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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

ABSTRACT: Abstract 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).

SUBMITTER: Antonio Chiocca E

PROVIDER: S-EPMC7650880 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch. Increased PD-1 expression in samples of rGBM following Ad+V (ASCO 2020) supports combination immunotherapy with a PD-1 inhibitor. Phase 1 trials in rGBM of Ad+V as monotherapy and in combination with PD-1 inhibitor revealed encouraging safety and survival data. This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0–14). Longitudinal sampling of serum assessed IL-12 and endogenous cytokines production. Anti-tumor effects were described upon preliminary review. Serial MRI evaluated tumor response. Follow-up described overall survival. Initial safety data (51 unique adverse reactions in 28 subjects) appeared similar to Ad+V and the cemi label, respectively, being manageable without synergistic toxicities and generally reversible. Of 35 SAEs reported in 18 subjects, 10 SAEs in 7 subjects were related to Ad+V. IL-12 and IFN-g levels increased after Ad+V administration peaking on Day 3 at 34 ± 11 pg/mL and 13 ± 5 pg/mL (mean ± SEM), respectively. Immune-mediated anti-tumor effects were noted, including a post-treatment biopsy to rule out progression which demonstrated an immune infiltrate consistent with pseudoprogression and loss of tumor cell heterogeneity suggesting immunoediting. Enrollment is anticipated to be completed in 2Q2020 with follow-up ongoing and initial survival data will be presented. V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.

Dataset Information

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

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