15353-j-veluchamy

1 General introduction and Scope of this Thesis | 15 Infused dose NK-cells Final product characteristics Outcome 4 Escalating doses: 5×10^6, 1×10^7, 5×10^7 and 1×10^8 cells/kg Mean purity: 98.9% CD56+/CD3- cells Well tolerated. No GvHD. 4/12 progressed or relapsed. (median of 21 months follow-up) 4 Escalating doses: Median DNKIs are 5×10^7, 5×10^7, 1×10^8and 2×10^8 cells/kg Median viability: 80%. Purity: 48-98% CD56+CD122+ cells. 0-22% CD3+CD56+ cells. 0-10.4% CD3+CD56- cells. Toxicity observed in 73% of patients, 9/45 aGvHD. 29/51 CR (9.3-34.7 months follow-up), 35/51 PD 4 Escalating doses: 1×10^6, 5×10^6, 3×10^7 and 3×10^7 cells/kg in Phase I study. 4 escalating doses of 5x10^6 cells/kg in Phase II study. Median purity: 0.02% CD3+ cells. 11.41% CD14+ cells. 21.84% CD19+ cells. 14.1% CD56+CD3- cells. Well tolerated, no GvHD. 5/21 CR, 5/21 died of transplantation related issues and 11/21 died of relapse Repeated doses (2x dose 1, 2 and 3): 1x10^5 cells/kg (dose 1), 1x10^6 cells/kg (dose 2) and 1x10^7 cells/kg (dose 3) Median purity: CD3+ cells 1.4x10^4 cells/kg. CD56+ cells≥90%. Viability: ≥70%. 5/9 aGvHD. 2/9 SD, 7/9 CR. 4/9 are still alive (12.5-27.4 months after treatment) Single dose: 1.61-32.2x10^6 CD56+/CD3- cells/kg Purity: CD56+CD3- cells 99.97%. CD3+ cells 0.95-7.4x10^4 cells/kg Toxicity correlated with haplo- HSCT. Deaths: 2/24 GvHD, 6/24 infections and 7/24 died of relapse. 9/24 CR (0.1-8.6year follow-up) Escalating doses (2x): 0.2x10^8 cells/kg (3 pts), 0.5x10^8 cells/kg (3 pts), 1.0x10^8 cells/kg (8 pts) and ≥1.0x10^8 cells/kg (27 pts) Viabillity:71-85%. Median purity: CD56+CD122+ cells >90%. CD3+CD56+ cells <3%. Fold expansion: 0.8-70 (after 13-20 days of culture) Well tolerated. 9/41 aGvHD, 10/41 cGVHD. In total 11 patients died of TRM. In AML (21/29) (4/8) ALL/ Lymphoma are in CR 4 Escalating doses: 1×10^5 , 1×10^6 , 1×10^7 and 2×10^7 MC/kg Median purity: 26% CD56+CD3- cells. 0.15% CD3+ cells. Median viability: 95% post wash. Well tolerated. No GvHD. 6/13relapsed and 7/13 in remission. Repeated doses (2-3): 0.3-3.8x10^7 cells/kg Median purity: CD3+ cells 0.03x10^5 cells/kg. Median viability: 84%. Safe and feasible. 4/16 aGvHD. Median follow-up of 5.8 years 4/16 are alive. 3/16 died from graft failure- Repeated doses (1-3 doses): Group I: 3.2- 38.3x10^6 cells/kg Group II: 6.0-45.1x10^6 cells/kg Purity: CD56+CD3- cells 84.4- 98.6%. CD3+ cells group I: 0.4- 53.4x10^3 cells/kg. CD3+ cells group II: 7.7-98.3x10^3 cells/ kg. Viability: freshly NK-cell unstimulated median 93%. Cryo NK-cell IL-2 stim 30-70% Well tolerated without GvHD > grade II. Group I: 5/9 died (126-498 days post SCT), 3/9 CR (742-2218 days). Group II: 5/9 died (27-373), 2/9 CR and 2/9 in remission Table 1: Summary of allogeneic NK cell clinical trials in a transplantation setting Study Malignancy Cli ical Trial design Cultur method* Ph se I (NCT 1729091) Shah et al (2017) ref 64 MM (n=12) Conditioning with Mel on day -7 and Lnd from days -8 to -2 prior to UCB- NK cell infusion (day -5), followed by autologous-HSCT on day 0 Ex vivo expanded MNCs from un lated UCB donors. Culture durati : 14 days with irradiated K562 clone 9.mbIL-21 aAPCs and IL-2 *CD3 depleted (on day 7) Ph se I (NCT01795378) Choi et al (2016) ref 65 AML (n=45) and ALL (n=6) Haplo-HSCT fo lowed by DNKI from the same donor on day 6, 9, 13 and 20 post HS T Ex viv expan ed and activated PBNK-cells from haploidentical donors. Culture duration :2-3 weeks with IL-15 and IL-21 Ph se I (NCT 0402558) Lee et al (2016) Phase II (NCT01390402) ref 66 AML (n=8), MDS (n=6) and CML (n=7) Conditioning with Flu/Bu prior to haplo- allo NK-cell infusion, followed by IL-2 therapy (5x, daily); conditioning with Thy/Tac prior to HLA matched related unrelated allo-HSCT Ex vivo expanded and activated PBNK-cells from ha loiden cal donor . Culture duration: o/n with IL-2. *CD3 depleted and CD56 selected (in 3 infusions) Phase I (NCT01287 04) Shah et al (2015) ref 67 EWS (n=5), DSRCT n=3), RMS (n=1) HLA m tched haplo- or unrelated allo-HSCT followed by aNK-DLI from th same donor on day 7 and 35 post HSCT Ex vi o expanded and activated PBNK-cells from haploidentical donors. Culture duration :9-11 days with KT64.4-BBL artificial antigen presenting cells. *CD3 depleted and CD56 selected Phase I/II (NCT01220544) Killig et al (2014) ref 68 AML (n=24) Haplo-HSCT followed by NK-cell infusion from same donor and OKT3 treatment from days -5 to+3 PBNK- ells from haploidentical donors. *CD3 depleted and CD56 s lected Phase I/II (NCT00823524) Choi et al (2014) ref 69 AML (n=32), ALL (n=7), MDS (n=1), DLBCL (n=1) HLA haplo-HSCT followed by DNKI from the same donor, 14 days and 21 days after HSCT Ex vivo expanded and activated PBNK-cells from h ploidentical donors. Culture duration :13-20 days wit IL-15, IL-21 and hydrocortisone. Ph se I (IND # 12971) Klingemann et al (2013) ref 70 NHL (n= ) MM (n=5) and HL (n=2) MHC-mismatched haploidentical NK-MC infusion, 49-191 days post auto-HSCT Ex vivo expanded and activated PBNK-cells from haploidentical donors. Culture duration: o/n with IL-2 Phase II (NCT01386619) Stern et al (2012) ref 71 AML (n=8), ALL (n=5), HL (n=2) sarcoma(n=1) Haplo-HSCT followed by NK-DLI from the same donor, +day 3, +day 40 and +d y 100 post HSCT PBNK-c lls from haploidentical donors. *CD3 depleted and CD56 selected Phase I/II (NCT01386619) Brehm et al (2011) ref 56 AML (n=6), ALL (n=5), NB (n=5), RMS (n=1) HL (n=1) Haplo-HSCT followed by IL-2 stimulated NK- l infusion (cryo) or unstimulated NK-cell infusion (fresh) from the same donor, +day 3, +day 40 and +d y 100 po t HSCT Ex vivo expanded and activated PBNK-cells from haplo dentical donors. Culture duration : -14 days with (group II or without (group I) IL-2 (fresh or cryo). *CD3 depleted and CD56 selected