TD2 Works Closely with ZIOPHARM Oncology to Conduct a Preclinical Study Being Presented at the Upcoming ASGCT Meeting in Washington, DC

April 28, 2016

Below is the abstract seelcted for presentation at the upcoming American Society of Gene & Cell Therapy 19th Annual Meeting:

Regulated Expression of IL-12 as Gene Therapy Concomitant with Blockade of PD-1 for Treatment of Glioma

John A. Barrett1, Hongliang Cai1, John Miao1, Margaret Murray2, Paul Gonzales2, Suma Krishnan3, Francois Lebel1, Laurence J.N. Cooper1

1 ZIOPHARM Oncology Inc., Boston, MA, United States, 02129

2 Translational Drug Development, Scottsdale, AZ, United States, 8525

3 Intrexon Corporation, Germantown, MD, United States, 20876

The utility of immunotherapy in the treatment of glioma may be improved through combination therapies that enhance cytotoxic immune-activation while concomitantly reducing immunosuppression. We provide data in mice to support evaluation of combining controlled local interleukin 12 (IL-12) administration and blockade of programmed cell death protein 1 (PD-1) in humans. To circumvent challenges surrounding the uncontrolled activation, we have implemented clinical trials using a replication-incompetent adenovirus engineered to conditionally express IL-12 (Ad-RTS-IL-12), via our RheoSwitch Therapeutic System® (RTS®) gene switch. When directly injected intra-tumorally in pre-clinical or clinical studies, IL-12 expression is “off” when devoid of the activator ligand (veledimex, V) and IL-12 production is turned “on” (in a dose-dependent manner) by oral administration of veledimex. PD-1 inhibitors using therapeutic monoclonal antibodies (mAbs) demonstrate an ability to reverse tumor immunosuppression and are effective in the treatment of some cancers. In the present pre-clinical study we assessed the effects of Ad-RTS-mIL-12+veledimex (Ad+V) alone (Ad 5×109 viral particles (vp) + V 10-30mg/m2/day for 14 days) or in combination with the antiPD-1-specific mAb RMP1-14 (antiPD-1, 7.5 & 15.0 mg/m2 for 4/day for 5 days i.p.) in the orthotopic GL-261 mouse model. All mice without treatment succumb to disease progression by Day 35. Eighty days after immunotherapy, 70-80% receiving Ad +V monotherapy survived, 30-40% receiving antiPD-1 monotherapy survived and 100% receiving Ad +V 30 mg/m2 + antiPD-1 15.0 mg/m2 combination survived.  There was an increase in tumor IL-12 (100 pg/mg) which was 15-times greater than that of plasma peak 5 days after Ad +V. Furthermore, the combination of Ad +V+antiPD-1 sustained peak IL-12 levels in tumor which was associated with a 100-150% increase of activated T cells in the spleen compared with the minimal changes observed with either immunotherapy alone. In addition, there was an additive reduction in regulatory T cells (FOXP3) compared with monotherapies. In summary we demonstrate that controlled local immunostimulation with IL-12 combined with inhibition of PD-1 is an attractive approach for the treatment of glioma. Since both Ad-RTS-IL-12 and mAb blocking PD-1 are clinically available, these data provide impetus for evaluating this combination immunotherapy in humans.

Emerging Trends in Radiopharmaceuticals

EVOLVING CLINICAL STRATEGIES Radiopharmaceuticals represent a significant advancement in oncology by integrating targeted radiation with biologically ...

Read more +

Optimizing Site Selection for Faster Patient Enrollment in Oncology Trials

Effective site selection is critical to the success of any clinical trial, especially in oncology, where patient recruitment can be particularly ...

Read more +

Choosing the Right DIO Mouse Model for Your Oncology Study

Diet-induced obesity (DIO) mouse models are integral to the exploration of obesity's role in cancer etiology, offering detailed insights into the ...

Read more +

Get Started

Contact Us Today!

If you’re looking for an expert team to guide your trial with efficiency in mind, we can help. As the creators of the Dynamic Trial, TD2 provides start-to-finish support with trial strategy, design and execution for faster go-to-market potential.