PR1 Peptide Vaccine
The Vaccine Company’s lead product, the PR1 peptide vaccine, is being investigated as a therapeutic cancer vaccine for the treatment of certain leukemias: AML, CML and MDS.
PR1 peptide vaccine is based on active immunization of the patient to a fragment of a surface serine protease, proteinase 3, that is uniquely overexpressed on leukemic myeloid cells. Proteinase 3 appears to be expressed only in the bone marrow. The fragment, PR1, is a proteinase 3-derived HLA-A2.1 nonapeptide (9 amino acid in length), that was discovered by Dr. Molldrem. When the nonapeptide binds to the MHC molecule, it causes a conformation change that makes the complex susceptible to binding by a T-cell receptor. This eventually leads to the immune system producing cytotoxic lymphocytes (CTLs) specific toward leukemic myeloid cells. In theory, these CTLs should be able to kill off the leukemic cells, without affecting normal cells.
Early Clinical Trials of PR1 peptide vaccine
An update of the Phase I-II study was reported at the 2004 Meeting of the American Society of Hematology. Data was presented on the initial 35 patients in the study. To date, more that 60 patients with advanced hematological neoplasms (AML, CML and myelodysplastic syndrome) have been treated. The dose of peptide has ranged from 0.25 mg to 1.0 mg and the either 3 or 6 doses have been administered. The peptide is administered subcutaneously along with Montanide ISA-51 and granulocyte-macrophage colony stimulating factor.
Treatment emergent adverse events have largely been limited to mild to moderate injection site reactions. A safety objective of the study was to determine if PR1 would elicit vasculitis-type syndromes as an unwanted side effect. The potential for vasculitis is suggested by the observation that proteinase 3 is the target antigen in Wegener's Granulomatosis, a serious disorder of vascular inflammation. Although there are theoretical reasons why PR1 is not expected to induce vasculitis, clinical and serological tests were closely monitored for any evidence of an autoimmune reaction. No patient on the study developed clinical or serologic evidence of a vasculitis.
Clinical Responses
Responses have occurred in all three disease indications: AML, CML and MDS. PR1 vaccination frequently eliminated the last residual AML detectable in the most sensitive molecular tests. For instance, one patient with persistent molecular AML has been disease-free for more that four years. Many patients have developed an immune response against leukemia cells. More that 60% of patients have developed anti-leukemia cells, detected in a specific test called the tetramer assay for PR1-cytotoxic lymphocytes. Moreover, immunologic responders had a significantly greater chance of developing a clinical response.
Future clinical development of the PR1 peptide will focus on AML and MDS. In AML, a Phase 3 study is underway. Patients with AML in remission are randomized to receive either placebo or the PR1 peptide. This study has been reviewed by the FDA, and enrollment is ongoing. A successful study would support approval by FDA in AML. Patients with AML in remission will be randomized to receive either placebo or the PR1 peptide. This study has been approved by the FDA, and enrollment is ongoing. Phase 2 studies in MDS and CML are also underway and enrolling patients in treatment. For more information, see the clinical trial page here.
References:
1. Molldrem J, Dermime S, Parker K, et al: “Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells.” Blood 88:2450-7, 1996
2. Molldrem JJ, Clave E, Jiang YZ, et al: “Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colonyforming units.” Blood 90:2529-34, 1997
3. Burchert A, Wolfl S, Schmidt M, et al: “Interferon-alpha , but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia.” Blood 101:259-264, 2003
4. Bories D, Raynal MC, Solomon DH, et al: “Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells.” Cell 59:959-68, 1989
5. Molldrem JJ, Lee PP, Wang C, et al: “Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia.” Nat Med 6:1018-23, 2000
6. Molldrem JJ, Lee PP, Kant S, et al: “Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells.” J Clin Invest 111:639-47, 2003
7. Molldrem JJ, Kant S, Jiang J, et al: “The basis of T-cell mediated immunity to chronic myelogenous leukemia.” Oncogene 21:8668-8673, 2002
The Vaccine Company’s lead product, the PR1 peptide vaccine, is being investigated as a therapeutic cancer vaccine for the treatment of certain leukemias: AML, CML and MDS.
PR1 peptide vaccine is based on active immunization of the patient to a fragment of a surface serine protease, proteinase 3, that is uniquely overexpressed on leukemic myeloid cells. Proteinase 3 appears to be expressed only in the bone marrow. The fragment, PR1, is a proteinase 3-derived HLA-A2.1 nonapeptide (9 amino acid in length), that was discovered by Dr. Molldrem. When the nonapeptide binds to the MHC molecule, it causes a conformation change that makes the complex susceptible to binding by a T-cell receptor. This eventually leads to the immune system producing cytotoxic lymphocytes (CTLs) specific toward leukemic myeloid cells. In theory, these CTLs should be able to kill off the leukemic cells, without affecting normal cells.
Early Clinical Trials of PR1 peptide vaccine
An update of the Phase I-II study was reported at the 2004 Meeting of the American Society of Hematology. Data was presented on the initial 35 patients in the study. To date, more that 60 patients with advanced hematological neoplasms (AML, CML and myelodysplastic syndrome) have been treated. The dose of peptide has ranged from 0.25 mg to 1.0 mg and the either 3 or 6 doses have been administered. The peptide is administered subcutaneously along with Montanide ISA-51 and granulocyte-macrophage colony stimulating factor.
Treatment emergent adverse events have largely been limited to mild to moderate injection site reactions. A safety objective of the study was to determine if PR1 would elicit vasculitis-type syndromes as an unwanted side effect. The potential for vasculitis is suggested by the observation that proteinase 3 is the target antigen in Wegener's Granulomatosis, a serious disorder of vascular inflammation. Although there are theoretical reasons why PR1 is not expected to induce vasculitis, clinical and serological tests were closely monitored for any evidence of an autoimmune reaction. No patient on the study developed clinical or serologic evidence of a vasculitis.
Clinical Responses
Responses have occurred in all three disease indications: AML, CML and MDS. PR1 vaccination frequently eliminated the last residual AML detectable in the most sensitive molecular tests. For instance, one patient with persistent molecular AML has been disease-free for more that four years. Many patients have developed an immune response against leukemia cells. More that 60% of patients have developed anti-leukemia cells, detected in a specific test called the tetramer assay for PR1-cytotoxic lymphocytes. Moreover, immunologic responders had a significantly greater chance of developing a clinical response.
Future clinical development of the PR1 peptide will focus on AML and MDS. In AML, a Phase 3 study is underway. Patients with AML in remission are randomized to receive either placebo or the PR1 peptide. This study has been reviewed by the FDA, and enrollment is ongoing. A successful study would support approval by FDA in AML. Patients with AML in remission will be randomized to receive either placebo or the PR1 peptide. This study has been approved by the FDA, and enrollment is ongoing. Phase 2 studies in MDS and CML are also underway and enrolling patients in treatment. For more information, see the clinical trial page here.
References:
1. Molldrem J, Dermime S, Parker K, et al: “Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells.” Blood 88:2450-7, 1996
2. Molldrem JJ, Clave E, Jiang YZ, et al: “Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colonyforming units.” Blood 90:2529-34, 1997
3. Burchert A, Wolfl S, Schmidt M, et al: “Interferon-alpha , but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia.” Blood 101:259-264, 2003
4. Bories D, Raynal MC, Solomon DH, et al: “Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells.” Cell 59:959-68, 1989
5. Molldrem JJ, Lee PP, Wang C, et al: “Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia.” Nat Med 6:1018-23, 2000
6. Molldrem JJ, Lee PP, Kant S, et al: “Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells.” J Clin Invest 111:639-47, 2003
7. Molldrem JJ, Kant S, Jiang J, et al: “The basis of T-cell mediated immunity to chronic myelogenous leukemia.” Oncogene 21:8668-8673, 2002
