Abstract 3499: CD56 targeted chimeric antigen receptors for immunotherapy of multiple myeloma

Abstract We have developed an adoptive T cell therapy strategy for treating multiple myeloma using chimeric antigen receptors targeting CD56. CD56 is strongly expressed by malignant plasma cells in 70% of patients with myeloma and represents a potential immunotherapy target. CD56 is also expressed at lower levels on normal tissue types including neuronal cells, NK cells and a subset of activated T cells. A second generation CAR was constructed containing the scFv of the murine monoclonal antibody against human CD56 (N901) as well as the CD28 transmembrane and cytoplasmic signaling domains. CD56 CAR cells were generated by retroviral transduction of human T cells and showed antigen dependent proliferation and cytokine secretion in vitro when stimulated with CD56 positive myeloma cells. In vitro cytotoxicity assays showed significant lysis (40-50% lysis at effector to target ratios 5: 1) of CD56 positive myeloma cell lines compared with a control prostate specific membrane antigen (PSMA) targeted CAR. To further assess the antitumor activity of CD56 CARs in vivo we developed a systemic xenograft model of myeloma by injecting the OPM2 myeloma cell line, modified to express the firefly luciferase gene, intravenously into NOD/SCID Il2rαnull mice. Bioluminescence imaging showed tumor progression predominantly within the bone marrow recapitulating the human disease phenotype. If untreated hind limb paralysis occurred at approximately 35 days following injection of 3x106 tumor cells. Cohorts of mice were then treated by intravenous injection of either 1 or 5 x106 CD56 CAR cells or control PSMA CAR cells at 7 days following tumor injection, when disease was firmly established. At the 1x106 T cell dose tumor development was significantly delayed compared to controls (median survival of 49 days compared with 34 days respectively, p=0. 02) but 7/8 mice eventually progressed and had to be euthanised. In contrast all mice receiving 5x106 cells (n=8) showed complete tumor regression and remained tumor free at 3 months. Interferon-α secreting CD56 CAR cells were detected in the peripheral blood of these mice and correlated with tumor bulk with numbers eventually declining to low levels that persisted even at 3 months. These results demonstrate for the first time the impressive anti-tumor efficacy of a CD56 targeted chimeric antigen receptor in a systemic xenograft model of myeloma. CD56 CAR therapy therefore represents an attractive immunotherapy option and its use in patients with relapsed refractory myeloma should be considered. Citation Format: Authors. Abstract title abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72 (8 Suppl): Abstract nr 3499. doi: 1538-7445. AM2012-3499