15353-j-veluchamy

1 General introduction and Scope of this Thesis | 21 Single dose: 2x10^7-1x10^8 cells/ kg Median purity: 78% CD3-CD56+ cells. CD3+/CD56- 0.1%. Viability cryopreserved: 94%. Viability fresh:93%. Recovery cryopreserved: 16%. Recovery fresh: 119% Feasible and safe. 1/8 PR, 6/8 PD, 1/8 NE and 3/8 died between day 11-98 after NK- cell infusion Single dose: 0.96 +/- 0.3x10^7 cells/kg (cohort 1) 0.34 +/- 0.05x10^7 cells/kg (cohort 2) 2.6 +/- 1.5x10^7 cells/kg (cohort 3) Purity: NK cells 39 +/- 9%, T cells: 0.7% (cohort 1) NK-cells 75 +/- 6%, T-cells: 1.3% (cohort 2) NK-cells 54 +/- 16%, T cells: 0.3% (cohort 3) Well tolerated, no GvHD and mild toxicities. 9/42 in remission (1.8-15 months) (cohort 1 and 2, n=42). 8/15 in remission (1-32 months) (cohort 3, n=15). DFS: 5% (cohort 1 and 2) and 33% in cohort 3 Repeated doses (2x 48h apart): 1x10^9 (cohort 1), 3x10^9 (cohort 2) and 1x10^6 (cohort 3) cells/m2 and additional dose level of 10^10 cells/m2 in some patients Viability: >80%. Fold expansion: 32 Infusion of 10^10 NK-92 cells/m2 were well tolerated. 12/15 PD, 2/15 MR, 1/15 SD for 2 years, OS: 13-801 days Single dose: 1.11- 5x10^6 CD3- CD56+ cells/kg Mean viability: 95%. Median purity: 93.5% NK-cells. Maximum T-cell dose 10^5 cells/kg Feasible and safe, no GvHD. 5/13 active disease: 1/5 CR (6 months), 4/5 died of PD. 3/6 treated in CR are DFS (34, 32, and 18 months), 2/13 in MR in CR (4 and 9 months) Single dose: 8,33x10^6-3,94x10^7 cells/kg Viability: >70%. Median T cells: 0.11% CD3+ cells. TLS and PLS and limited infusion or IL-2 related toxicities. 1/20 died due to grade 5 toxicity. 4/20 PR, 12/20 SD and 3/20 PD (between 31–109 days) Single dose: 21+/- 19 x 10^6 NK cells/kg Purity: 43 +/- 11% NK-cells. 0.16 +/- 0.12% T-cells Feasible and safe. 2/6 CR, 2/6 relapsed at 6 months, 2/6 died Single dose: 5-81x10^6 cells/kg Median purity: B-cells 0.097x10^6 cells/kg. T-cells 1x10^3 cells/kg Feasible and safe. 10/10 in remission (569- 1162 days) Repeated doses (2-4): 0.2-29x10^6 cells/kg per dose Median purity: (T-cells) CD3+CD56+CD28- 0.12x10^6 cells/ kg. CD56+CD3- cells 97.9% (after20 days culture). Fold expansion: 23 Safe, no GvHD. 2/16 PR, 6/16 SD, 7/16 PD, 1/16 not treated. 1-year OS 56% (9/16), 2-year OS 19% (4/16) Infused dose NK-cells Final product characteristics Outcome Phase I (BB-IND- 4560) Szmania et al (2015) ref 79 MM (n=8) Conditioning with Bor (+/- Cy/ Flu/Dex) followed by fresh haplo-(n=6) or cryopreserved auto (n=2) NK cells. Ex vivo expanded and activated PBNK cells from haploidentical (fresh) and autologous (cryopreserved) donors. Culture: 8-9 days with K562-mb15-41BBL stimulator cells and IL-2 Phase II (NCT00274846) Bachanova et al (2014) ref 80 AML (n=57) Conditioning with Cy/F u; IL2DT in cohort 3 followed by haploidentical NK-cell infusion 1 day later; IL-2 therapy (14x, daily) Ex vivo expanded and a vated PBNK-cells fr m aploiden cal donors. Culture duration: o/n with IL-2. *CD3 depleted (cohort 1) or CD3 depleted/CD56 selected (cohort 2) or CD3/CD19 depleted (cohort 3) Tonn et al (2013) ref 50 Solid tumors/ sarcoma (n=12) Leukemia/ lymphoma (n=2) Pr -treatment with mPred following NK-92 cell infusion Ex vivo expanded and activated allogeneic NK-92 cells. Culture duration :100-300h with IL-2. *no selection Pilot tudy (NCT00799799) Curti et al (2011) ref 63 AML (n=13) Conditio ing with Cy/ Flu followed by KIR l gand mismatched NK-cell infusion; IL-2 therapy (3x weekly f r 2 weeks) PBNK-cells from haploid ntical donors. *CD3 depleted and CD56 sel cted Phase II (BB-IND 8847) Geller et al (2011) ref 40 Refractory Metastatic Breast Cancer (n=14) Ovarian Cancer (n=6) Conditioning with Cy/Flu with or without TBI followed by allogeneic NK-cell infusion; IL-2 therapy (3x weekly for 2 weeks) Ex vivo expanded and activated PBNK-cells from haploidentical donors. Culture duration: o/n with IL-2 Pilot tudy Bachanova et al (2010) ref 62 B-cell NHL (n=6) Conditioning with Cy/Flu and mAb (Rituximab, 4x) before and after haplo NK-cell infusion followed by IL-2 therapy (6x, every other day) Ex vivo expanded nd activated PBNK-cells from haploidentical donors. Culture duration :8-16h with IL-2 Pilot tudy NKAML Rubnitz et al (2010) ref 61 AML (n=10) Conditioning with Cy/Flu followed by KIR mismatched NK-cell infusion; IL-2 therapy (6x) starting 1 day before and after NK-cell infusion PBNK-cells fro haploidentical donors. *CD3 depleted and CD56 selected Phase I (EudraCT number: 2005-005125-58) I liopoulou et al (2010) ref 60 Non-SCLC (n=16) Haploidentical NK cell infusion after chemotherapy Ex vivo expanded and activated PBNK-cells from haploidentical donors. Culture duration :21-23 days with IL-15 followed by 1h with IL-15 and hydrocortisone. *Only CD56 selected Study Malig ncy Clinical Trial design Culture method*