A phase I-IIa study of genetically modified Tie-2 expressing monocytes in patients with glioblastoma multiforme (TEM-GBM Study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2532-2532
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Francesca Farina ◽  
Alessia Capotondo ◽  
Marica Eoli ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phase I ◽  
Transgene Expression ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Conditioning Regimen ◽  
Poor Performance Status ◽  
Tumor Type

2532 Background: Genetically modified cell-based therapies are relevant in immuno-oncology due to their potential for tumor specificity & potential durability. We developed a cell-based treatment, Temferon, relying on ex-vivo transduction of autologous HSPCs to express therapeutic payloads within the tumor microenvironment. Temferon targets IFNa to Tie-2 expressing macrophages (TEMs). Methods: TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety & efficacy of Temferon in up to 21 newly diagnosed patients with glioblastoma & unmethylated MGMT promoter. Autologous HSPCs are transduced ex-vivo with a lentiviral vector encoding for IFNa. The transgene expression is confined to TEMs due to the Tie2 promoter & the post-transcriptional regulation by miRNA-126. Results: As of January 17 2021, 15 patients have been enrolled; 9 received Temferon (D+0) with follow-up of 61 – 559 days. There was rapid engraftment & hematological recovery after the conditioning regimen. Median neutrophil & platelet engraftment occurred at D+13 & D+12, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood & bone marrow cells, were found within 14 days post treatment & persisted subsequently, albeit at lower levels (up to 18 months). We also detected very low concentrations of IFNa in the plasma (median 5pg/ml at D+30; baseline < LLOQ) & in the cerebrospinal fluid, suggesting tight regulation of transgene expression. Three deaths occurred: two at D+343 & +402 after Temferon administration due to disease progression, & one at D+60 due to complications following the conditioning regimen. Seven patients had progressive disease (PD; range D+27-239) as expected for this tumor type. SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation & poor performance status compatible with autologous stem cell transplantation, concomitant medications & PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present & increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient a stable lesion (as defined by MRI) had a higher proportion of T cells & TEMs within the myeloid infiltrate & an increased IFN-response signature than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Tumor microenvironment characterization by scRNA & TCR sequencing is ongoing. Conclusions: Our interim results show that Temferon is well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon potential to modulate the TME of GBM patients, as predicted by preclinical studies. Clinical trial information: NCT03866109.

scholarly journals TEM-GBM: An Open-Label, Phase I/IIa Dose-Escalation Study Evaluating the Safety and Efficacy of Genetically Modified Tie-2 Expressing Monocytes to Deliver IFN-α within Glioblastoma Tumor Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2844-2844
Author(s):  
Bernhard Gentner ◽  
Gaetano Finocchiaro ◽  
Francesca Farina ◽  
Marica Eoli ◽  
Capotondo Alessia ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phase I ◽  
Transgene Expression ◽  
Ex Vivo ◽  
Conditioning Regimen ◽  
Open Label ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Open Label Phase ◽  
D 12

Abstract Background: We developed a macrophage-based treatment relying on ex vivo transduction of autologous hematopoietic stem and progenitor cells (HSPC) to express immune-payloads within the TME. Our ATMP (Temferon) targets IFN-a, an immune-modulatory molecule counteracting also neo-angiogenesis and tumor growth, to a subset of Tie2-expressing, tumor-infiltrating macrophages known as TEMs. Materials and Methods: TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed glioblastoma patients with unmethylated MGMT promoter. Key eligibility criteria include age 18-70 years, ECOG 0-1 and KPS &gt;70%, and adequate cardiac, renal, hepatic and pulmonary function. Important exclusion criteria include the presence of active autoimmune disease or receipt of any oral or parenteral chemotherapy or immunotherapy within 2 years of screening. Autologous CD34+ HSPC are mobilized with lenograstim and plerixafor, collected by apheresis, purified and transduced ex vivo with a 3 rd generation lentiviral vector encoding for IFN-a2. Transgene expression is confined to TEMs by the Tie2 promoter and post-transcriptional regulation by microRNA-126 thus achieving tumor specificity. The study evaluates safety and biological activity of Temferon in 7 cohorts of three patients each, where escalating doses of Temferon are co-administered with a fixed CD34+ cell dose of non-manipulated supporter cells following a sub-myeloablative conditioning regimen (Thiotepa + BCNU or + Busulfan). The primary endpoints for this study are: Engraftment of Temferon over the first 90 DaysThe proportion of patients achieving hematologic recovery by Day +30 from ASCTShort-term tolerability of Temferon; stable blood counts and absence of cytopenias, absence of significant organ toxicities (&gt; grade 2); absence of Replication Competent Lentivirus The figure below reports the TEM-GBM study design. Results: As of 28th June 2021, 18 patients have been enrolled; 15 received Temferon (D+0) with follow-up of 30 - 697 days. There was rapid engraftment and hematological recovery after the conditioning regimen. Median neutrophil and platelet engraftment occurred at D+13 and D+12 for patients in cohort 1-3 and D+16 and D+15 for patients assigned to cohort 4 and 5, respectively. Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, were found within 14 days post treatment and persisted subsequently, albeit at lower levels (up to 18 months). Very low concentrations of IFNa were detected in the plasma (average 7.8 pg/ml at D+30; baseline &lt; LLOQ) and in the cerebrospinal fluid (average 1.6 pg/ml at D+30; baseline &lt; LLOQ), suggesting tight regulation of transgene expression. Seven deaths occurred: six at D+241, +322, +340, +402, +478, +646 after Temferon administration due to disease progression, and one at D+60 due to complications following the conditioning regimen. Nine patients had progressive disease (PD; range D-12 to +239). SAEs include infections, venous thromboembolism, brain abscess, hemiparesis, GGT elevation and poor performance status compatible with autologous stem cell transplantation, concomitant medications and PD. Four patients underwent second surgery. These recurrent tumors had gene-marked cells present and increased expression of IFN-responsive gene signatures compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion (as defined by MRI) had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. The T-cell immune repertoire changed with evidence for expansion of tumor-associated clones. Tumor microenvironment characterization by scRNA and TCR sequencing is ongoing. Conclusion: These interim results show that Temferon is generally well tolerated by patients, with no dose limiting toxicities identified to date. The results provide initial evidence of Temferon's potential to activate the immune system and reprogram the tumor microenvironment (TME), as predicted by preclinical studies. Figure 1 Figure 1. Disclosures Naldini: Genenta Science: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder.

CTIM-19. TEM-GBM: A PHASE I-IIA DOSE-ESCALATION STUDY DELIVERING IFN-Α WITHIN GLIOBLASTOMA MULTIFORME TUMOR MICROENVIRONMENT BY GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi54-vi54
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Eoli Marica ◽  
Farina Francesca ◽  
Alessia Capotondo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Phase I ◽  
Dose Escalation ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Dose Escalation Study ◽  
Immune System Activation ◽  
Tract Infections

Abstract Temferon is an ex vivo gene therapy consisting of autologous HSPCs genetically modified to deliver IFN-α2 within the tumor microenvironment (TME) by Tie-2 expressing macrophages. TEM-GBM is an open-label, Phase I/IIa dose-escalation study evaluating safety and efficacy of Temferon in up to 21 newly diagnosed GBM patients with unmethylated MGMT. Autologous HSPCs are transduced with a LVV encoding for IFN-a2 gene. As of 30th April 2021, 18 patients have been enrolled; 13 received Temferon (D+0) with follow-up of 8 – 662 days. After conditioning and Temferon infusion, a rapid engraftment and hematological recovery occurred, with median neutrophil and platelet engraftment at D+13 and D+12, respectively. No dose limiting toxicities were reported. Temferon-derived cells were found within 14 days post treatment and persisted albeit at lower levels in the long-term. Five deaths occurred: one at +478, three at +322, +340 and +402 days due to PD, and the fourth at +60 due to complications following the conditioning regimen. Eight patients had PD (-12 to +239). SAEs include respiratory tract infections, pulmonary embolism, CMV and C.Diff infections, febrile neutropenia, hemiparesis, seizure, brain abscess, worsening of performance status and respiratory failure compatible with ASCT, concomitant medications and PD. Four patients underwent second surgery. Recurrent tumors had gene-marked cells present and increased expression of ISGs compared to diagnosis, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased IFN-response signature than in a progressing lesion. Characterization of T-cell immune repertoire suggests the expansion of tumor-associated clones. TME characterization by scRNA and TCR sequencing is ongoing. Interim results show that Temferon is well tolerated, with no dose limiting toxicities identified to date and provide initial evidence of potential immune system activation within the TME.

Efficient Viral Transduction of Murine Hematopoietic Stem Cells Using HIV-1 Gag-Pol Cross Packaged Simian Immunodeficiency Viral Backbone.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5484-5484
Author(s):  
Yuan Lin ◽  
Stanton L. Gerson
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Transgene Expression ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Bioluminescent Imaging ◽  
Hematopoietic Stem ◽  
Murine Bone Marrow ◽  
Hiv 1 ◽  
Marrow Cells

Abstract Lentiviral vectors have been shown to infect non-dividing cells, including hematopoietic stem cell [HSC], and HIV lentiviral vector has been studied extensively in preclinical models. However low HIV lentiviral vector transduction efficiency compared to retroviral vectors, is seen in murine HSC, hampering transplantation and long-term expression of transgene in the recipients. Furthermore, concerns remain regarding the safety of HIV based vectors. Simian Immunodeficiency Viral [SIV] vectors could be safer since the parent virus does not cause disease in humans. However, to model this approach has been difficult because native SIV vectors do not transduce murine cells. We have generated a bicistronic SIV lentiviral SIN vector, containing MGMT and firefly luciferase genes linked by a self-cleavage FMDV 2A sequence. The SIV backbone was kindly provided by Dr. Donald Kohn (University of Southern California). The transgenes are controlled by the MND promoter, which has been shown to express well in murine hematopoietic stem cells. The vector was generated by cross-packaging SIV RNA with HIV-1 ΔR8.91 packaging plasmid and VSVG pseudotyped envelope (Ref. Retrovirology2005, 2:55). Unconcentrated viruses had an average titer of 1E+06 iu/ml, which was similar to HIV-1 lentiviral vectors. In vitro, HIV-1 cross-packaged SIV-mnd-MGMT-2A-Luc vector was able to transduce both human and murine cell lines with no reduction of expression for 10 weeks. In addition, this cross-packaged SIV vector was also able to transduce primary murine bone marrow cells from Balb/C mice with low MOI of 0.5 to 1. Transduced primary murine bone marrow cells maintained transgene expression during a 4 week culture. To analyze in vivo expression, Balb/C bone marrow cells were transduced for 48 hrs in cytokines with the HIV-1 packaged SIV vector and transplanted into irradiated recipients. We used bioluminescent imaging (BLI) to monitor the transgene expression and the dynamic engraftment of transduced murine bone marrow cells. At MOI of 0.5 or 5, transduction efficiencies in murine progenitor cells were 24.4% and 46.7% respectively by PCR of transgene from CFU colonies. Bioluminescent imaging indicated similar engraftment patterns of transduced bone marrow cells by HIV-1 lentiviral vector or cross-packaged SIV lentiviral vector, as early as day 5. Consistent BLI signals indicated sustained expression of transgene in SIV vector transduced bone marrow cells beyond 30 days. With this study, cross-packaged SIV SIN vector could be used as a potential gene transfer vector in both preclinical murine studies and perhaps in clinical trials.

Murine Hemophilia A With Or Without Pre-Existing Anti-Factor VIII Inhibitors Is Partially Corrected By Factor VIII Stored In Platelets After Intraosseous Infusion Of Lentiviral Vectors Into Bone Marrow Without Preconditioning

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 719-719
Author(s):  
Xuefeng Wang ◽  
Simon C. Shin ◽  
Chiang Andy ◽  
Dao Pan ◽  
David Rawlings ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgene Expression ◽  
Hemophilia A ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Lentiviral Vectors ◽  
Antigen Level ◽  
Gfp Expression ◽  
Marrow Cells

Abstract Introduction Platelets may comprise an ideal vehicle for delivering FVIII in hemophilia A (HemA) as FVIII stored in platelet α-granules is protected from neutralization by inhibitory antibodies and, during bleeding, activated platelets locally excrete their contents to promote clot formation. In order to avoid specific challenges posed by ex vivo gene delivery including, in particular, the requirement to pre-condition the subject, we evaluated intraosseous (IO) infusion of self-inactivating lentiviral vectors (LV) for in situ gene transfer into bone marrow cells. In previous studies, we confirmed that hematopoietic stem cells (HSCs) can be efficiently transduced to express GFP after IO administration of LV driven by a MND promoter (M-GFP-LV). Methods In the current study, we aimed at limiting transgene expression to the megakaryocyte lineages using IO delivery of 20 µL LV containing either GFP (G-GFP-LV) or a B-domain variant human FVIII (G-F8-LV) gene under the control of megakaryocyte strictly specific promoter glycoprotein 1bα (Gp1bα). Results In M-GFP-LV treated control mice, GFP was detected in 6.4% of HSCs, 3.4% of B220+, and 9.0% of CD11c+ bone marrow cells on day 29. In contrast, in G-GFP-LV (6.0E+08 TU/mL) treated mice, GFP was undetectable in bone marrow HSCs, B220+, CD11c+ or CD11b+ cells. GFP expression level in platelets of G-GFP-LV treated mice was ten folds of that in M-GFP-LV treated mice (0.1% vs 0.01%). It indicated that in platelets, the activity of Gp1bα was stronger than that of MND. More importantly, GFP expression levels were stable over 100 days, suggesting that platelets containing the transgene products did not elicit transgene-specific immune responses. Next, we treated HemA mice with G-F8-LV (6.0 E+07 TU/mL). There was no detectable hFVIII expression in bone marrow HSCs on day 8 or in blood cells (CD3ε+, B220+, CD11c+ or CD11b+) on day 35. However, up to 3% platelets express hFVIII on day 91. These results suggested that HSCs in HemA mice were successfully transduced by G-F8-LV after IO infusion, and in the long term, FVIII was synthesized in megakaryocytes and stored in platelet α-granules. In treated mice, the average percentage of platelets expressing hFVIII was stable at 1-2% from day 27 to day 160. The average FVIII antigen level in platelets on day 112 was 1 mU per 1 × 108 platelets, which was comparable with platelet FVIII in transgenic and ex vivo gene therapy treated mice. We also evaluated LV-treated HemA animals for phenotypic correction of bleeding diathesis by tail clip assay. The blood loss was 41% (n=7), 48% (n=5) and 33% (n=5) compared with control HemA (normalized to 100%), mock treated HemA (∼100%), and wild-type (2.5%) mice on days 35, 118 and 160, respectively. Additionally, there was neither detectable FVIII activity nor anti-FVIII antibodies in blood on day 160, which indicated that there was insignificant leaky expression of FVIII in other cells. Finally, we also infused G-F8-LV into HemA inhibitor mice. Inhibitors were induced by repeated injection of 3U recombinant hFVIII. The average antibody level was 80 Bethesda Unit before IO infusion of the vectors. In G-F8-LV treated mice, the average hFVIII antigen level on day 27 was 0.74 mU per 1 x 108 platelets (n=5). Bleeding assay was performed on day 160. The blood loss of treated mice was significantly reduced compared with untreated HemA mice, indicating that IO infusion of G-F8-LV can overcome anti-FVIII antibodies and correct hemophilia phenotype. Conclusion We have successfully transduced HSCs in situ by a single infusion of LVs into bone marrow to correct hemophilia A. Gp1bα promoter in lentiviral vectors can specifically direct the transgene expression in mouse platelets. Following IO infusion of G-F8-LV, FVIII stored in platelets can persistently and partially correct the HemA phenotype for at least five months (experimental duration) in mice with and without pre-existing inhibitors. Overall, direct transduction of bone marrow cells targeting platelet-specific FVIII expression may provide an effective therapy to treat severe hemophilia A patients with high-titer inhibitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome

Science ◽  
2013 ◽  
Vol 341 (6148) ◽  
pp. 1233151 ◽  
Author(s):  
Alessandro Aiuti ◽  
Luca Biasco ◽  
Samantha Scaramuzza ◽  
Francesca Ferrua ◽  
Maria Pia Cicalese ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Conditioning Regimen ◽  
Immune Functions ◽  
Gene Encoding ◽  
Hematopoietic Stem ◽  
Wiskott Aldrich Syndrome ◽  
Vector Integration ◽  
Lentiviral Gene Therapy

Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS79-TPS79 ◽  
Author(s):  
Jennifer M Specht ◽  
Sylvia Lee ◽  
Cameron Turtle ◽  
Carolina Berger ◽  
Josh Veatch ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Lentiviral Vector ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Orphan Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.

scholarly journals CTIM-24. AUTOLOGOUS CD34+ ENRICHED HEMATOPOIETIC PROGENITOR CELLS GENETICALLY MODIFIED FOR HUMAN INTERFERON-α2, ARE WELL TOLERATED & RAPIDLY ENGRAFT IN PATIENTS WITH GLIOBLASTOMA MULTIFORME (TEM-GBM_001 STUDY)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Gaetano Finocchiaro ◽  
Bernhard Gentner ◽  
Marica Eoli ◽  
Farina Francesca ◽  
Elena Anghileri ◽  
...  
Keyword(s):  
Disease Progression ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Conditioning Regimen ◽  
Gene Promoter ◽  
Human Interferon ◽  
Open Label ◽  
Antitumor Effects ◽  
Open Label Phase ◽  
Interferon Α2

Abstract GBM with an unmethylated MGMT gene promoter is associated with very poor prognosis. A subset of tumor associated macrophages expressing the angiopoietin receptor Tie2 (TEMs) can be genetically modified for local & tumor restricted release of interferon-α2 (IFN). IFN has antitumor effects, inhibits angiogenesis & modulates the immune system. Temferon consists of autologous HSPCs transduced ex-vivo with an LVV encoding an IFN gene & expression control sequences for TEMs. TEM-GBM is an open-label, Phase I/IIa study (Part A: 3x3x3 dose escalation; Part B: n=12), & Temferon (single dose) is given to patients with first diagnosis of GBM & unmethylated MGMT promoter. Part A 3rd cohort is ongoing & completes dosing in September 2020. Eight patients completed screening; one patient died (disease progression) before Temferon was administered. Six patients received Temferon (3 women, 3 men, mean age 52.3 years). Cohort 1 received Temferon 0.5x106 cells/kg & Cohort 2, 1x106 cells/kg. Neutropenia & thrombocytopenia occurred as expected following conditioning & hematologic recovery (HR) occurred median D+13. Transduced PBMCs were identified by vector copy number (VCN) on myeloid cells at HR & at later timepoints. In general, a dose-ordered increase in VCN was observed (mean VCN D+30 CD14+ Cohort 1: 0.094, cohort 2: 0.125); 1 patient in each cohort had low VCNs. VCN remained detectable up to recent follow up visits (≤ D+180). No dose-limiting toxicities have been reported. Four SAEs occurred in 3 patients who received Temferon (pneumonia, pulmonary embolism, febrile neutropenia, fatigue) but these events were not attributed to Temferon, resolved, & may have been related to the conditioning regimen (carmustine & thiotepa). Disease progression has been confirmed in 3 patients who received Temferon. These preliminary results indicate feasibility of engrafting a pre-determined fraction of Temferon cells in the bone marrow of GBM patients without, so far, causing dose-limiting toxicity.

scholarly journals IMMU-01. TEM-GBM: AN OPEN-LABEL, PHASE I/IIA DOSE-ESCALATION STUDY EVALUATING THE SAFETY AND EFFICACY OF GENETICALLY MODIFIED TIE-2 EXPRESSING MONOCYTES TO DELIVER IFN-A WITHIN GLIOBLASTOMA TUMOR MICROENVIRONMENT

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv4-iv4
Author(s):  
Gaetano Finocchiaro ◽  
Marica Eoli ◽  
Bernhard Gentner ◽  
Alessia Capotondo ◽  
Elena Anghileri ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Conditioning Regimen ◽  
Tumor Type ◽  
Open Label ◽  
Dose Escalation Study ◽  
Differentiated Cells ◽  
Open Label Phase ◽  
Concomitant Medications ◽  
General Physical ◽  
Post Transcriptional Regulation

Abstract Temferon is a macrophage-based treatment relying on ex-vivo transduction of autologous HSPCs to express immune-payloads within the TME. Temferon targets the immune-modulatory molecule IFN-a, to a subset of tumor infiltrating macrophages known as Tie-2 expressing macrophages (TEMs) due to the Tie2 promoter and a post-transcriptional regulation layer represented by miRNA-126 target sequences. As of 31st May 2021, 15-patients received Temferon (D+0) with follow-up of 3 – 693 days. After conditioning neutrophil and platelet engraftment occurred at D+13 and D+13.5, respectively. Temferon-derived differentiated cells, as determined be the number of vector copy per genome, were found within 14 days post treatment and persisted albeit at lower levels up to 18-months. Very low concentrations of IFN-a in the plasma (8.7 pg/ml-D+30) and in the CSF (1.6 pg/ml-D+30) were detected, suggesting tight regulation of transgene expression. Five-deaths occurred at D+322, +340, +402, +478 and +646 due to PD, and one at D+60 due to complications following the conditioning regimen. Eight-patients had progressive disease (range: D-11 to +239) as expected for this tumor type. SAEs include GGT elevation (possibly related to Temferon) and infections, venous thromboembolism, brain abscess, hemiparesis, seizures, anemia and general physical condition deterioration, compatible with ASCT, concomitant medications and PD. Four-patients underwent 2ndsurgery. Recurrent tumors had gene-marked cells and increased expression of ISGs compared to first surgery, indicative of local IFNa release by TEMs. In one patient, a stable lesion had a higher proportion of T cells and TEMs within the myeloid infiltrate and an increased ISGs than in the progressing lesion, detected in the same patient. Tumor-associated clones expanded in the periphery. TME characterization by scRNA and TCR-sequencing is ongoing. To date, Temferon is well tolerated, with no DLTs identified. The results provide initial evidence of Temferon potential to activate the immune system of GBM patients, as predicted by preclinical studies.

Phase I adoptive cellular therapy trial with ex-vivo stimulated autologous CD8+ T-cells against multiple targets (ACTolog IMA101) in patients with relapsed and/or refractory solid cancers.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS77-TPS77
Author(s):  
Apostolia Maria Tsimberidou ◽  
Chad Stewart ◽  
Carsten Reinhardt ◽  
Hong Ma ◽  
Steffen Walter ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Cellular Therapy ◽  
Ex Vivo ◽  
Performance Status ◽  
Conditioning Regimen ◽  
Tumor Escape ◽  
Adoptive Cellular Therapy

TPS77 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy; however, only a small proportion of solid tumor patients have benefited from these advances due to i) heterogeneity of tumor antigen expression, ii) tumor escape (e.g. only one target is addressed), or iii) off-target toxicities (e.g. expression of targets on normal tissues). The ACTolog concept, utilizing antigen specific T cells (IMA101) against targets identified by the Immatics’ proprietary XPRESIDENT technology, is intended to overcome these limitations by addressing multiple novel relevant tumor antigens per patient. ACTolog is a personalized, multi-targeted ACT approach in which autologous T-cell products are manufactured against the most relevant tumor target peptides for individual patients whose tumors are positive against a predefined target warehouse. Methods: This study is an open-label first-in-human phase I trial in patients with relapsed or refractory solid tumors expressing at least one target from a warehouse of 8 cancer targets. Key eligibility criteria include: HLA-A*02:01 phenotype, qPCR expression of warehouse target(s), prior established lines of therapy, RECIST v1.1 measurable lesions, and ECOG performance status 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells for manufacturing of IMA101 cells. Patients will receive their last line of established therapy during the production phase of IMA101. IMA101 will be infused after a pre-conditioning regimen (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and tolerability of IMA101. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objective is to assess the in vivo persistence and ex vivo functionality of transferred T cells in addition to evaluation of target expression in tumors. Enrollment to the study is currently ongoing. Clinical trial information: NCT02876510 .

scholarly journals Chemokine-induced recruitment of genetically modified bone marrow cells into the CNS of GM1-gangliosidosis mice corrects neuronal pathology

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2259-2268 ◽  
Author(s):  
Renata Sano ◽  
Alessandra Tessitore ◽  
Angela Ingrassia ◽  
Alessandra d'Azzo
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Genetically Modified ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Gm1 Gangliosidosis ◽  
Ex Vivo Gene Therapy ◽  
Stromal Cell Derived Factor ◽  
Marrow Cells

AbstractBone marrow cells (BMCs) could correct some pathologic conditions of the central nervous system (CNS) if these cells would effectively repopulate the brain. One such condition is GM1-gangliosidosis, a neurodegenerative glycosphingolipidosis due to deficiency of lysosomal β-galactosidase (β-gal). In this disease, abnormal build up of GM1-ganglioside in the endoplasmic reticulum of brain cells results in calcium imbalance, induction of an unfolded protein response (UPR), and neuronal apoptosis. These processes are accompanied by the activation/proliferation of microglia and the production of inflammatory cytokines. Here we demonstrate that local neuroinflammation promotes the selective activation of chemokines, such as stromal-cell-derived factor 1 (SDF-1), macrophage inflammatory protein 1-α (MIP-1α), and MIP-1β, which chemoattract genetically modified BMCs into the CNS. Mice that underwent bone marrow transplantation showed increased β-gal activity in different brain regions and reduced lysosomal storage. Decreased production of chemokines and effectors of the UPR as well as restoration of neurologic functions accompanied this phenotypic reversion. Our results suggest that β-gal-expressing bone marrow (BM)-derived cells selectively migrate to the CNS under a gradient of chemokines and become a source of correcting enzyme to deficient neurons. Thus, a disease condition such as GM1-gangliosidosis, which is characterized by neurodegeneration and neuroinflammation, may influence the response of the CNS to ex vivo gene therapy.

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