Emergence of Idiotype Variants during Treatment of B-Cell Lymphoma with Anti-Idiotype Antibodies

Abstract

We studied two patients with malignant B-cell lymphoma that manifested resistance to the therapeutic effects of anti-idiotype antibody because of the emergence of subclones with changes in their immunoglobulin idiotypes. In both patients, tumor-cell populations arose that were unreactive with anti-idiotype antibody but that retained surface immunoglobulin. One of the patients had an additional subpopulation of tumor cells that had switched from mu to gamma heavy-chain expression. Study of the immunoglobulin genes in the tumors confirmed that the subpopulations were derived from the same original clone of neoplastic B cells in each patient. The available data suggest that the idiotypic variation observed was the result of somatic mutation in the variable region of the active immunoglobulin genes. The fact that such mutations became evident over a short time and in the context of a partial tumor response suggests that the antibody therapy exerted a strong selective force against tumor cells that expressed the idiotype determinant. Multiple anti-idiotype antibodies may therefore be needed to identify all cells of a malignant clone, and some patients may require treatment with more than one monoclonal antibody.

B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

“…However, subunits of the BCR are not typically lost in FL (35). Furthermore, under the selection pressure of antibody therapy directed against lymphoma BCR idiotype, resistance in FL occurs most often by mutation of the target BCR idiotype rather than loss of BCR expression (36), again in accordance with the view that some aspect of a functional BCR signaling complex is required for lymphoma cell survival, similar to the requirement in mature healthy B cells (18,19).…”

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

“…As shown in Figure 10, almost all (10 out of 13) of the predicted epitopes presented a high probability of proteasomal cleavage in at least one of the terminal aa residues (aa1 or aa9 of the sequence). HLA-A*2402-restricted GTF [27][28][29][30][31][32][33][34][35] , and HLA-B*0702-restricted SCK [21][22][23][24][25][26][27][28][29] and AIS 33-41 had low probability values in both aa1 and aa9, while HLA-A*0101-restricted epitopes seemed to have a high probability of proteasomal processing (i.e. positive prediction values in both the terminal residues).…”

“…It is well known that BCR supplies important survival signals to normal B cells and recent observations support this BCR critical role also in lymphoma B cells. Treatment of patients with follicular lymphoma with anti-Id antibodies did not result in the emergence of BCR-negative lymphoma variants [32], demonstrating the pivotal role of BCR in cancer cell survival [18]. Moreover, immunoglobulin loss variants have rarely been described and only in certain B-NHL, such as follicular lymphoma [6].…”

Anti-idiotype antibodies in cancer treatment

“…Nearly half of these patients experienced objective remissions with clinical significance, although it was immediately clear that a number of features concerning this new therapeutic approach needed to be refined. For instance, patients with circulating, soluble, tumor-specific Id protein had to be considered less prone to respond from a clinical standpoint, and human anti-mouse antibodies were produced over time by a considerable number of patients treated with anti-Id mAbs (Meeker et al, 1985).…”

“…In particular, the addition of chemotherapy did not interfere with the anti-tumor effect of anti-Id mAbs, nor prevented the emergence of Id-negative tumor cell variants (Maloney et al, 1992). This latter fact, together with the in vivo emergence as well of Id variants on the clonal cells of human B-cell malignancies -regardless of whether they had been previously treated with anti-Id mAbs (Meeker et al, 1985) or not (Raffeld et al, 1985) and with the unsustainable logistical problems, ultimately decreed the downfall of passive immunotherapy of B-cell malignancies based on anti-Id mAbs. What we are left with is a largely unfeasible therapeutic approach, by which as many as 45 indolent B-cell lymphoma patients were treated in a single center between 1991 and 1993.…”