Autologous lymphoma vaccines induce human T cell responses against multiple, unique epitopes
Sivasubramanian Baskar, … , Carol B. Kobrin, Larry W. Kwak
Sivasubramanian Baskar, … , Carol B. Kobrin, Larry W. Kwak
Published May 15, 2004
Citation Information: J Clin Invest. 2004;113(10):1498-1510. https://doi.org/10.1172/JCI20312.
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Article Oncology

Autologous lymphoma vaccines induce human T cell responses against multiple, unique epitopes

Abstract

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 framework, regions of Ig heavy chain specifically stimulated CD4+ and CD8+ T cells to proliferate and secrete proinflammatory cytokines in an MHC-associated manner. Detailed analysis revealed a minimal determinant of an immunodominant epitope, comprising critical residues at the amino terminus that may be a product 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.

Authors

Sivasubramanian Baskar, Carol B. Kobrin, Larry W. Kwak

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Dose-response curves of LE T cells and determination of a minimal CDR2 T...
Dose-response curves of LE T cells and determination of a minimal CDR2 T cell epitope. (A) The EBV-583 cells were incubated at 37°C for 2_3 hours with the indicated amounts of LE-CDR2-1 peptide. After three washes, peptide-pulsed EBV-583 cells were irradiated and cultured with T cells. The proliferation responses by LE-1 (filled circles) and LE-2 (open circles) T cells are shown. (B) Culture supernatants from parallel experiments, as described for A, were collected, and cytokine responses were determined. (C) LE T cells were cultured with irradiated EBV-583 cells in the absence or presence of 50 ∝M individual peptide from an LE-CDR2 library. Proliferation responses (Ø cpm) from a representative experiment are shown. The responses to 10 and 1 ∝M of peptide ITNTSSYISYADSVK (CDR2-2) were 37,026 and 19,981 Ø cpm, respectively. The responses to 10 and 1 ∝M of peptide TNTSSYISYADSVK (CDR2-3) were 320,602 and 14,069 Ø cpm, respectively. Dose-response curves for other maximally stimulatory peptides, YITNTSSYISYADSV (CDR2-7), YITNTSSYISYADS (CDR2-8), and YITNTSSYISYAD (CDR2-9), are depicted in Figure 3C. A similar pattern of response was seen with 5 ∞ 104 and 2 ∞ 105 T cells (data not shown).