by PR1-HLA-A2 tetramer techniques in patients who are HLA-A2 positive
3. the change of immunophenotype of peripheral lymphocytes
4. the cytogenetic remission of Philadelphia chromosome from the bone marrow
Allocation: Non-Randomized, Control: Uncontrolled, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Heat Shock Protein 70 HSP70
University of Connecticut Health Center
University of Connecticut Health Center
Published on BioPortfolio: 2014-08-27T03:56:28-0400
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Heat and cold stress-inducible, transcription factors that bind to inverted 5'-NGAAN-3' pentamer DNA sequences and are regulated by poly(ADP) ribosylation. They play essential roles as transcriptional activators of the HEAT-SHOCK RESPONSE by inducing expression of large classes of MOLECULAR CHAPERONES and heat-shock proteins. They also function in DNA REPAIR; transcriptional reactivation of latent HIV-1; and pre-mRNA processing and nuclear export of HSP70 HEAT-SHOCK PROTEINS during heat stress.
A constitutively expressed subfamily of the HSP70 heat-shock proteins. They preferentially bind and release hydrophobic peptides by an ATP-dependent process and are involved in post-translational PROTEIN TRANSLOCATION.
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