Chronic myelogenous leukemia is among the malignancies most susceptible to immune recognition and eradication. The strongest evidence for this immune response is the graft-versus-leukemia effect, which is most clearly seen in chronic myelogenous leukemia after allogeneic stem-cell transplantation (allo-Stem-cell transplantation) and donor lymphocyte infusion (DLI). The cancer vaccines being developed are designed to induce antigen-specific antitumor immune responses against the specific cancer cells present in the patient.
Problems with production, storage, and administration could deter the acceptance and use of vaccines in the clinic, especially because of the availability of an effective oral drug, imatinib. Among patients treated with imatinib, though, only 39% achieve an major molecular response (defined as a reduction in BCR-ABL transcript levels of at least 3 log). Therefore, vaccines might instead be used to control and reduce minimal residual disease levels (the BCR-ABL transcript level) in patients being treated with drug therapy.
Mechanism Of Action
Some vaccines contain antigens or parts of antigens purified from cancer cells obtained from the patient or from another individual. DNA vaccines are being tested that contain the DNA encoding the specific antigen. In some approaches, cells are isolated in the laboratory and start making antibodies after the cancer antigen is inserted. In each case, the vaccines’ method of action is to render the cancer cells susceptible to immune attack by cytotoxic T lymphocytes (CTLs) by heightening the recognition of markers within cancer cells. The goal is to encourage the patient’s immune system to inhibit the growth of cancer cells.
Antigenics’ AG-858 (HSPPC-70-C) is a personalized HSP70 cancer vaccine. A Phase II trial of the agent in combination with imatinib is underway.
AG-858 is a vaccine comprising HSP70-peptide complexes that have been isolated from individual patients’ cancer cells. Patients undergo a blood-filtering process called leukopheresis, during which white blood cells (WBCs) are collected. The WBCs are then sent to Antigenics for production of the personalized vaccines.
HSPs are a family of chaperone proteins that participate in the degradation process of intracellular proteins. Because it associates with multiple potentially anti-genic peptides and cannot interact with antigen-presenting cells (APCs), HSP70 was proposed as an approach to develop tumor-specific vaccines. When the patient is vaccinated, the HSP70-peptide complexes interact with the immune system’s APCs at the site of injection. The HSP complexes bind to the CD91 receptor on APCs, and are taken into the cells. The APCs then travel to the lymph nodes where they re-present the antigenic peptides on their surfaces. This process triggers a response by cytotoxic T-lymphocytes against antigens expressed in cells from which the HSP70 was derived.
A Phase II study is evaluating the safety and efficacy of AG-858 in combination with imatinib in up to 120 patients in the United Kingdom and the United States with chronic chronic myelogenous leukemia who are receiving imatinib but have not achieved complete cytogenetic response (cytogenetic response).
In a pilot trial, 11 chronic myelogenous leukemia patients who had failed to achieve an major cytogenetic response after six months of imatinib therapy were treated with AG-858 and imatinib. HSP was successfully purified from all patients and, after vaccination, a cytogenetic response was achieved in all five patients who had completed the eight planned injections; two patients had a complete molecular response (complete molecular response).