Novel Strategies for Peptide-Based Vaccines in Hematological Malignancies

Abstract

Peptides vaccination is an interesting approach to activate T-cells toward desired antigens in hematological malignancies. In addition to classical tumor associated antigens, such as cancer testis antigens, new potential targets for peptide vaccination comprise neo-antigens including JAK2 and CALR mutations, and antigens from immune regulatory proteins in the tumor microenvironment such as programmed death 1 ligands (PD-L1 and PD-L2). Immunosuppressive defenses of tumors are an important challenge to overcome and the T cell suppressive ligands PD-L1 and PD-L2 are often present in tumor microenvironments. Thus, PD-L1 and PD-L2 are interesting targets for peptide vaccines in diseases where the tumor microenvironment is known to play an essential role such as multiple myeloma and follicular lymphoma. In myelodysplastic syndromes the drug azacitidine re-exposes tumor associated antigens, why vaccination with related peptides would be an interesting addition. In myeloproliferative neoplasms the JAK2 and CALR mutations has proven to be immunogenic neo-antigens and thus possible targets for peptide vaccination. In this mini review we summarize the basis for these novel approaches, which has led to the initiation of clinical trials with various peptide vaccines in myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and follicular lymphoma.

Keywords: PD-1; cancer testis antigen; follicular lymphoma; multiple myeloma; myelodysplastic syndrome; myeloproliferative neoplasms; neo-antigens; peptide vaccination.

Figure 1

Targeting PD-L1 and PD-L2 expressing cells. (A) T cells in the tumor microenvironment often express PD-1 and are vulnerable to stimulation from the ligands PD-L1 or PD-L2 expressed on tumor cells or tumor infiltrating cells such as macrophages or Myeloid-derived suppressor cells (MDSC). (B) Immunogenic peptides derived from the PD-L1 and PD-L2 can be injected in the patients where they are endocytosed and processed by antigen presenting cells (APC). (C) The APCs present the peptides to T cells in the draining lymph node along with co-stimulatory signals, which are necessary for priming and optimal cytotoxicity. (D) Tumor cells, macrophages and MDSCs expressing PD-L1 and PD-L2 also present epitopes derived from these proteins on surface MHC molecules and are vulnerable to primed PD-L1 and PD-L2 specific T cells.

Figure 2

Expression of antigens in myelodysplastic syndrome and myeloproliferative neoplasms. (A) DNA methyltransferase (DNMT) add methyl (M) groups to parts of the genome to prevent transcription. The drug azacitidine binds to cytidine nucleotides where it covalently attaches to DNMT to prevent further methylation. This results in the transcription of otherwise suppressed genes such as cancer testis antigens (CTA) and retroviral DNA. The CTA are processed as proteins and presented by MHC molecules on the cell surface, while the double stranded RNA (dsRNA) trigger intracellular pattern recognition receptors causing inflammation and increased MHC expression. (B) Mutations in the JAK2 gene results in the substitution of valine (V) to phenylalanine (F) in position 617 of the JAK2 protein. This results in the generation of a mutant antigen. Likewise, the CALR exon 9 mutations generate a novel mutant C-terminus in the CALR protein, thus generating several mutant antigens.