Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia.

Abstract

PURPOSE:

Approximately 30% of patients with chronic lymphocytic leukemia (CLL) can be grouped into subsets with stereotyped B-cell receptor immunoglobulin (BcR IG) displaying remarkable similarity in the heavy complementarity-determining region 3 (VH CDR3). Here, we investigated whether the consensus VH CDR3 sequences from CLL stereotyped subsets can be exploited for immunotherapy approaches.

EXPERIMENTAL DESIGN:

Immunogenic epitopes from the consensus VH CDR3 sequence of the clinically aggressive subsets #1 and #2 and from Eμ-TCL1 mice, which spontaneously develop CLL with BcR IG stereotypy, were identified and used to generate specific HLA class I- and II-restricted T cells in vitro. T-cell reactivity was assayed in vitro as IFNγ production. Bone marrow-derived dendritic cells loaded with the peptides were used as vaccination strategy to restrain leukemia development in the Eμ-TCL1 mouse model.

RESULTS:

These stereotyped epitopes were naturally processed and presented by CLL cells to the VH CDR3-specific T cells. Furthermore, we validated the efficacy of VH CDR3 peptide-based immunotherapy in the Eμ-TCL1 transplantable mouse model. Immunization of mice against defined VH CDR3 peptide epitopes, prior to the challenge with the corresponding leukemia cells, resulted in the control of CLL development in a significant fraction of mice, and increased overall survival.

CONCLUSIONS:

Our data highlight the immunogenicity of stereotyped VH CDR3 sequences and support the feasibility and efficacy of their use for novel cancer vaccine in CLL. Such approach has the advantage to generate "off-the-shelf" therapeutic vaccines for relevant groups of patients belonging to stereotyped subsets.See related commentary by Seiffert, p. 659.

• Authors: Alessandra Rovida, Cristina Maccalli, Lydia Scarfò, Paolo Dellabona, Kostas Stamatopoulos, Paolo Ghia
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 3 Pg. 729-739 (02 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33051305 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines
• Complementarity Determining Regions
• Epitopes, T-Lymphocyte
• Immunoglobulin Heavy Chains
• Proto-Oncogene Proteins
• Receptors, Antigen, B-Cell
• TCL1A protein, human
• Vaccines, Subunit

Topics

• Aged
• Aged, 80 and over
• Animals
• Antigens, Neoplasm (genetics, immunology, metabolism)
• Cancer Vaccines (genetics, immunology, therapeutic use)
• Complementarity Determining Regions (genetics, immunology, metabolism)
• Disease Models, Animal
• Epitopes, T-Lymphocyte (genetics, immunology, metabolism)
• Female
• Humans
• Immunoglobulin Heavy Chains (genetics, immunology, metabolism)
• Leukemia, Lymphocytic, Chronic, B-Cell (blood, genetics, immunology, therapy)
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Primary Cell Culture
• Proto-Oncogene Proteins (genetics)
• Receptors, Antigen, B-Cell (genetics, immunology, metabolism)
• T-Lymphocytes (immunology, metabolism)
• Vaccines, Subunit (genetics, immunology, therapeutic use)