AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-ALPHA2, RAPIDLY ENGRAFT AND MATURE IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)
Author(s): ,
Fabio Ciceri
Affiliations:
Unit of Hematology and Bone Marrow Transplantation,IRCSS San Raffaele Scientific Institute,Milan,Italy;San Raffaele Vita-Salute University,Milan,Italy
,
Bernhard Gentner
Affiliations:
Unit of Hematology and Bone Marrow Transplantation,IRCSS San Raffaele Scientific Institute,Milan,Italy;San Raffaele Telethon Institute for Gene Therapy,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Farina Francesca
Affiliations:
Unit of Hematology and Bone Marrow Transplantation,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Stefania Girlanda
Affiliations:
Unit of Hematology and Bone Marrow Transplantation,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Matteo Carrabba
Affiliations:
Unit of Hematology and Bone Marrow Transplantation,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Marica Eoli
Affiliations:
Molecular Neuro-oncology,Istituto Neurologico Carlo Besta,Milan,Italy
,
Valeria Cuccarini
Affiliations:
Neuroradiology,Istituto Neurologico Carlo Besta,Milan,Italy
,
Bianca Pollo
Affiliations:
Pathology,Istituto Neurologico Carlo Besta,Milan,Italy
,
Alessia Capotondo
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Mariagrazia Gattamone
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,IRCSS San Raffaele Scientific Institute,Milan,Italy
,
Stefania Mazzoleni
Affiliations:
Genenta Science,Milan,Italy
,
Andrew Zambanini
Affiliations:
Genenta Science,Milan,Italy
,
Carlo Russo
Affiliations:
Genenta Science,Milan,Italy
,
Gaetano Finocchiaro
Affiliations:
Molecular Neuro-oncology,Istituto Neurologico Carlo Besta,Milan,Italy
Luigi Naldini
Affiliations:
San Raffaele Vita-Salute University,Milan,Italy
(Abstract release date: 05/14/20) EHA Library. Ciceri F. 06/12/20; 295103; S283
Fabio Ciceri
Fabio Ciceri
Contributions
Abstract

Abstract: S283

Type: Oral Presentation

Session title: Immunotherapy - Clinical

Background
Glioblastoma (GBM) is associated with very poor prognosis particularly in patients with an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter. This may be related to a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of TAMs expressing the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & infrequently found in normal organs. Tie2 is upregulated upon tumor homing. Gene therapy technology allows TEMs to be used as carriers for local & tumor restricted release of interferon-α2 (IFN). IFN has anti-tumor effects, inhibits angiogenesis & modulates the immune system.  Temferon consists of autologous human hematopoietic stem & progenitor cells (HSPCs) transduced ex vivo with a 3rd generation lentiviral vector encoding an IFN gene controlled by a human Tie2/TEK enhancer/promoter sequence & a post-transcriptional regulation layer of miRNA-126  restricting IFN transgene expression to TEMs. Temferon modifies the TME & induces de novo CD8+ T cells.

Aims
To assess tolerability & safety of Temferon over the first 90 days following administration. Long term safety, clinical response, immunological responses & IFN gene signatures  will be evaluated.

Methods
An open-label, Phase I/IIa study (Part A: Phase I, 3x3x3 dose escalation; Part B: Phase II, n=12) using a single intravenous administration of Temferon given to 21 patients with GBM & unmethylated MGMT promoter (NCT03866109). Autologous HSPCs are collected by single apheresis after G-CSF/Plerixafor stimulation & used to manufacture Temferon. Conditioning occurs with carmustine 400mg/m2 at D-6 & thiotepa 5mg/kg is given twice on D-5. At Day 0 prior to Temferon, 3x106 CD34+/kg non-manipulated HSPCs are infused as support. After hematological recovery (HR), follow up occurs over 2 years.

Results
As this is an open label, ongoing study yet to recruit the 3rd cohort in Part A, preliminary data are shown.  To date, 6 patients have been successfully screened & recruited (4 women, 2 men, mean age 57.3 years).  Temferon production was successful, with a median vector copy number (VCN) of 0.6 & transduction efficiency 54% (most HSPCs carry a single integrant). 3 patients (Cohort 1) received Temferon 0.5x106 cells/kg & 2 patients from cohort 2 had an intermediate dose of 1x106 cells/kg. 1 patient will receive an intermediate dose shortly. Neutropenia & thrombocytopenia occurred as expected following conditioning in a consistent manner across all the patients with a nadir occurring by approximately D+8 & HR by D+13. Transduced PBMCs were identified by VCN on myeloid cells at HR & at later timepoints. 2 patients in Cohort 1 achieved a VCN in CD14+ monocytes at D+30 of 0.155 and 0.116, respectively. The measured VCN is aligned with the expected chimerism of approx 9%. The 3rd patient had a low level of engraftment with a VCN of 0.011 in BM CD33+ (D+30). A dose ordered increase in CD14VCN was achieved in the 1st patient of cohort 2 at D+30 (0.185). In the 2 patients with high VCN at D+30 in Cohort 1, a reduction in VCN in CD14+ cells was observed between D+30 & +60, but the VCN remained stable thereafter (Pt#1: D+120, 0.055; Pt#3, D+90, 0.066). Analyses of IFN expression & gene signatures in blood & tissues are ongoing.

Conclusion

These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the BM of GBM patients, which stabilizes after D+60 & remains detectable until the latest follow up. Updated results will be presented.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Immunotherapy, Interferon alpha, Solid tumor, Stem cell transplant

Abstract: S283

Type: Oral Presentation

Session title: Immunotherapy - Clinical

Background
Glioblastoma (GBM) is associated with very poor prognosis particularly in patients with an unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter. This may be related to a highly immunosuppressive tumor microenvironment (TME). The TME in GBM is mainly composed of tumor associated macrophages (TAMs) & microglia. A subset of TAMs expressing the angiopoietin receptor Tie2 (TEMs) have features of M2-TAMs, promote tumor angiogenesis & infrequently found in normal organs. Tie2 is upregulated upon tumor homing. Gene therapy technology allows TEMs to be used as carriers for local & tumor restricted release of interferon-α2 (IFN). IFN has anti-tumor effects, inhibits angiogenesis & modulates the immune system.  Temferon consists of autologous human hematopoietic stem & progenitor cells (HSPCs) transduced ex vivo with a 3rd generation lentiviral vector encoding an IFN gene controlled by a human Tie2/TEK enhancer/promoter sequence & a post-transcriptional regulation layer of miRNA-126  restricting IFN transgene expression to TEMs. Temferon modifies the TME & induces de novo CD8+ T cells.

Aims
To assess tolerability & safety of Temferon over the first 90 days following administration. Long term safety, clinical response, immunological responses & IFN gene signatures  will be evaluated.

Methods
An open-label, Phase I/IIa study (Part A: Phase I, 3x3x3 dose escalation; Part B: Phase II, n=12) using a single intravenous administration of Temferon given to 21 patients with GBM & unmethylated MGMT promoter (NCT03866109). Autologous HSPCs are collected by single apheresis after G-CSF/Plerixafor stimulation & used to manufacture Temferon. Conditioning occurs with carmustine 400mg/m2 at D-6 & thiotepa 5mg/kg is given twice on D-5. At Day 0 prior to Temferon, 3x106 CD34+/kg non-manipulated HSPCs are infused as support. After hematological recovery (HR), follow up occurs over 2 years.

Results
As this is an open label, ongoing study yet to recruit the 3rd cohort in Part A, preliminary data are shown.  To date, 6 patients have been successfully screened & recruited (4 women, 2 men, mean age 57.3 years).  Temferon production was successful, with a median vector copy number (VCN) of 0.6 & transduction efficiency 54% (most HSPCs carry a single integrant). 3 patients (Cohort 1) received Temferon 0.5x106 cells/kg & 2 patients from cohort 2 had an intermediate dose of 1x106 cells/kg. 1 patient will receive an intermediate dose shortly. Neutropenia & thrombocytopenia occurred as expected following conditioning in a consistent manner across all the patients with a nadir occurring by approximately D+8 & HR by D+13. Transduced PBMCs were identified by VCN on myeloid cells at HR & at later timepoints. 2 patients in Cohort 1 achieved a VCN in CD14+ monocytes at D+30 of 0.155 and 0.116, respectively. The measured VCN is aligned with the expected chimerism of approx 9%. The 3rd patient had a low level of engraftment with a VCN of 0.011 in BM CD33+ (D+30). A dose ordered increase in CD14VCN was achieved in the 1st patient of cohort 2 at D+30 (0.185). In the 2 patients with high VCN at D+30 in Cohort 1, a reduction in VCN in CD14+ cells was observed between D+30 & +60, but the VCN remained stable thereafter (Pt#1: D+120, 0.055; Pt#3, D+90, 0.066). Analyses of IFN expression & gene signatures in blood & tissues are ongoing.

Conclusion

These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the BM of GBM patients, which stabilizes after D+60 & remains detectable until the latest follow up. Updated results will be presented.

Session topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): Immunotherapy, Interferon alpha, Solid tumor, Stem cell transplant

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