The STEAP1_262–270 peptide encapsulated into PLGA microspheres elicits strong cytotoxic T cell immunity in HLA‐A*0201 transgenic mice—A new approach to immunotherapy against prostate carcinoma

Abstract

BACKGROUND. PLGA microsphere-based vaccination has been proven to be effective in immunotherapy of syngeneic model tumors in mice. The critical step for the translation to humans is the identification of immunogenic tumor antigens and potent vaccine formulations to overcome immune tolerance. METHODS. HLA-AÃ 0201 transgenic mice were immunized with eight different human prostate cancer peptide antigens co-encapsulated with TLR ligands into PLGA microspheres and analyzed for antigen-specific and functional cytotoxic T lymphocyte responses. RESULTS. Only vaccination with STEAP1 262-270 peptide encapsulated in PLGA MS could effectively crossprime CTLs in vivo. These CTLs recognized STEAP1 262-270 /HLA-A Ã 0201 complexes on human dendritic cells and prostate cancer cell lines and specifically lysed target cells in vivo. Vaccination with PLGA microspheres was much more potent than with incomplete Freund's adjuvant. CONCLUSIONS. Our data suggests that there exist great differences in the immunogenicity of human PCa peptide antigens despite comparable MHC class I binding characteristics. Immunogenic STEAP1 262-270 peptide encapsulated into PLGA microspheres however was able to induce vigorous and functional antigen-specific CTLs and therefore is a promising novel approach for immunotherapy against advanced stage prostate cancer.

Harnessing Dendritic Cells for Poly (D,L-lactide-co-glycolide) Microspheres (PLGA MS)—Mediated Anti-tumor Therapy

“…weak self-antigens in tumor tissue. While soluble peptide immunizations elicited only very poor CD8+ T cell responses, microencapsulation of the HLA-A * 0201 restricted immunodominant epitope STEAP 1 (six transmembrane epithelial antigen of the prostate) was shown to induce potent prostate cancer peptide-specific CTL activation and cytotoxic effector function (36, 41).…”

Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation

“…ELISPOT assay ELISPOT was performed as detailed previously. 38 The spots were assessed with an ImmunoScan reader (CTL, Bonn, Germany).…”

Structural basis for targeting human cancer antigen STEAP1 with antibodies

“…More recently, clinical studies employing humanized variants of mAb120.545 that target STEAP1 were conducted, including: 1) a phase I trial using an antibody-drug-conjugate (termed DSTP3086S or Vandortuzumab Vedotin) to target prostate cancer (6)(7)(8), and 2) a combined Phase I / Phase II trial for the PET-imaging of metastatic castration-resistant prostate cancer patients using Zr 89 labelled antibody (termed [ 89 Zr]Zr-DFO-MSTP2109A) (9)(10)(11). Besides antibody-based strategies, several in vitro and in vivo studies revealed that STEAP1-derived peptides are immunogenic and thus suitable for recognition by cytotoxic T lymphocytes (12)(13)(14)(15)(16), indicating that STEAP1 could represent a potential candidate for the development of anticancer vaccines (4,17). STEAP1 belongs to a protein family that comprises three metalloreductases (18,19) (STEAP2-4, also known as STAMP1-3 (20)(21)(22) ), which reduce iron(III) and copper(II) and are also associated with cancer progression (23)(24)(25).…”