Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches

Abstract

The expression of tumor-associated antigens (TAAs) might play a critical role in the control of minimal residual disease (MRD) in acute myeloid leukemia (AML), and therefore might be associated with clinical outcome in AML. In a DNA microarray analysis of 116 AML samples, we found a significant correlation between high mRNA levels of G250/CA9 and longer overall survival (P ‫؍‬ .022), a similar trend with high mRNA levels of PRAME (P ‫؍‬ .103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1, we found no correlation with clinical outcome. High expression of at least 1 of the 3 TAAs, RHAMM/HMMR, PRAME, or G250/ CA9, provided the strongest favorable prognostic effect (P ‫؍‬ .005). Specific Tcell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease (P < .001). Furthermore, we could demonstrate specific lysis of T2 cells presenting these epitope peptides.In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control. Thus, these TAAs represent interesting targets for polyvalent immunotherapeutic approaches in AML. IntroductionTumor-associated antigens (TAAs) have been shown to induce specific T-cell immune responses in tumor patients, and thus represent potential target structures for specific immunotherapies. [1][2][3][4] Recently, a large number of TAAs inducing specific T-cell responses have been identified and functionally characterized in different solid tumors, but several TAAs also seem to be expressed in hematologic malignancies like acute myeloid leukemia (AML). 5,6 AML is the most common acute leukemia in adults. With intensive induction therapy, complete remission (CR) rates between 65% and 75% are achieved in younger patients (Ͻ 60 years). However, more than 50% of these patients will relapse, leading to an overall survival rate of only 30% to 40% after 5 years. Results are more unfavorable in patients older than 60 years. 7,8 Immunotherapeutic approaches targeting TAAs to prevent relapse may represent a promising novel treatment option to improve the outcome of AML patients.Recently, in patients with AML, specific T-cell responses of cytotoxic T-lymphocytes (CTLs) were detected against the Wilms tumor gene WT1, proteinase 3 (PRTN3), and the receptor for hyaluronic acid-mediated motility (RHAMM; also known as CD168 or HMMR). 9-15 For these TAAs, clinical peptide vaccination trials have been initiated including patients with AML. 9,16,17 Furthermore, additional TAAs known to induce specific immune responses of CD8 ϩ T cells, such as PRAME, G250/CA9, BCL2, LAMR1, and hTERT, are also frequently expressed in AML. [18][19][20][21] While immunotherapy eliciting a specific T-cell response to TAAs expressed by leukemic ...

A Causal Role for the Human Tumor Antigen Preferentially Expressed Antigen of Melanoma in Cancer

“…Patients with the BCR/ABL t(9;22) (Ph+) and AML1/ETO t(8;21) translocations show particularly high PRAME mRNA levels (8,15,16). It cannot be excluded, however, that the correlation of PRAME expression with good prognosis is secondary to its correlation with these translocations (17). Indeed, it has been shown that PRAME is a BCR/ABL-inducible gene (15).…”

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

“…88 A similar observation was made regarding PRAME, which is known to contain at least four different HLA-A*0201-restricted epitopes that can be naturally recognized (PRA [100][101][102][103][104][105][106][107][108] , PRA 142-151 , PRA 300-309 and PRA [425][426][427][428][429][430][431][432][433] ). 64 According to Greiner et al, 25 up to 70% of AML patients in complete remission spontaneously exhibit circulating PRA 300-309 -specific CTLs, further underscoring the significant natural immunogenicity of PRAME. 25 CD8 þ T cells specific for G250/CAIX [24][25][26][27][28][29][30][31][32] , G250/CAIX 254-262 and RHAMM [165][166][167][168][169][170][171][172][173] are also regularly detected in the peripheral blood of AML patients, with frequencies of 60%, 13% and 47%, respectively.…”

“…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 …”

“…25 CD8 þ T cells specific for G250/CAIX [24][25][26][27][28][29][30][31][32] , G250/CAIX 254-262 and RHAMM [165][166][167][168][169][170][171][172][173] are also regularly detected in the peripheral blood of AML patients, with frequencies of 60%, 13% and 47%, respectively. 25 In a series of 15 AML patients, Siegel et al 22 observed spontaneous T-cell immune responses to different HLA-A*0201-restricted T-cell epitopes derived from OFA-iLRP, including iLR1 [59][60][61][62][63][64][65][66][67][68] (6/15) …”

“…24 Preferentially expressed antigen in melanoma (PRAME) is by far the best characterized AMLassociated CTA. 25 However, it is important to note that the normal tissue expression pattern of PRAME is somewhat broader than that of 'classical' CTAs. Low-level PRAME expression has also been observed in the adrenal glands, the endometrium and the pancreas.…”