Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity

Abstract

02:01C ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors.

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

“…Differences in phenotypes were most likely due to varying expansion protocols. 14,17,19 T cells of patients #1, #2, and #3 were 29.2%, 99.7%, and 45.1% positive for the CHM1 319 -specific multimer, respectively, and 63.5% positive for the EZH2 666 multimer in patient #1 (Fig. S3).…”

“…23 For efficacious T cell therapy, both, the identification of proteins essential for cancer survival and TCR reactivity have to be addressed. 2,14,17,19,24 Utilization of TCRs from the allogeneic repertoire, exploiting a naturally occurring mechanism of self-defense, may circumvent both the requirement for affinity enhancement and anergy of T cells to tumor self-antigens. 15,25 Attempts to translate recent achievements of cellular therapy with e.g., chimeric antigen receptor T cells into the treatment of solid tumors, in particular pediatric sarcomas, has had limited success so far.…”

“…19 However, high manufacturing complexity, low cell numbers and rapid T cell exhaustion prompted us to generate large-scale ES-specific TCR transgenic T cells with less differentiated phenotypes off-the-shelf. 14,17 To facilitate the generation of highly enriched ES-specific T cells with a central memory-like phenotype, we successfully transduced allogeneic donor cells and autologous cells with CHM1-specific TCRs. We demonstrate here that adoptively transferred haplodisparate HLA-A Ã 02:01/CHM1 319 -specific allorestricted TCR-driven T cells are well tolerated without GvHD even at doses up to 8 £ 10 6 /kg.…”

“…Cell lines, donor PBMC, PCR, expression analyses, ELISpot, identification, and expansion of CHM1 316 -specific TCR CHM1-4B4, and generation of CHM1 319 -TCR-transgenic T cells including their immunophenotyping were all used as described previously (Blaeschke et al, 14 Schirmer et al, 17 Supplemental data sheet 1, Table S3). …”

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).…”