TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas

Abstract

Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identification of novel immunogenic lymphomaassociated 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 TCL1 [71][72][73][74][75][76][77][78] IntroductionMalignancies of B-cell origin are highly responsive to combination chemotherapy, and complete remissions can be induced in most patients. The use of rituximab, an anti-CD20 monoclonal antibody, in combination with chemotherapy has improved the overall and complete response rates, progression-free survival, overall survival, and curability of patients with B-cell non-Hodgkin lymphomas. [1][2][3] However, relapse remains a significant cause of treatment failure, and novel treatments are needed to eradicate minimal residual disease to further improve clinical outcome in these patients.Therapeutic agents used to eradicate minimal residual disease should ideally be directed at different targets and have different mechanisms of action than agents used in induction therapy. They also should be safe with minimal adverse effects because they may need to be administered as maintenance therapy over several months. Therapeutic vaccines have many of these desirable features because they can target different antigens on the lymphoma tumor cells than those targeted by rituximab or chemotherapy agents, and they are safe and well tolerated. 4 Furthermore, by inducing immunologic memory and polyclonal humoral and cellular immune responses, vaccines may potentially produce a sustained antitumor effect, and unlike monoclonal antibodies, they may prevent the emergence of antigen-loss variants. Thus, therapeutic vaccines against lymphomas can be complementary to passive immunotherapeutic agents such as monoclonal antibodies and cytotoxic chemotherapeutic agents and could be ideal for eradicating minimal residual disease.Several groups have used the clonal tumor immunoglobulin expressed on the surface of mature B-cell malignancies, termed idiotype, as a tumor-specific antigen for development of therapeutic vaccines against lymphomas. [5][6][7][8][9][10][11] Idiotype vaccines were shown to be safe and induced sustained antitumor antibody and CD4 ϩ and CD8 ϩ T-cell responses in patients with follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). [5][6][7][8][9][...

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…17,18 In order to test the in vivo function of these L-chain-specific T cells, we stimulated HLA A2+ normal donors' T cells as previously reported, 19 and purified Id L-chain, peptide-specific CD8 C T cells and expanded them with IL-2 (180 IU/mL) or IL-15 (50 ng/mL) using the rapid expansion protocol (REP). 20,21 After 14 d, we subsequently transferred the same number of T cells (1 £ 10 7 ) into the immune-deficient mice, bearing 3 d U266 xenografts.…”

Role of 99mTc‐DPD scintigraphy in imaging extra‐cardiac light chain (AL) amyloidosis

“…TCL1A peptides for immunotherapy have been recently patented (patent: WO 2013075105 A3): they bind to major histocompatibility complex (MHC) I (HLA-A2) on tumour cells or other antigen-presenting cells and are recognized by T-cell receptors on T cells. These peptides may be therapeutically used to treat leukaemia and lymphoma (Weng et al, 2012). Here, we demonstrated that TCL1A interacts with the TP63 protein.…”

Exploring and analysing immune single cell multi-omics data with VDJView

“…Pseudo-time analysis on these immune cells showed that a common repertoire of B cells is involved in breast cancer with a migratory pattern between primary and metastatic tissues (Figure 1). We used VDJView to integrate immune receptor could also indicate presence of malignant immune cells as these genes are often found in leukemia and likely to contribute to oncogenesis BCL6 [19,20]. Further analysis of this data is detailed in Supplementary Note 2.…”