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Abstract: Active immunization of follicular lymphoma patients with idiotypic vaccines elicits antigen-specific antibody responses, T-cell responses, and antitumor effects. We hypothesized that these vaccinated patients could generate tumor-specific immune responses, not only against idiotype, but also against other tumor-associated antigens (TAA) by a mechanism of epitope spreading. To identify potential antigens, a phage surface expressed cDNA library derived from primary tumor cells was screened with sera from idiotype-vaccinated patients. Consistent with our hypothesis, we identified two immunogenic peptides (FL-aa-7 and 18), unrelated to idiotype, which were recognized by postvaccine sera but not by prevaccine or normal human sera. These peptide sequences derived from the 5′-untranslated regions of the human GTPase, IMAP family member 7 gene (FL-aa-7) and an alternative reading frame of U1-snRNP 70 (FL-aa-18), respectively, suggesting that epitope spreading had occurred. [Copyright &y& Elsevier]

Examines the importance of dendritic cells to immunize against tumor antigens in improving the prospects for cancer vaccines. Two approaches to harnessing dendritic cells antitumor response; Immunization of mice with tumor RNA transfected dendritic cells; Issues related to the selection of candidate tumor antigens.

Background: There is now a renewed interest in cancer vaccines. Patients responding to immune checkpoint blockade usually bear tumors that are heavily infiltrated by T cells and express a high load of neoantigens, indicating that the immune system is involved in the therapeutic effect of these agents; this finding strongly supports the use of cancer vaccine strategies. Lymphoplasmacytic lymphoma (LPL) is a low grade, incurable disease featuring an abnormal proliferation of Immunoglobulin (Ig)-producing malignant cells. Asymptomatic patients are currently managed by a "watchful waiting" approach, as available therapies provide no survival advantage if started before symptoms develop. Idiotypic determinants of a lymphoma surface Ig, formed by the interaction of the variable regions of heavy and light chains, can be used as a tumor-specific marker and effective vaccination using idiotypes was demonstrated in a positive controlled phase III trial.Methods: These variable region genes can be cloned and used as a DNA vaccine, a delivery system holding tremendous potential for streamlining vaccine production. To increase vaccination potency, we are targeting antigen-presenting cells (APCs) by fusing the antigen with a sequence encoding a chemokine (MIP-3α), which binds an endocytic surface receptor on APCs. Asymptomatic phase LPL is an excellent model to test our vaccine since patients have not received chemotherapeutics that interfere with innate immune function and have low tumor burden. We are evaluating the safety of this next-generation DNA vaccine in a first-in-human clinical trial currently enrolling asymptomatic LPL patients. To elucidate the mode of action of this vaccine, we will assess its ability to generate tumor-specific immune responses and examine changes in the immune profile of both the peripheral blood and bone marrow.Discussion: This vaccine could shift the current paradigm of clinical management for patients with asymptomatic LPL and inform development of other personalized approaches.Trial Registration: ClinicalTrials.gov identifier NCT01209871; registered on September 24, 2010. [ABSTRACT FROM AUTHOR]

The clonotypic surface Ig receptor expressed by malignant B cells,idiotype,is a tumor-specific antigen and an attractive target for active immunotherapy.While Ab's specific for tumor idiotype have been well described in patients with B cell malignancies,the precise antigenic epitopes in human idiotype recognized by autologous T cells remain largely unknown.We report here that T cell lines generated from lymphoma patients actively immunized with idiotype protein specifically recognized multiple,unique immunodominant epitopes in autologous tumor idiotype.Synthetic peptides corresponding to hypervariable,but not frame- work,regions of Ig heavy chain specifically stimulated CD4 +and CD8 +T cells to proliferate and secrete proinf lammatory cytokines in an MHC-associated manner.Detailed analysis revealed a minimal determi- nant of an immunodominant epitope,comprising critical residues at the amino terminus that may be a prod- uct of somatic hypermutation.Association of idiotype-specific T cell responses with previously documented molecular remissions in idiotype-vaccinated patients suggests that the newly identified T cell epitopes may be clinically relevant.Such antigenic epitopes may serve as candidates for novel peptide-vaccine strategies,and as tools to selectively expand tumor antigen --specific T cells for adoptive immunotherapy and for monitoring T cell immunity in vaccinated patients. [ABSTRACT FROM AUTHOR]

Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identifica-tion of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vac-cines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncopro-tein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malig-nancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, in-cluding follicular lymphoma, chronic lym-phocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We dem-onstrated that TCL1-specific CD8+ T cells can be generated from HLA-A*0201 (HLA-A2)+ normal donors and identified TCLI71-78 (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL171-78 peptide-specific T cells were present In the peripheral blood and tumor-infiltrating lymphocytes of lymphoma patients, could be expanded in vitro, and lysed autologous tumor cells but not normal B cells in an HLA-A2-restricted manner. Our results suggest thatTCLI is naturally processed and pre-sented on the surface of lymphoma cells for recognition by cytotoxic T cells and can serve as a novel target for develop-ment of immunotherapeutic strategies against common B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Abstract: Adoptive therapy with antigen-specific T cells is a promising approach for the treatment of infectious diseases and cancer. However, cloning of antigen-specific T cells by the traditional approach of limiting dilution is a time-consuming, laborious, and inefficient process. Here, we describe a novel flow cytometric strategy for rapid isolation of human tumor antigen-specific T-cell clones by using T-cell receptor (TCR) Vβ antibodies in combination with carboxyfluorescein succinimidyl ester (CFSE)-based proliferation assay. The CFSE dilution following antigen stimulation identified proliferating antigen-specific T cells, and the TCRVβ antibodies allowed distinguishing T cells at the clonal level from a heterogeneous T-cell population. This method of TCRVβ/CFSE dilution was used for the isolation of four different human lymphoma and melanoma-specific CD4+ and CD8+ T-cell clones reactive against defined and undefined tumor antigens. Isolated tumor-specific T-cell clones could be expanded to large numbers ex vivo while maintaining phenotype, function, and tumor antigen specificity. The method was simple, efficient, and reproducible, and may have potential application for the development of adoptive immunotherapeutic strategies. [Copyright &y& Elsevier]