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Targeting the Leukemia Antigen PR1 with Immunotherapy for the Treatment of Multiple Myeloma.

Alatrash, Gheath; Perakis, Alexander A; Kerros, Celine; Peters, Haley L; Sukhumalchandra, Pariya; Zhang, Mao; Jakher, Haroon; Zope, Madhushree; Patenia, Rebecca; Sergeeva, Anna; Yi, Shuhua; Young, Ken H; Philips, Anne V; Cernosek, Amanda M; Garber, Haven R; Qiao, Na; Weng, Jinsheng; St John, Lisa S; Lu, Sijie; Clise-Dwyer, Karen; Mittendorf, Elizabeth A; Ma, Qing; Molldrem, Jeffrey J.
Clin Cancer Res; 24(14): 3386-3396, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29661776

PURPOSE:

PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen-presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. As multiple myeloma is derived from B cells, we investigated whether multiple myeloma is also capable of PR1 cross-presentation and subsequently capable of being targeted by using PR1 immunotherapies.

EXPERIMENTAL DESIGN:

We tested whether multiple myeloma is capable of cross-presenting PR1 and subsequently becomes susceptible to PR1-targeting immunotherapies, using multiple myeloma cell lines, a xenograft mouse model, and primary multiple myeloma patient samples.

RESULTS:

Here we show that multiple myeloma cells lack endogenous NE and P3, are able to take up exogenous NE and P3, and cross-present PR1 on HLA-A2. Cross-presentation by multiple myeloma utilizes the conventional antigen processing machinery, including the proteasome and Golgi, and is not affected by immunomodulating drugs (IMiD). Following PR1 cross-presentation, we are able to target multiple myeloma with PR1-CTL and anti-PR1/HLA-A2 antibody both in vitro and in vivoConclusions: Collectively, our data demonstrate that PR1 is a novel tumor-associated antigen target in multiple myeloma and that multiple myeloma is susceptible to immunotherapies that target cross-presented antigens. Clin Cancer Res; 24(14); 3386-96. ©2018 AACR.
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