Clinical data from three ongoing trials of Ad-RTS-hIL-12 plus veledimex (referred to as Controlled IL-12) for the treatment of recurrent or progressive glioblastoma multiforme (rGBM) and diffuse intrinsic pontine glioma (DIPG) were presented at the annual (virtual) meeting of the 2020 Society of NeuroOncology (SNO).

The data for the new treatment option, being developed by Ziopharm Oncology, included the first discussion of interim results of a phase II study of Controlled IL-12 in combination with cemiplimab (Libtayo®; Regeneron Pharmaceuticals and Sanofi-aventis) for the treatment of rGBM that has recently completed enrollment, and updated interim data from the phase I study of Controlled IL-12 in combination with nivolumab for the treatment of rGBM and data from the first patient enrolled in the ongoing phase I/II study of Controlled IL-12 monotherapy for the treatment of DIPG.

“Glioblastoma is a highly aggressive tumor and despite advances in oncology over the last few decades, median overall survival for patients with progressive GBM remains less than one year,” explained Rimas Lukas, M.D., Associate Professor of Neurology at Northwestern Memorial Hospital Malnati Brain Tumor Institute and investigator on the phase II trial of Controlled IL-12 in combination with cemiplimab.

“We’ve reported data for the first time from the ongoing phase II study of Controlled IL-12 in combination with PD-1 inhibitor cemiplimab, showing activation of the immune system across patients. These data are highly encouraging and underscore the potential of Controlled IL-12 to transform the treatment landscape of recurrent glioblastoma.”

Interleukin 12 or IL-12, a cytokine that is produced by dendritic cells, monocytes, and macrophages, and to a lesser extent by B-cells, induces TH1 differentiation in T-lymphocytes and the subsequent expression of interferon γ (INFγ). The cytokine belongs to the family of interleukin-12 which comprises the only heterodimeric cytokines, including IL-12, IL-23, IL-27, and IL-35.

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IL-12 also promotes the expansion and survival of activated T-cells and NK cells and modulates the cytotoxic activity of CTLs and NK cells. During the adaptive immune response, IL-12 is known to primes antigen-specific T-cells for high IFN-g production, which drives the differentiation toward the Th-1 pathway. IL-12 can also act as an adjuvant for humoral immunity by enhancing the production of IgG2a and IgG2b antibodies, and it may enhance antibody production by B-cells.

Ziopharm’s Ad-RTS-hIL-12 plus veledimex is a gene therapy with an Adenoviral vector (Ad) providing the vehicle engineered to express IL-12 under the control of the RheoSwitch Therapeutic System® (RTS®). Ad-RTS-hIL-12 + veledimex has demonstrated a dose-related increase in tumor IL-12 mRNA and IL-12 protein expression. Discontinuation of veledimex resulted in a return to baseline IL-12 mRNA and protein expression in numerous syngeneic mouse tumor models. Image courtesy Ziopharm Oncology.[1]
Although interleukin-12 (hIL-12) has anticancer activity, the systemic application is limited as a result of a toxic inflammatory responses. To solve the problem, scientists at Ziopharm assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. [1]

Ziopharm’s Controlled IL-12 platform turns on the expression of IL-12 on demand, signaling for T-cells to attack and destroy cancerous tissue. As part of the treatment, genes coded to produce IL-12 are delivered to tumor sites.  Following this step, patients are given a dose of veledimex to trigger the implanted genes to produce IL-12. This approach allows treating physicians to increase or decrease expression levels of IL-12 or turn it off altogether.[1]

PD-1 inhibitor
“The updated data on combining Controlled IL-12 with nivolumab reveal a subset of patients with rGBM that demonstrate very encouraging survival at 16 months. This observation reveals that immune modulation with IL-12 and anti-PD-1 is well tolerated with an apparent survival benefit that will need further confirmation in upcoming more advanced clinical trials,” said E. Antonio Chiocca, M.D., Ph.D., study investigator, Chairman of Neurosurgery at Brigham and Women’s Hospital, Professor of Neurosurgery at Harvard Medical School, and Surgical Director of the Center for Neuro-oncology at Dana-Farber Cancer Institute.

“These survival data in conjunction with previously reported MRIs showing partial responses is consistent with immune-mediated anti-tumor effects,” Chiocca added.

The results from the ongoing Phase II study of Controlled IL-12 in combination with PD-1 inhibitor cemiplimab for the treatment of adult patients with recurrent or progressive glioblastoma multiforme (rGBM), showed an activation of the immune system across patients with rGBM.

The combination trial demonstrated promising initial survival data, with median overall survival not yet reached. The data was comparable to results from a Controlled IL-12 monotherapy study previously presented at the 2020 annual meeting of the American Society of Clinical Oncology (ASCO).

Even with the best available therapies, the median overall survival for patients with rGBM is capped at 12 months. The Controlled IL-12 monotherapy has shown it can bring median overall survival to 16+ months.

Across its Controlled IL-12 studies to date, Ziopharm has identified a total of six partial responses, highlighting the promising potential of this therapy for the treatment of rGBM.

Remote-controlled therapy
The drug itself works like a “remote-controlled therapy.” The vector is injected directly into the tumor, but the gene of interest, IL-12, is under a transcriptional regulator, meaning that IL-12 is only expressed when the patient takes a drug that activates its transcription. Physicians can remotely control IL-12 expression by telling the patient when to take this pill.

Platform technology
“As we reflect on the growing body of evidence across our efforts utilizing our Controlled IL-12 platform, we are encouraged by the signs of efficacy we are seeing in these very hard-to-treat cancers. Not only are we observing cytokine production, increases in intra-tumoral T-cells, and predictable safety after treatment with Controlled IL-12 as a monotherapy and in combination with PD-1 inhibitors, but we have reported at least one partial response in each rGBM trial we have conducted to date, for a total of six,” noted Laurence Cooper, M.D., Ph.D., Chief Executive Officer of Ziopharm

“These MRI data, along with IL-12-driven immune response complement our encouraging survival data and we look forward to future data read-outs in 2021. Further, the initial look at data from the first patient in our phase 1/2 pediatric glioma study supports Controlled IL-12’s safety profile and continued development,” Cooper added.

Key studies: Controlled IL-12 + cemiplimab 
Controlled IL-12 in combination with PD-1 inhibitor cemiplimab is currently being examined in a phase 2 study for the treatment rGBM (NCT04006119). Preliminary data in the on-demand presentation include:

  • Serum cytokine levels, including IL-12 and downstream IFN-g, were detected following initiation of Controlled IL-12, and sustained longer than previously reported data of Controlled IL-12 as monotherapy
  • Treatment resulted in activation of the immune system, with a significant increase in circulating killer (cytotoxic) T-cells by Day 28
  • Serial MRIs showed evidence of an immune-mediated anti-tumor response
    • One partial response was confirmed on Week 16 and is ongoing through Week 32
  • Median overall survival (mOS) has not been reached, with mean a follow-up time of 6.5 months
  • Controlled IL-12 with cemiplimab was well tolerated
  • Enrollment was by design biased toward unifocal cases (82.5%) and is now complete with cemiplimab dosing and follow-up ongoing
  • Most patients received low dose steroids, defined as <= 20 mg cumulative dosing of dexamethasone during veledimex administration

Key studies: Controlled IL-12 + nivolumab
Controlled IL-12 in combination with the PD-1 inhibitor nivolumab is currently being examined in a phase I study for the treatment of rGBM. Interim data highlights shared in an oral on-demand presentation include:

  • Results are comparable to Controlled IL-12 monotherapy
    • Veledimex plasma and tumor plasma pharmacokinetics demonstrated a dose-response relationship and crossing of the blood-brain barrier
    • Serum IL-12 was detected in all subjects following Controlled IL-12 treatment, typically followed by a transient increase in downstream IFN-γ
  • Pre- and post-treatment biopsies show increased levels of tumor-infiltrating T cells and decreased levels of PD-1
  • mOS for the cohorts receiving 10 mg veledimex (n=6; 83% unifocal, 67% low dose steroids) was 16.9 months
  • mOS among all subjects (across both 10 mg and 20 mg veledimex dosing, n=21) was 9.8 months
  • Most patients (81%) in this substudy received low dose steroids
  • Drug-related toxicities were comparable to Controlled IL-12 monotherapy, being predictable, dose-related, and promptly reversible upon discontinuation of veledimex
  • Enrollment is complete; anti-PD-1 administration in one subject and follow-up in six patients is currently ongoing

As a follow up to our prior readout (ASCO 2020) for this combination which reported partial responses by MRI, the two patients had meaningful improvements in survival with one patient on 20 mg veledimex surviving 17.4 months and the other (10 mg veledimex) surviving 21.0 months (in follow up).

Diffuse Intrinsic Pontine Glioma
Controlled IL-12 monotherapy is being studied in a phase 1/2 dose-escalation study for the treatment of children with gliomas, including DIPG. Data highlights from the first patient in the study shared in a poster discussion, included:

  • Controlled IL-12 monotherapy was well-tolerated at the initial dose level (10 mg/day veledimex, BSA adjusted)
    • High veledimex compliance was reported, with no dose limiting toxicity (DLTs), Serious Adverse Events (SAEs) or suspected unexpected serious adverse reactions (SUSARs) occurring during the active study period
    • Adverse Events (AEs) were similar to adult and older pediatric supratentorial brain tumor subjects in being mild to moderate and predominantly reversible upon withholding of veledimex doses
  • Preliminary evidence of immune system activation
    • Although an increase in serum recombinant IL-12 was not detected after initial dosing of veledimex (patient received 5 mg per day), endogenous IFN-γ was detected which peaked at Day 3 consistent with downstream IL-12-driven immune response
    • Circulating cytotoxic T-lymphocyte levels increased between Days 7 and 28
    • Partial eyebrow loss was observed, suggestive of immune-mediated alopecia areata
  • Survival of the first subject dosed was within the historical reference range
  • Enrollment is ongoing with the plan to investigate two dose levels of veledimex (10 to 20 mg, BSA adjusted) as planned per protocol

“It is important to note that these trials, including our previously disclosed monotherapy study, now consist of over 125 patients with rGBM. These provide deep learning that is ongoing and is part of the efforts to develop Controlled IL-12 as a potential therapy for brain cancers. We will continue to monitor the data across both the monotherapy and checkpoint inhibitor combination studies in the coming months. We believe there are multiple potential paths to registration for our Controlled IL-12 program, either as a monotherapy therapy or in combination with other agents,” Cooper concluded.

Clinical trials
Evaluation of Ad-RTS-hIL-12 + Veledimex in Subjects With Recurrent or Progressive Glioblastoma, a Substudy to ATI001-102 – NCT03679754
A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Glioblastoma or Malignant Glioma – NCT02026271
Study of Ad-RTS-hIL-12 + Veledimex in Combination With Cemiplimab in Subjects With Recurrent or Progressive Glioblastoma – NCT04006119
A Study of Ad-RTS-hIL-12 With Veledimex in Combination With Nivolumab in Subjects With Glioblastoma; a Substudy to ATI001-102 – NCT03636477
A Study of Ad-RTS-hIL-12 + Veledimex in Pediatric Subjects With Brain Tumors Including DIPG – NCT03330197

Highlights of Prescribing information
Cemiplimab (Libtayo®; Regeneron Pharmaceuticals and Sanofi-aventis) [Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb) [Prescribing Information]

Meeting presentations
Lukas RV, Chiocca EA, OberheimBush NA, Landolfi J, Cavaliere R, Yu J, Kurz SC, Demars N, et al. Phase 2 Trial of Controlled IL-12 in Combination with PD-1 Inhibitor in Adult Subjects with Recurrent Glioblastoma (Abstract #901183) SNO 2020 Annual Meeting; Presented by: Rimas V. Lukas, MD [Presentation]
Chiocca EA, Lukas RV, Chen CC, Rao G, Reardon D, Wen P, Bi WL, Peruzzi P, et al. 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 #901050) SNO 2020 Annual Meeting; Presented by: Antonio Chiocca, MD.[Presentation]
Goldman S, Mueller S, Chi S, Saratsis A, Allen R, Buck J, Demars N, Hadar N, Estupinan T, et al. Phase I/II Study of Controlled IL-12 as Immunotherapy for Diffuse Intrinsic Pontine Glioma (DIPG) (Abstract #901123), presented by Stewart Goldman, M.D., Division Head Hematology-Oncology, Neuro-Oncology & Stem Cell Transplantation at Lurie Children’s Hospital. [Poster]

[1] Barrett JA, Cai H, Miao J, Khare PD, Gonzalez P, Dalsing-Hernandez J, Sharma G, Chan T, Cooper LJN, Lebel F. Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System® (RTS®) gene switch as gene therapy for the treatment of glioma. Cancer Gene Ther. 2018 Jun;25(5-6):106-116. doi: 10.1038/s41417-018-0019-0. Epub 2018 May 14. PMID: 29755109; PMCID: PMC6021367.
Featured Image: Doctor report and recommend a method with patient treatment, results on brain x-ray film. Photo courtesy: © 2020 Fotolia/Adobe. Used with permission.

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