15353-j-veluchamy

1 General introduction and Scope of this Thesis | 23 Repeated doses (3x in cohort): 1x10^8 (cohort 1), 3x10^8 (cohort 2), 1x10^9 (cohort 3) and 3x10^9 (cohort 4) cells/m2 Fold expansion: 200 over 15-17 days. Viability: ≥80% Safe and feasible, mild toxicities (1 grade 4, hypoglycaemia). 10/12 PD (died between day 101-1059), 1/12 alive (1450 days) and 1/12 died of bronchopneumonia (day 832) Escalating doses: Low cy/mPred: 1x10^5, 1x10^6, 1x10^7 or 2x10^7 cells/kg (at least 3 per cohort). Flu or High-Cy/Flu: 2x10^7 cells/kg Viability: >70%. Purity: NK-cells 40 +/- 2%. T-cells 1.75 +/- 0.3x10^5 cells/kg is 0.9 +/-0.1%. Monocytes 25 +/- 1.6% and B-cells 19 +/-2% Feasible and tolerated without toxicities. Low-Cy/mPred: 2/17 with MRCC SD for 20 and 21 months. 4/17 with MM SD for 4-9 months. (n=17) High-Cy/Flu: 5/19 AML pts in CR (n=19) 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), Muromonab-CD3 (OKT3). Abbreviations others: Human Stem and Progenitor Cells (HSPC), acute Graft versus Host Disease (aGvHD), Donor NK cell Infusion (DNKI), Stimulated (Stim), Unstimulated (Unstim), DFS : Disease Free Survival , Complete Remission (CR), 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), Not Evaluable (NE). *Culture method displays CD3 depleted PBMC’s, otherwise deviated selection method is mentioned in product characteristics. Infused dose NK-cells Final product characteristics Outcome Phase I Arai et al (2008) ref 49 Metastatic RCC (n=11) or M lignant Melanoma (n=1) NK-92 cell infusion Ex vivo expand d and ctivated allogeneic NK-92 cells. Culture duration :15-17 days with or without IL-2. * o selection Phase I (BB-IND 8847) Miller et al (2005) ref 57 Metastatic Melanoma (n=10), Metastatic RCC (n=13), Refractory HL (n=1) and AML (n=19) Conditioning with Low Cy/ mPred or Flu or high-Cy/Flu followed b NK-cell i fusion; IL-2 therapy (14x, daily) Ex vivo expanded and activated PBNK-cells from haploidentical donors. Culture duration: o/n with IL-2. Abbreviations Malignancies: Central Nervous System (CNS), Myeloprolif rativ Disorders (MPD), Lymphopr liferative Disorder (LPD), Multiple Myeloma (MM), Myelodysplastic Syndromes (MDS), Myelodysplastic Neoplasms (MDN) Myeloproliferative Neopl sms (MPN), Acute Myeloid Leukemia (AML), Lymphoblastic Leukemia-Lymph ma (LBLL), Acute Lymphoblastic Leukemia (ALL), Neuroblastoma (NB), Rhabdomyosarcoma (RMS), Chronic Myelogenous Leukemia (CML), Non- Hodgkin’s Lymp oma (NHL), Mantle Cell Lymphoma (MCL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Anaplastic Large C ll Lymphoma (ALCL), Hodgkin’s Lymphoma (HL), R nal Cell Cancer (RCC), S all Cell Lung C ncer (SCLC), Chronic Lymphocytic Leuk mia (CLL), H patocellular Carcinoma (HCC), Primitive Neuroecto rmal Tumor (PNET), Adrenal Cortical Carcinoma (ACC), Mantle Cell Lymphoma ( CL), Diffuse Large B Cell Lymphoma (DLBCL), Anaplastic Large C ll Lymphoma (ALCL), Ewing sarcoma (EWS), Desmoplastic Small Round ell Tumor (DSRCT). Study Malig ncy Clinical Trial design Culture method*