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J2 - Cell Therapy and Cell-Based Gene Therapy Trails

7: Reprogramming of the Tumor Microenvironment in Glioblastoma Multiforme by Transplantation of Genetically-Engineered Hematopoietic Stem Cells

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium

Introduction: Glioblastoma multiforme (GBM) is an incurable, highly aggressive tumor affecting the central nervous system, with a reported median survival of only 12.7 months in the unfavorable subgroup of patients with unmethylated (u)MGMT promoter. Immunotherapy has largely failed, due to intratumor heterogeneity, low T cell infiltration and a highly immunosuppressive myeloid tumor microenvironment (TME). Methods: We are conducting a phase 1/2a study in newly diagnosed patients presenting with (u)MGMT GBM (NCT03866109) evaluating the safety and biological activity of Temferon, a hematopoietic stem cell (HSC)-based gene therapy that induces local release of alpha-interferon (IFNα) from tumor-infiltrating macrophages. We performed scRNAseq and scTCRseq analysis of second surgery GBM tumors from n=5 patients enrolled in the Temferon study (post gene therapy) and n=6 control patients treated according to best standard-of-care to evaluate Temferon’s effect on immune cell reprogramming. Findings were validated on an extended control group encompassing >100 GBM patients from publicly available scRNAseq datasets. Results: As of June 30th, 2023, 21 uMGMT GBM patients in 7 cohorts received 4 incremental doses of Temferon (0.5-3.0x10^6/kg). With a median follow-up of 29 months, all patients show long-term engraftment of genetically engineered cells, with no dose-limiting toxicities. The interim survival rate at 2 years is 28% (5 out of 18 patients; 3 patients excluded due to FU<12 months), which is higher than what is reported in the literature (15%). One patient is alive for >3 years after diagnosis, without further therapy. Genetically engineered cells were locally detected within the tumor lesion at levels >3% in 2/5 patients, and tumors showed increased IFNα-induced gene expression compared to the pre-treatment sample. These data indicate the recruitment of Temferon progeny into the TME, where they locally release IFNα. scRNAseq allowed unbiased identification of multiple subclusters within myeloid, lymphoid, tumor and stroma cell compartments. Most of these clusters showed strong up-regulation of IFNα and inflammatory responses. Tumors from Temferon patients were characterized by an increase in M1-like and a decrease in M2-like macrophages. Of note, this population shift was particularly evident when comparing a stable with a progressive tumor lesion biopsied contemporaneously in 1 GBM patient, reproducing findings from a GBM mouse model (PMID: 35857642). Concomitant with myeloid cell reprogramming, it is striking that Temferon patients had more CD8 effector cells that were enriched with signatures of antitumor neoantigen-reactive T cells, a novel finding that challenges the prevailing dogma that GBM is an immune wasteland. Conclusion: Temferon, a first-in-class gene therapy targeting the myeloid TME in GBM patients is safe and biologically active at the tumor site favoring anti-tumor immunity. Preliminary survival data are promising, but longer follow-up is needed.

Bernhard Rudolf Gentner1, Matteo Barcella2, Francesca Farina3, Marica Eoli4, Alessia Capotondo2, Filippo Gagliardi5, Silvia Snider5, Quintino Giorgio D'Alessandris6, Valeria Cuccarini7, Elena Anghileri4, Mariagrazia Garramone2, Valentina Brambilla8, Francesco Di Meco9, Paolo Ferroli9, Valeria Ferla3, Federico Legnani9, Stefania Mazzoleni8, Alessandro Olivi6, Roberto Pallini6, Marina Grisoli7, Gaetano Finocchiaro10, Carlo Russo11, Fabio Ciceri3, Luigi Naldini2

1CHUV, Lausanne, Switzerland,2SR-Tiget, Milan, Italy,3Hematology and Bone Marrow Transplant Unit-HSR, Milan, Italy,4Neuro-Oncology Unit - INCB, Milan, Italy,5Neurosurgery Unit - HSR, Milan, Italy,6Neurosurgery Unit - Policlinico Gemelli, Rome, Italy,7Neuroradiology Unit - INCB, Milan, Italy,8Genenta Science, Milan, Italy,9Neurosurgery Unit - INCB, Milan, Italy,10Neuro-Oncology Unit - HSR, Milan, Italy,11Genenta Science, New York, NJ"

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