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3032 Background: MM is increasing in incidence and remains incurable. NK cells have modest killing activity against MM cells in part because of inhibitory signals from HLA class 1 antigens which act via the KIR receptors on NK cells. A novel anti-KIR blocking antibody (1–7F9 named IPH 2101) enhances patient NK cell cytotoxicity against autologous MM tumor cells in vitro and appears safe in an ongoing phase 1 clinical trial. Methods: NK cells from healthy controls or patients were pre-treated with IPH 2101 or IgG4 isotype control and co-cultured with MM cell lines or autologous MM tumor targets. NK cell production of interferon-gamma (IFN-γ) or granzyme B (GrB) were measured by ELISPOT. An open-label, single-agent, phase 1 dose escalation study of IPH 2101 is being conducted in patients with relapsed/refractory MM. KIR binding, pharmacokinetics, pharmacodynamics, effects on NK cell maturation, and biological effects of IPH 2101 are being monitored in all patients. Results: At an effector to target (E:T) ratio of 1:1, IPH 2101 significantly enhances NK cell IFN-γ release against MM targets (mean 33 spots/well ± 12, SEM vs. 11 ± 0.3, p = 0.005). At an E:T ratio of 10:1, IPH 2101 enhances NK cell cytotoxicity, by GrB release, of patient NK cells against autologous MM tumor cells (mean 111 spots/well ± 14, SEM vs 56 ± 10, p = 0.002). By Western blot, IPH 2101 may reduce levels of src, a kinase known to be involved in inhibitory KIR signaling. Dose escalation in the phase 1 study has been completed from 0.0003 mg/kg to 0.075 mg/kg in 14 evaluable patients. At the highest dose tested, KIR occupancy has been detected at a mean 95% ± 1.4 at 2 hours post dose, lasting up to 56% ± 18 during 2 weeks post dose. At this dose level, PK data show good correspondence with previous modeling activity. No deleterious effect on NK cell maturation has been seen. IPH 2101 has been well tolerated to date. Conclusions: IPH 2101 improves autologous NK cell killing of MM tumor cells by blocking inhibitory KIR. In the ongoing clinical trial, the antibody appears safe and well tolerated at the doses tested. This immunotherapeutic approach may hold promise as treatment for MM and further study is warranted. [Table: see text]

3064 Background: The Vγ9Vd2 T (γd) blood lymphocyte subset has a strong cytotoxic potential and can be selectively activated with chemically-synthesized, structural analogues of non-conventional antigens like BrHPP (IPH1101). Their proliferation requires low dose of Interleukin-2 (IL-2). Methods: We developed several in vitro and in vivo models to assess the immunotherapeutic potential of IPH1101-activated γd cells: - Direct cytotoxicity assays on patient-derived primary tumor cell lines - Extensive pharmacodynamics in the non human primate (NHP) - Small scale in vitro amplification assays for IPH1101-sensitive patient pre-selection Then, two Phase I clinical trials were performed in solid tumor patients: - Autologous cell therapy with ex vivo IPH1101- expanded γd cells (1, 4 or 8.109 cells) - Direct administration of IPH1101 (200 to 1800 mg/m2 i.v.) and low dose IL-2 (106 U/m2 s.c.). Results: In NHP, IPH1101 and low dose IL-2 induce early pro-inflammatory cytokine release and dose-dependent γd cell amplification in peripheral blood. In vitro, mRCC tumor cells are efficiently and selectively killed by autologous γd cells. In Phase I clinical trials, both ex vivo expanded γd cells and IPH1101 were well tolerated. - Cell therapy-related AEs included mainly gastrointestinal disorders, flu-like symptoms and hypotension. Six patients showed stabilized disease. Median duration of stabilization was 25.7 weeks. 2 pts treated with 4.109 or 8.109 cells showed substantial tumor shrinkage at the 14-week evaluation (-22% and -48%, respectively). - When IPH1101 was administered with low dose of IL-2, a significant increase of blood γd T cells was observed (up to 240 times the basal values) and in terms of clinical activity assessment, among the evaluable mRCC population (n=15), 8 patients presented disease stabilization for more than 35 weeks, including 6 for more than 51 weeks. Conclusions: For the first time, a specific γd immunotherapy was fully developed and led to Phase I clinical trials. It has been found well tolerated. Encouraging signs of disease stabilisation in mRCC patients suggest that γd may have a role in the treatment of cancers resistant to conventional therapies. A phase 2 is ongoing in mRCC patients. No significant financial relationships to disclose.

4518 Background: Over-expression, non-polarity and under-glycosylation of the mucin glycoprotein molecule, MUC1, are associated with many cancers, making MUC1 an attractive target antigen for vacci...

4653 Background: MUC1 is a glycoprotein located at the apical surface of glandular epithelial cells. In some tumors, MUC1 is often aberrantly over-expressed and hypoglycosylated, unmasking new antigenic epitopes. This makes it a potential target for tumor-specific vaccination. In renal cell carcinoma (RCC), MUC1 expression is associated with a poor prognosis. TG4010 is a cancer vaccine based on a modified vaccinia virus (MVA) expressing both MUC1 and Interleukin 2. The phase II study objective was to determine the overall response rate of TG4010 alone and in combination with cytokines in a two-step design. Methods: Patients (pts) with progressive metastatic RCC, expressing MUC1 in at least 50% of the tumour cells, received subcutaneous injections of TG4010 weekly for 6 weeks then every 3 weeks until progression, then the TG4010 was combined with Interferon alpha-2a (INF) and Interleukin 2 (IL2). Response to treatment was evaluated every 12 weeks according to the RECIST criteria. Median time to progression...

3039 Background: CL has been successfully treated with interferons (IFNs), which can offset the Th2 dominance associated with CL. Intratumoral (IT) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFN-g cDNA insert) allows high local levels of IFN-g without severe toxicity induced by systemic delivery. Methods: We undertook a phase I/II, open-label, trial of repeated, IT injection of TG1042 in patients with advanced primary T cell (CTCL) and multilesional B cell (CBCL) cutaneous lymphomas. The designated lesions were injected on days 1, 8, and 15 with no injection in the fourth week (1 cycle) and thereafter up to 4 cycles. Immunohistochemistry and qPCR were performed on injected lesions biopsied at baseline and after each cycles. In the phase I, 9 patients were enrolled in 3 successive cohorts at the doses of 3x10E9 total particles (tp), 3x10E10 and 3x10E11 tp. In the phase II, 7 out of 27 additional planned patients have been treated at 3x10E11 tp. Results: To date 12 CTCL and 4...