Targeting the Leukemia Antigen PR1 with Immunotherapy for the treatment of Multiple Myeloma

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. Since multiple myeloma (MM) is derived from B cells, we investigated whether MM is also capable of PR1 cross-presentation and subsequently capable of being targeted using PR1 immunotherapies. Experimental Design: We tested if MM is capable of cross-presenting PR1 and subsequently becomes susceptible to PR1-targeting immunotherapies, using MM cell lines, a xenograft mouse model, and primary MM patient samples. Results: Here we show that MM 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 MM utilizes the conventional antigen processing machinery, including the proteasome and Golgi, and is not affected by immune modulating drugs (IMiDs). Following PR1 cross-presentation, we are able to target MM with PR1-cytotoxic T lymphocytes (CTL) and anti-PR1/HLA-A2 antibody both in vitro and in vivo. Conclusions: Collectively, our data demonstrate that PR1 is a novel tumor associated antigen target in MM and that MM is susceptible to immunotherapies that target cross-presented peptides.

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