Definition of a target for immunotherapy and results of the first Peptide vaccination study in chronic lymphocytic leukemia.
Results of bone marrow transplantation, as well as remission phenomena after viral infections, suggest that chronic lymphocytic leukemia (CLL) might be targeted effectively by T-cell-based immunotherapy. Antigen-targeted immunotherapies represent novel treatments for CLL patients. Earlier, we screened the mRNA expression of several tumor associated antigens (TAAs), observing the presence of RHAMM/CD168, fibromodulin, syntaxin, and NY-Ren60 in 55%-90% of CLL patients. RHAMM/CD168, fibromodulin, PRAME, and MPP11 were expressed in CLL patients but not in healthy volunteers. Quantitative reverse transcriptase polymerase chain reaction revealed higher RHAMM expression in high-risk CLL patients as well as in advanced stages of the disease. CLL cases with higher RHAMM expressions showed significantly shorter median treatment-free survivals. Among patients with mutated IgVH genes, an analysis of RHAMM expression enabled us to distinguish a subgroup of patients with a favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL. Because of the exquisite tissue expression of RHAMM and its high expression frequency in CLL patients, we further characterized RHAMM-specific CD8+ T cells in these patients. CD8+ T cells primed with the RHAMM-derived epitope R3, which is restricted by human leukocyte antigen (HLA)A2, lysed RHAMM+ CLL cells. Therefore, we initiated a Phase I clinical trial of R3 peptide vaccination. Four patients exhibited reduced white blood cell counts during the vaccination process. In 5/6 patients, R3-specific CD8+ T cells were detected with the corresponding peptide/HLA-A2 tetrameric complex; these populations were verified functionally in 4/5 patients using ELISpot assays. In conclusion, RHAMM expression seems to be of prognostic value, and may reflect the proliferative capacity of CLL cells; it may therefore represent an interesting target for immunotherapy. Peptide vaccination in CLL patients was safe eliciting specific CD8+ T-cell responses against the tumor antigen RHAMM.
Clinical Immunology Department, Medical University of Lublin, Lublin, Poland.
J
J
Tabarkiewicz
K
K
Giannopoulos
D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000628:therapy*; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016896:Treatment Outcome
D019496:Cancer Vaccines; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D010455:Peptides; C098946:hyaluronan-mediated motility receptor