The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Abstract

Adoptive therapy with T-cell receptor (TCR)-engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-␣␤ repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8 ؉ T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion. (Blood. 2011; 118(4):946-954) IntroductionImmunotherapy of cancer through adoptive transfer of genemodified T cells is a promising approach 1-3 ; however, the choice of target antigen is decisive for its success. 4 Although targeting tumor-associated self-antigens is an approach applicable to a variety of tumors, serious side effects are occasionally seen. Adoptive transfer of autologous peripheral lymphocytes genetically engineered to express TCRs specific for melanocyte differentiation antigens Melan-A/MART-1 and gp100 in melanoma patients led to a partial clinical response, accompanied by autoimmune attack against skin, retina, and inner ear. 5 Targeting ERBB2, which is overexpressed in a variety of tumors, through chimeric antigen receptor (CAR)-transduced lymphocytes in a colon cancer patient resulted in a serious adverse event, because of recognition of low levels of ERBB2 on normal lung cells. 6 Targeting true tumor specific mutations, such as the products of translocations in leukemias, should reduce such a risk of autoimmunity. The chimeric protein TEL-AML1, resulting from the chromosomal translocation 12;21 represents the most common fusion gene in childhood BCP-ALL, 7 which places it among principal target candidates. Furthermore, because the TEL-AML1 fusion protein is an important transforming factor in leukemogenesis, 8,9 selection of antigen-loss variants is less likely to occur.A nonamer peptide derived from the TEL-AML1 fusion region has been described as immunogenic in HLA-A*0201 restriction settings. 10 Using reverse immunology approach, 11 a peptide which binds to HLA-A*0201 was identified. The peptide was used to induce cytotoxic T-cell (CTL) lines, which recognized autologous leukemic cells and the leukemi...

Molecular Pathways: Comparing the Effects of Drugs and T Cells to Effectively Target Oncogenes

“…However, despite continuous claims of their immunogenicity, often analyzed by reverse immunology, firm evidence that T cells raised against shared TSAs reject tumors is lacking. For example, the TEL-AML chromosomal breakpoint region was claimed to generate an immunogenic HLA-A0201-resticted epitope (62), but subsequently, it was shown that it is not processed and presented (63). Thus, raising T cells against shared TSAs is difficult and likely possible only for a few HLA restriction molecules.…”

Targeting mutations predictably

“…For example, it was not expected that the predicted HLA-A*0201 binding TEL-AML1 fusion peptide was not naturally generated by cells because of multiple proteasomal cleavage sites within the sequence of this fusion peptide. 1 Thus, the candidate peptide is probably not produced in useful amounts to serve as a target presented on MHC complexes on the surface of the acute lymphoblastic leukemia cells harboring this fusion protein.…”

“…1 Another important lesson to be learned from Popovic et al is that the relatively high affinity to the HLA-A*0201 molecule predicted by computer algorithms did not translate to biologic efficacy of either inducing T cells or serving as their targets. In fact, the peptide had to be anchored artificially to the MHC to accomplish these effects.…”

Discovery of T Cell Epitopes Implementing HLA-Peptidomics into a Reverse Immunology Approach

“…This approach has the advantage of specifically screening for T cells that recognize MiHA exclusively expressed by hematopoietic cells. However, we and others have previously reported that when such peptide predictions are solely based on computer algorithms that predict peptide-HLA binding affinity and proteolytic cleavage, the vast majority of T cell responses detected are directed against epitopes that are not naturally processed and presented and, as a consequence, will not kill their target cells (25)(26)(27). The identification of the HLA-associated peptidome of hematopoietic cells by mass spectrometric analysis evades this peptide selection problem.…”