CTIM-05. COMBINATION OF CONTROLLED INTERLEUKIN-12 GENE THERAPY WITH IMMUNE CHECKPOINT BLOCKADE IN RECURRENT GLIOBLASTOMA: UPDATED RESULTS OF A MULTI-INSTITUTIONAL, OPEN LABEL PHASE 1 TRIAL
| Autor: | Yunxia Wang, Taylor Estupinan, Rimas V. Lukas, Christina Amidei, John Loewy, Nathan Demars, Jill Buck, Arnold Gelb, Ganesh Rao, Nira Hadar, E. Antonio Chiocca, Laurence J.N. Cooper, John Miao, Clark C. Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty Cell cycle checkpoint business.industry Genetic enhancement medicine.medical_treatment Immunotherapy Clinical Trials: Immunologic Immune checkpoint Blockade Internal medicine medicine Interleukin 12 Combined Modality Therapy Neurology (clinical) Nivolumab business |
| Zdroj: | Neuro Oncol |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noaa215.139 |
| Popis: | A published clinical trial of veledimex (V)-regulatable interleukin-12 (IL-12) gene therapy (“Controlled IL-12”) under the control of a transcriptional switch (RheoSwitch Therapeutic Systemâ, RTSâ) as monotherapy in recurrent glioblastoma (rGBM) showed sustained infiltration of activated T cells within the tumor months after treatment (Sci Transl Med. 2019;11(505)). These T cells demonstrated up-regulation of immune checkpoint signaling, providing a rationale for combination therapy with the PD-1 inhibitor, nivolumab (nivo). We report interim findings following completion of enrollment (with follow-up ongoing) for a multi-institutional, open label, dose-escalation phase 1 trial (NCT03636477) evaluating safety and tolerability of loco-regional Controlled IL-12 in combination with nivo in adults with rGBM. Replication-incompetent adenovirus coding for RTS-IL-12 (Ad) was administered during surgery by free-hand injection into the tumor and periphery (2 x 1011 viral particles, Day 0) accompanied by V (10 or 20 mg) PO QD x 15 (Days 0 to 14) in combination with nivo (1 or 3 mg/kg) IV on Days -7, 15, then Q2W. Twenty-one subjects were treated (Cohort 1: V 10 mg, nivo 1 mg/kg, n=3; Cohort 2: V 10 mg, nivo 3 mg/kg, n=3; and Cohort 3: V 20 mg, nivo 3 mg/kg, n=3 & 12 in expansion). Safety data were comparable to Ad+V monotherapy. Adverse reactions (ARs) during follow-on nivo dosing were consistent with nivo labeling. ARs were manageable and generally reversible with no synergistic toxicities. Updated overall survival findings will be presented. Baseline and post-treatment histochemical staining and multiplex immunofluorescence analyses for a subgroup of subjects will be discussed. The safety of this combination immunotherapy has been established, leading to a currently accruing phase 2 clinical trial of loco-regional Controlled IL-12 gene therapy in combination with the PD-1 inhibitor cemiplimab-rwlc (NCT 04006119). |
| Databáze: | OpenAIRE |
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