T cell mediated immunotherapy for B cell lymphoma (original) (raw)
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Leukemia & Lymphoma, 2005
Despite advances in chemotherapy, radiotherapy and combined modality treatment, a significant proportion of non-Hodgkin's lymphomas remain incurable. The disease usually responds well to chemotherapy or radiation, but relapses are observed within months to a few years, with frequent failure of subsequent therapies. High-dose chemotherapy with or without radiation and autologous or allogeneic hematopoietic stem cell transplantation provide higher cure rates and longer remissions in certain patients with aggressive lymphomas. However, the higher treatment-related morbidity and mortality of high-dose chemotherapy has driven a search for new and more tumor-specific treatment modalities, such as immunotherapy. Tumor antigens expressed by B-cell lymphomas, such as the ''idiotype antigen'', are seen as unique and specific target molecules for direct lymphoma immunotherapy. This review will delineate advances, problems and prospects for approaches to anti-B cell lymphoma immunotherapy where pre-clinical studies and proof of principle have been directly translated to patient care.
TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas
Blood, 2012
Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identification of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vaccines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncoprotein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malignancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, including follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We demonstrated that TCL1-specific CD8+ T cells can be generated from HLA-A*0201 (HLA-A2)+ normal donors and identified TCL171-78 (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL171-78 peptide-specific T cells were pre...
Blood, 2003
Immunoglobulin (Ig) variable (V) region idiotypes (Id's) are highly tumor-specific antigens produced by B-lymphoma cells and are promising targets for immunotherapy. Id vaccination has proven effective in experimental mouse models and may possibly prevent recurrence of B lymphomas in humans. It has previously been shown that anti-Id antibodies protect against B-cell lymphoma in the absence of T cells. We here demonstrate in a T-cell-receptor transgenic mouse model that the contrary is also true: Id-specific CD4+ T cells can protect against Id+ B-lymphoma cells in the absence of B cells, antibodies, and CD8+ T cells. Moreover, Id-specific CD4+ T cells have a curative potential since they could be transferred as late as 17 days after subcutaneous tumor cell injection of severe combined immunodeficiency (SCID) mice and still abrogate tumor development in about 50% of mice. Such mice undergo an acute inflammatory swelling with infiltration of neutrophils at the site of tumor injection, which subsides over weeks, with some mice cured and delayed emergence of lymphomas in other mice. Adoptively transferred CD4+ T cells accumulated in the tumor and were activated (CD69+). In vitro experiments demonstrated that memory, but not naive, Id-specific CD4+ T cells kill Id+ B-lymphoma cells. The results show that Id-specific CD4+ T cells, in the absence of antibodies home to subcutaneous Id+ B lymphoma, become activated, induce inflammation, and prevent tumor development.
Clinical Cancer Research, 2004
Purpose: To investigate potential immunotherapeutic strategies in B lymphocytic malignancies we looked for CTLs recognizing CD19 and CD20 epitopes. Experimental Design: Three CD19 and CD20 peptides binding to HLA-A*0201 were identified and used to detect peptide specific CTLs by a quantitative real-time PCR to measure IFN-␥ mRNA expression in 23 healthy individuals and 28 patients (18 chronic lymphocytic leukemia (CLL), 7 follicular lymphoma, 2 acute lymphocytic leukemia, and 1 large cell lymphoma). Peptide-specific CTLs were expanded in culture with CD40-activated B cells to test lytic activity in three patients. Results: In healthy individuals, CD8 ؉ T-cell responses were detected in one to CD19 74-82 , in three to CD20 127-135 , and three to CD20 188-196. Seven of 27 patients (6 with CLL) had CD8 ؉ T cells recognizing CD19 74-82. Seven patients responded to CD20 127-135 and three to CD20 188-196. All were CLL patients. CD19 74-82-specific CTLs from three patients were expanded over 4 weeks. These cells were HLA-A*0201 specific and lytic for peptide-loaded antigenpresenting cells but not to malignant or unpulsed B cells. Conclusions: CTLs that recognize CD19 and CD20 epitopes exist in healthy individuals and may be increased in CLL patients. They are of low avidity and require high doses of peptide for activation. Strategies to increase T-cell avidity would be necessary for T-cell immunotherapeutic approaches using the peptides studied.
Lymphomas can develop from B cells chronically helped by idiotype-specific T cells
Journal of Experimental Medicine, 2007
B cell lymphomas have been associated with chronic infections and autoimmunity. However, most lymphomas develop in the absence of any known chronic antigenic stimulation. B cells process their highly diversified endogenous immunoglobulin and present clonally unique variable-region idiotypic (Id) peptides on their major histocompatibility complex (MHC) class II molecules to Id-specific T cells. We show that B cells chronically helped by Id-specific Th2 cells developed into large B cell lymphomas with cytogenetic DNA aberrations. The lymphomas expressed high amounts of Id, MHC class II, CD80/86, and CD40 and bidirectionally collaborated with Th2 cells. Thus, MHC class II–presented Id peptides may represent a chronic self-antigenic stimulus for T cell–dependent lymphomagenesis. Eventually, B lymphomas grew independent of T cells. Thus, T cells do not only eliminate cancers as currently believed. In fact, Id-specific Th2 cells can induce B lymphomas.
Blood, 2011
Idiotype vaccination for follicular lymphoma is primarily being developed as remission consolidation after chemotherapy. We investigated idiotype vaccination as primary intervention for treatment-naive indolent B-cell lymphoma and in a separate cohort as remission consolidation after chemotherapy to assess immunization-induced immune responses in relation to progression-free survival (German Clinical Trials Register, DRKS00000227). Twenty-one patients in each cohort received 6 intradermal injections of adjuvanted recombinant idiotype Fab fragment (FabId); 76% of patients in both groups developed anti-idiotype antibodies and/or cellular immunity as measured by enzyme-linked immunosorbent assay and interferon-γ ELISpot. In treatment-naive patients, only cellular responses correlated with superior progression-free survival (P < .002) and durable objective remissions (P = .04). Immunization-induced T cells recognized hypermutated or complementarity-determining region 3 epitopes. Afte...
Idiotypic Vaccine for Treatment of Human B-Cell Lymphoma
Human Immunology, 1997
Immunoglobulin idiotypes (Id) of malignant B cells represent highly specific markers which can be used for vaccination. PCR-amplification of immunoglobulin genes enables the rapid production of large amounts of Id vaccines. However, the separate amplification and subsequent recombination of heavy and light chains can lead to a loss of the relevant Id. To preserve the original chain pairs, we used single malignant B cells derived from an immunocytoma patient. Cytoplasm was extracted and the mRNA transcribed into cDNA. The VH and VL genes were then amplified by PCR and cloned into a vector for expression in E. coli. Id production was checked using an anti-Id mouse monoclonal Ab raised against the patient's tumor-specific IgG. One out of 3 constructs expressed the relevant Id. Analysis of the first 31 light chain residues revealed an identical sequence for the malignant B cells' IgG and the recombinant Id construct. Exchange of either the heavy or light chain with an unrelated chain resulted in loss of the Id. An unrelated sequence derived from the c-myc protein is coupled to the Id vaccine. The lymphoma patient was shown to have Abs to the c-myc sequence. This sequence therefore, increases the Id ϩ AbЈs antigenicity. CD spectroscopy showed an ␣-helical structure for the c-myc epitope. In conclusion, a B-cell lymphoma autovaccine was produced containing immunogenic sequences that do not alter the steric conformation of the tumor-specific Id. Human Immunology 56, 17-27 (1997).