High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma

Abstract

BackgroundRecently, we demonstrated immunological and clinical responses to a RHAMM-R3 peptide vaccine in patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. To improve the outcome of the vaccine, a second cohort was vaccinated with a higher dose of 1,000 μg peptide. Design and MethodsNine patients received four vaccinations subcutaneously at a biweekly interval. Immunomonitoring of cytotoxic CD8+ as well as regulatory CD4 + T cells was performed by flow cytometry as well as by enzyme-linked immunospot (ELISpot) assays. Parameters of clinical response were assessed. ResultsIn 4 of 9 patients (44%) we detected positive immunological responses. These patients showed an increase of CD8-effector T cells and an increase of R3-specific CD8+ T cells. Two of these patients showed a significant decrease of regulatory T cells (Tregs). In one patient without response Tregs frequency increased from 5 to 16%. Three patients showed clinical effects: one patient with myelodysplastic syndrome RAEB-1 showed a reduction of leukemic blasts in the bone marrow, another myelodysplastic syndrome patient an improvement of peripheral blood counts and one patient with multiple myeloma a reduction of free light chains. Clinical and immunological reactions were lower in this cohort than in the 300 μg cohort. ConclusionsHigh-dose RHAMM-R3 peptide vaccination induced immunological responses and positive clinical effects. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematologic malignancies. However, higher doses of peptide did not improve the frequency and intensity of immune responses in this trial. (This study is registered at http://ISRCTN.org as ISRCTN32763606)Key words: acute myeloid leukemia, leukemia-associated antigens, receptor for hyaluronic acid mediated motility, RHAMM/CD168, epitope peptides, cancer vaccines. Haematologica 2010;95:1191-1197. doi:10.3324/haematol.2009 This is an open-access paper.High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma

Is it time to abandon RHAMM/HMMR as a candidate antigen for immunotherapy of acute myeloid leukemia?

“…Furthermore, the presence of these immune responses was associated with better clinical outcome in AML; 6 v) finally, RHAMM-derived peptide vaccination resulted in potent immune responses that were linked with a clinical benefit, while a negative impact on normal HSC function was not reported. 7,8 Together these observations support the hypothesis that RHAMM/HMMR may be suitable for AML, by fulfilling several parameters that have been identified as important in the selection of candidate antigens for immunotherapy for cancer. 9 Nevertheless, two further considerations are equally important.…”

Leukemia-associated antigens and their relevance to the immunotherapy of acute myeloid leukemia

“…Majeti et al 29 compared the gene expression signature of LSCs with that of normal HSCs and identified over 3000 genes with dysregulated expression in LSCs. 29 The published data set also includes several genes encoding proteins that can be recognized by the immune system and act as LAAs, such as Elicited (T) 47,95 Natural (B/T) 25 …”

“…47 A second trial of high-dose RHAMM 165-173 vaccination in nine patients with diverse myeloid malignancies failed to show any clinical benefit in the sole AML patient who was included; three other patients, two with myelodysplastic syndromes and one with myeloma, had variable clinical responses. 95 The potential use of hTERT in active specific immunotherapy for AML is currently under investigation. 96 Preliminary data from a phase I/II clinical trial of hTERT-loaded dendritic cell vaccination in AML patients have suggested an improvement in disease-free survival at 12 months, particularly among patients with a high risk of relapse.…”

Frequent T cell responses against immunogenic targets in lung cancer patients for targeted immunotherapy

“…CD8 -antigen presenting cells (APCs) were irradiated with 30 Gy and pulsed for 2 h with either a TAA-derived peptide or a control peptide at a concentration of 20 µg/ml. For all peptides, as well as for the control peptides, the same conditions and reagents were used as previously described (27).…”

“…After 8 days of MLPC culture, the T2-cell line pulsed with peptide was used as APCs in the ELISpot. IFNγ and GrB ELISpot assays were performed as previously described (22,27). Fig.…”