15353-j-veluchamy

1 General introduction and Scope of this Thesis | 17 Repeated dose (1-3): median dose in 3-5/6 HLA match: 9,21x10^6 CD3+/CD56- cells/ kg, median dose 6/6 HLA match: 10.6x10^6 CD3+/CD56- cells/kg 6/6 HLA-matched: Purity: 87-100% CD56+ cells. 0.53 +/- 1.1x10^6 cells/kg CD3+CD56-. 3-5/6 HLA- matched: Purity: 86-100% CD56+ cells. 0.27 +/- 0.78x10^6 cells/kg CD3+CD56- Safe. Low toxicity. 6/6 HLA- matched: 6/14 aGvHD (1 severe) and median OS 12 months. 3-5/6 HLA-matched: 8/16 aGvHD and median OS 27 months Single dose: 0.33-24.5x10^6 cells/kg Mean purity: CD56+CD122+ cells 64%. CD3+ cells 1.0%. Mean viability: 88%. 1/14 aGvHD and 4/14 cGvHD. 9/14 died (between 1.7-15.5 months), 4/14 CR (between 16.2-21.6 months) 1/14 PD (25.9 months) Combined dose (day 0 and day +2): 2.7- 92x10^6 cells/kg Purity: Median CD3+ cells 5.5x10^4 cells/kg. Viability: 95%. Safe and no GvHD. 5/10 CR, 1/10 PR, 1/10 MR, 1/10 SD and 2/10 PD. 4/10 are alive at 1.4, 1.5, 2.3 and 3 years post NK-cell therapy Repeated doses (1-3): 8.9-29.5x10^6 cells/ kg (1st infusion), 3.3 and 11.1x10^6 cells/ kg (2nd infusion), 33.8x10^6 cells/kg (3rd infusion) Purity: CD56+CD3- cells 95%. Median CD3+ cells 0.04%, 45- 1100x10^3 cells. Viability: 95%. Fold expansion: median 5 (after 14 days of culture) Well tolerated, no GvHD. 1/3 CR (152 days), 2/3 died (80 days and 45 days after NK-cell infusion) Single dose: 0.21-1.41x10^7 cells/kg Median purity: CD56+CD3- cells 97.3%. T-cell 0.22x10^5 cells/kg Well tolerated and feasible. 4/5 continuous remission (8-18 months), 1/5 PD Abbreviations drugs: Cyclophosphamide (Cy), Fludarabine (Flu), Bortezomib (Bor), Dexamethasone (Dex), Clofarabine (Clo), Etoposide (Eto), Cisplatin (Cis), Paclitaxel (Pac), Docetaxel (Doc), Vinorelbine (Vin), Gemcitabine (Gem), Carboplatin (Car), Pemetrexed (Pem), Total Body Irradiation (TBI), Tacrolimus (Tac), Prednisolone (Pred), Methylprednisolone (mPred), Thymoglobulin (Thy), Vincristine (Vin), Adriamycin (Adr), Prednisone (Predn), Melphalan (Mel), Lenalidomide (Lnd),Muromonab-CD3 (OKT3). Abbreviations others: Human Stem and Progenitor Cells (HSPC), acute Graft versus Host Disease (aGvHD), chronic Graft versus Host Disease (cGvHD), Donor NK cell Infusion (DNKI), Stimulated (Stim), Unstimulated (Unstim), Complete Remission (CR), DFS : Disease Free Survival , Partial Response (PR), Minimal Response (MR), Stable Disease (SD), Progressive Disease (PD), Donor derived IL-15/4-1BBL activated NK cell infusion (aNK-DLI), Transplant-related Mortality (TRM), Mononuclear Cell (MC), Tumor Lysis Syndrome (TLS), Passenger Lymphocyte Syndrome (PLS). *Culture method displays CD3 depleted PBMC’s, otherwise deviated selection method is mentioned. Infused dose NK-cells Final product characteristics Outcome Phase I (NCT00586690) Rizzieri et al (2010) ref 55 Lymphoma (n=30) 3-6/6 HLA-matched haploidentical NK- cell infusion, 6 to 8 weeks post haplo- HSCT from the same donor PBNK-cells from haploidentical donors. * Only CD56 sel ct d Phase I (NCT00569283) Yoon et al (2010) ref 54 AML (n=12) MDS (n=2) HLA mismatched HSCT followed by allo NK-cell infu ion from the same donor Ex vivo exp ed, differentiated and activa ed CD34+ progenitor-cells (PB-derived) from haploidentical donors. Culture duration: 21 days with FLt3, IL-7 and hydrocortisone followed by 21 days with IL-15, IL-21 and hydrocortisone (BB-IND-11347) Shi et al (2008) ref 53 MM (n=10) Conditioning with Flu/D x/Mel followed by haplo- KIR-ligand mismatched NK-cell infusion on day 0 and day +2; IL-2 therapy daily (11x) starting on day +1 after NK-cell infusion; auto-HSCT on day +14 Ex vivo expanded and activated PBNK-cells from haploi entical donors. Cultur duration: o/n with IL-2 (pts 1-5) and brief incubation with IL-2 and anti-CD3 beads (pts 5-10). Pilot study Koehl et al (2004) ref 52 AML (n=1) ALL (n=2) Haplo-HSCT followed by KIR mismatched NK-cell infusion on day + or +2 post HSCT and additional infusions every 4-6 weeks; IL-2 therapy +2 days post HSCT, every second day for 2-4 weeks Ex vivo expanded and activated PBNK-cells from haploidentical donors. Culture duration :>12 days with IL-2. *CD3 depleted and CD56 selected (in 3 infusions) Pilot tudy Passweg et al (2004) ref 51 AML (n=4), CML (n=1) Haplo-HSCT followed by NK DLI from the same donor 3-12 months post HSCT PBNK-cells from haploid ntical donors. *CD3 depleted and CD56 selected Abbreviations Malignancies: Central Nervous System (CNS), Myeloproliferative Disorders (MPD), Lymphoproliferative Disorder (LPD), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Myelodysplastic Neoplasms (MDN) Myeloproliferative Neoplasms (MPN), Acute Myeloid Leukemia (AML), Lymphoblastic Leukemia-Lymphoma (LBLL), Acute Lymphoblastic Leukemia (ALL), Neuroblastoma (NB), Rhabdomyosarcoma (RMS), Chronic Myelogenous Leukemia (CML), Non- Hodgkin’s Lymphoma (NHL), Mantle Cell Lymphoma (MCL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Anaplastic Large Cell Lymphoma (ALCL), Hodgkin’s Lymphoma (HL), Renal Cell Cancer (RCC), Small Cell Lung Cancer (SCLC), Chronic Lymphocytic Leukemia (CLL), Hepatocellular Carcinoma (HCC), Primitive Neuroectodermal Tumor (PNET), Adrenal Cortical Carcinoma (ACC), Mantle Cell Lymphoma (MCL), Diffuse Large B Cell Lymphoma (DLBCL), Anaplastic Large Cell Lymphoma (ALCL), Ewing sarcoma (EWS), Desmoplastic Small Round Cell Tumor (DSRCT). Study Malignancy Cli ical Trial design Cultur method*