DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma.
We previously described PASD1 as a new cancer testis antigen in multiple myeloma (MM) that is retained post-therapy, suggesting the use of vaccination strategies to induce anti-PASD1 immunity in a setting of minimal residual disease. We have focused on DNA fusion gene vaccines, coupling fragment C domain (DOM) of tetanus toxin with PASD1 sequence, and examined efficacy in Human Leukocyte Antigen (HLA)-A2 (HHD) transgenic mice using a human MM cell line expressing PASD1 protein and chimeric HLA-A2 class I molecules as target. DNA vaccines encoded two HLA-A2-restricted epitopes (p.DOM-PASD1(1), p.DOM-PASD1(2)) and full-length PASD1 (p.DOM-PASD1FL). p.DOM-PASD1(1) proved superior to p.DOM-PASD1(2) in generating T-cell responses in HHD mice, able to lyse the chimeric murine RMA-HHD cells. Boosting by electroporation significantly enhanced p.DOM-PASD1(1). Only p.DOM-PASD1(1) induced cytotoxic T-lymphocytes (CTLs) were able to lyse human MM target cells expressing endogenous antigen. The p.DOM-PASD1FL vaccine predominantly induced strong PASD1(1) over PASD1(2) T-cell immune responses, indicative of immunodominance. Importantly, p.DOM-PASD1FL generated immune-mediating killing of native chimeric MM cells, in the absence of exogenous added peptide, implicating PASD1(1) specific CTLs. These data demonstrate that PASD1-derived epitopes are both efficiently and selectively processed and presented by native human MM cells. Notably, they permit the use of PASD1-encoding DNA vaccine therapy in a clinical setting.
Joseph-Pietras
D
D
Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK.
Gao
Y
Y
Zojer
N
N
Ait-Tahar
K
K
Banham
A H
AH
Pulford
K
K
Rice
J
J
Savelyeva
N
N
Sahota
S S
SS
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D034961:Antigens, Nuclear / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D034961:Antigens, Nuclear; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C515845:PASD1 protein, human; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA