On April 18, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, reported results from two programs will be presented in oral sessions at the upcoming 19th Annual American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Meeting (Press release, Ziopharm, APR 18, 2016, View Source [SID:1234511002]). The first presentation highlights preclinical data from the Company’s novel viral gene therapy candidate for the controlled expression of IL-12 in combination with inhibition of programmed cell death protein 1 (PD-1) in a mouse model of glioma. The second presentation highlights preclinical data from the Company’s evolution of the Sleeping Beauty (SB) non-viral transposon-transposase system in a mouse model of leukemia. The ASGCT (Free ASGCT Whitepaper) meeting will take place May 4-7 at the Marriott Wardman Park Hotel in Washington, D.C.

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Title: Regulated Expression of IL-12 as Gene Therapy Concomitant with Blockade of PD-1 for Treatment of Glioma
Session Title: Cancer-Immunotherapy, Cancer Vaccines II
Date and Time: Friday, May 6, 2016 4:00 PM – 6:00 PM ET
Abstract Number: 509
Room: Washington 1-2
Summary: The utility of clinically-feasible immunotherapy in the investigational treatment of glioma may be improved through combination therapies that enhance cytotoxic immune-activation while concomitantly reducing immunosuppression. ZIOPHARM and Intrexon evaluated the combination of controlled local interleukin 12 (IL-12) administration using a virus (Ad-RTS-IL-12) activated by an oral ligand (veledimex) (Ad +V) and blockade of PD-1 using a checkpoint inhibitor:

Results demonstrated that survival of mice treated with Ad +V and anti-PD-1 therapy was superior to either treatment alone;
Combination showed 100% survival;
Because Ad-RTS-IL-12 and anti-PD-1 are clinically available, these data provide impetus for evaluating this combination immunotherapy in humans;
ZIOPHARM plans to initiate a combination study in 2016 and is currently in discussion with partners to provide anti PD-1 therapy.
"The use of PD-1 checkpoint inhibitors in solid tumors has yielded impressive clinical outcomes, yet these results have not yet translated to gliomas, due in part to the immunologic privilege of the central nervous system," said Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer at ZIOPHARM. "By combining PD-1 inhibitors, which release a brake on the immune system, with the controlled tumor-directed release of IL-12, which steps on the immune system’s accelerator, we see significant anti-tumor activity. These data provide a strong rationale for studying Ad-RTS-IL-12 + veledimex in combination with anti-PD-1 in the clinic, a trial we look forward to initiating later this year."

Title: Next-Generation Non-Viral Gene Transfer to Redirect T-Cell Specificity
Session Title: Cancer-Immunotherapy, Cancer Vaccines I
Date and Time: Thursday, May 5, 2016 4:00 PM – 5:45 PM ET
Abstract Number: 278
Room: Washington 5-6
Summary: Non-viral gene transfer using the SB transposon/transposase system has been successfully tested in humans to express a chimeric antigen receptor (CAR) to redirect T-cell specificity to CD19. A next-generation SB system has been modified by MD Anderson Cancer Center researchers to improve the design of a CD19-specific CAR as well as reduce the time to manufacture:

Changing the "stalk" of the CAR improved the anti-tumor activity of SB-modified T cells;
These data support the use of new CAR in an ongoing clinical trial (IND#16474).
Decreasing the time the SB-modified T cells were in culture improved the anti-tumor effect;
These data provide support for ZIOPHARM’s efforts to address the challenges of cost and time of bioprocessing cell therapies;
"Targeting CD19 with CAR-modified T cells is an effective approach to treating CD19-expressing leukemias and lymphomas, as demonstrated by current clinical studies," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "Fundamental to advancing this approach, and any modified cell-based therapy, into a broadly deployed treatment option is a streamlined and simplified manufacturing process, with a reduction in the associated cost. These data demonstrate our ability to address these challenges by leveraging the less costly, non-viral Sleeping Beauty system and reducing cell culture time, all while improving the effectiveness of the CD19-specific CAR. We look forward to understanding how these next-generation ideas translate into outcomes in an ongoing Phase 1 study and future clinical studies."

On April 18, 2016 Varian Medical Systems (NYSE: VAR) reported it is supporting a phase III trial comparing outcomes of radiosurgery versus surgical resection for the treatment of early-stage, high-risk, operable non-small cell lung cancer (NSCLC) (Press release, Varian Medical Systems, APR 18, 2016, View Source [SID:1234511001]).

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Known as the "Stablemates Trial," the randomized study will test the hypothesis that the 3-year overall survival in high risk operable patients with stage I NSCLC is equivalent or greater in patients who undergo stereotactic ablative radiotherapy (SAbR) as compared with conventional sublobar resection (SR) surgery. Led by co-chairs Hiran Fernando, MD, Boston Medical Center, and Robert Timmerman, MD, University of Texas Southwestern Medical Center, the study currently involves 34 institutions and 258 patients.

"In addition to a potentially longer survival rate, SAbR may benefit some lung cancer patients by offering them a noninvasive, outpatient treatment option that is easier to tolerate and that doesn’t interfere greatly with their normal, everyday living activities," said Dr. Timmerman.

Sponsored by the Joint Lung Cancer Trialist’s Coalition, the study is being administered by the Department of Radiation Oncology at the University of Texas Southwestern Medical Center. Over the next five years, the study will examine patients’ overall, disease-free, and regional recurrence-free survival rates three years after treatment, as well as adverse events and post-treatment quality of life measures.

"Varian believes in supporting high quality clinical research," said Kolleen Kennedy, president of Varian’s Oncology Systems business. "This clinical trial presents the opportunity to advance radiation oncology and enhance the standard of patient care by giving clinicians a noninvasive treatment option in determining the appropriate therapy for patients."

On April 18, 2016 MabVax Therapeutics Holdings, Inc. (OTCQB: MBVX), a clinical-stage immuno-oncology drug development company, reported that its fully human antibody approach to cancer therapeutics and imaging will be featured in three separate poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting currently underway in New Orleans (Press release, MabVax, APR 18, 2016, View Source [SID:1234511000]).

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"We are an innovator in using fully human antibodies to identify and combat cancer antigens that have historically proven difficult to target," said David Hansen, CEO of MabVax. "It is highly gratifying that our novel approach to harnessing the human immune system is being recognized in multiple presentations at the prestigious AACR (Free AACR Whitepaper) Annual Meeting. We are currently in a Phase I trial with our lead candidate MVT-5873 as an immunotherapy for patients with metastatic pancreatic cancer. Preparations are also underway to begin a second Phase I trial in May, which will evaluate MVT-2163 as a next-generation PET imaging agent for the diagnosis and management of pancreatic cancer. We look forward to announcing preliminary data from both trials during the third quarter of this year."

An overview of the poster presentations at the AACR (Free AACR Whitepaper) Annual Meeting are as follows:

"Phase I trial of HuMab-5B1 (MVT-5873), a novel monoclonal antibody targeting sLea, in patients with advanced pancreatic cancer and other CA19-9 positive malignancies" (O’Reilly, et al.) is being presented today by Paul Maffuid, Ph.D., MabVax’s Executive Vice President of Research and Development. The poster provides an overview of the development and rationale for evaluating MabVax’s HuMab-5B1 antibody in patients with the CA19-9 tumor biomarker that is expressed in approximately 90% of pancreatic cancers. As background for HuMab-5B1’s clinical development, the poster covers antibody discovery, tissue binding selection, cytotoxicity profile, antitumor efficacy and pharmacokinetics. The poster features MabVax’s Phase I development platform for evaluating HuMab-5B1, which includes the ongoing trial as a therapeutic antibody in patients with pancreatic cancer, as an immune-PET imaging agent with the trial slated to begin in May 2016, and as a radioimmunotherapy targeting pancreatic and other CA19-9 positive tumors, with that trial expected to commence in early 2017.

"Improving the efficacy of pretargeted radioimmunotherapy in preclinical murine models by utilizing bioorthogonal click chemistry" (Houghton, et al) is being presented by Jacob Houghton, Ph.D., Memorial Sloan-Kettering Cancer Center, on Tuesday, April 19. Pretargeted radioimmunotherapy employs the process of attaching a radioactive label to monoclonal antibodies after the antibodies have accumulated at the target site within the body. This allows for harnessing the power of monoclonal antibodies to deliver therapeutic radiation to cancer cells while limiting high radiation doses to healthy organs. Recently an innovative approach based on the use of a radioligand and modified monoclonal antibodies has yielded PET images with high contrast while delivering only a small fraction of the radiation dose produced by directly labeled monoclonal antibodies. This novel approach also overcomes intrinsic problems with past pretargeted radioimmunotherapy such as immunogenicity and noncovalent binding. Research in the poster evaluated leveraging this novel technology for the development of a safe and effective therapy. Single-dose therapy using this approach in studies in mice bearing human xenografts cancer showed marked reduction in size or complete elimination of the tumors, while reducing the effective absorbed dose of radiation. Studies to expedite clinical translation are currently underway.

"Novel fully human anti-GD2 monoclonal antibodies with potent therapeutic activity against neuroblastoma, sarcoma and melanoma" (Ragupahti, et al.) is being presented by Wolfgang Scholz, Ph.D., MabVax’s Vice President of Antibody Discovery, on Wednesday, April 20. Gangliosides such as GD2, GD3 and GM2, are promising targets for antibody-mediated cancer therapy since they are expressed at high levels on the surface of several cancers, including neuroblastomas, sarcomas and melanomas. Monoclonal antibodies with anti-GD2 abilities have shown promising clinical outcomes in neuroblastoma and a chimeric anti-GD2 antibody was recently approved by FDA. However, murine-derived antibodies discovered so far show adverse effects that limit their clinical utility. The research presented in this poster evaluated the ability of two select fully human antibodies derived from immunized patients to overcome the limitations of murine-derived antibodies. The development candidates used in this research were derived from vaccinated, patient-produced antigen-specific antibodies with single and dual specificity for GD2 and GM2. These antibodies were shown to be very active in functional assays. Based on favorable in vitro and in vivo studies conducted in this research, the two selected fully human monoclonal antibodies merit further development efforts to evaluate potential utility for treatment of GD2-positive cancers.

On April 18, 2016 Heron Therapeutics, Inc. (NASDAQ: HRTX), reported that the U.S. Food and Drug Administration (FDA) has provided the Company with an update on its review of the New Drug Application (NDA) for SUSTOL (granisetron) Injection, extended release (Press release, Heron Therapeutics, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2158021 [SID:1234510998]). The FDA has indicated that there are no substantive deficiencies in the NDA and has begun labeling discussions with the Company.

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SUSTOL is a long-acting formulation of the FDA-approved 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist granisetron being developed for the prevention of both acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). SUSTOL is formulated utilizing Heron’s proprietary Biochronomer drug delivery technology, and has been shown to maintain therapeutic drug levels of granisetron for at least five days with a single subcutaneous injection.

On April 18, 2016 Mustang Bio, Inc. ("Mustang"), a Fortress Biotech (NASDAQ: FBIO) Company, reported that two abstracts pertaining to its MB-101 (IL13Rα2-specific CAR-T cells) product candidate in development were selected for presentation at the upcoming American Society of Gene and Cell Therapy 19th Annual Meeting (ASGCT) (Free ASGCT Whitepaper), to be held May 4-7, 2016, at the Marriott Wardman Park Hotel in Washington, DC (Filing, 8-K, Fortress Biotech, APR 18, 2016, View Source [SID:1234510996]).

Pre-clinical Oral Presentation:
· Title: Optimization of IL13Rα2-specific CAR T cells for Clinical Development Using Orthotopic Human Glioblastoma Models in NSG Mice
o Abstract Number: 275
o Session: Oral Abstract Session 243 – Cancer-Immunotherapy, Cancer Vaccines I
o Date and Time: Thursday, May 5, 2016; 4:00 – 5:45 PM ET
o Location: Marriott Wardman Park Hotel, Washington 4
o Presenter: Dr. Christine Brown, Associate Director, T cell Therapeutics Research Laboratory at the City of Hope Medical Center ("COH")

Clinical Oral Presentation:
· Title: Phase I Study of Second Generation Chimeric Antigen Receptor–Engineered T cells Targeting IL13Rα2 for the Treatment of Glioblastoma
o Abstract Number: 247
o Session: Scientific Symposium 201 – Clinical Trials Spotlight
o Date and Time: Thursday, May 5, 2016; 8:00 AM – 10:00 AM ET
o Location: Marriott Wardman Park Hotel, Thurgood Marshall NE
o Presenter: Dr. Benham Badie, Vice Chair and Professor, Department of Surgery, Chief, Division of Neurosurgery, Director, Brain Tumor Program and Neurosurgeon at the City of Hope Medical Center ("COH")

Copies of the above referenced abstracts can be viewed online through the ASGCT (Free ASGCT Whitepaper) meeting website at View Source

About Glioblastoma multiforme (GBM)
Glioblastomas (GBM) are tumors that arise from astrocytes—the star-shaped cells that make up the supportive tissue of the brain. These tumors are usually highly malignant (cancerous) because the cells reproduce quickly and they are supported by a large network of blood vessels. GBM is the most common brain and central nervous system (CNS) malignancy, accounting for 15.1% of all primary brain tumors, and 55.1% of all gliomas. There are an estimated 12,120 new glioblastoma cases predicted in 2016 in the U.S. Malignant brain tumors are the most common cause of cancer-related deaths in adolescents and young adults aged 15-39 and the most common cancer occurring among 15-19 year olds in the U.S. (Brain Tumor Statistics. American Brain Tumor Association. December 2015). While GBM is a rare disease (2-3 cases per 100,000 person life years in the U.S. and E.U.), it is quite lethal with 5-year survival rates historically less than 10%. Chemotherapy with temozolomide and radiation are shown to extend mean survival from ~12 to ~15 months, while surgery remains the standard of care. GBM remains difficult to treat due to the inherent resistance of the tumor to conventional therapies. Treatment is further complicated by the susceptibility of the brain to damage, difficulty of the brain to repair itself and limitation to drugs crossing the blood brain barrier. Immunotherapy approaches targeting brain tumors offer promise over conventional treatments.

About MB-101 (IL13Rα2-specific CAR-T cells)
IL13Rα2 is an attractive target for CAR-T therapy as it has limited expression in normal tissue but is over-expressed on the surface of the majority of GBM. CAR-T cells designed to express a membrane-tethered IL-13 receptor ligand (IL-13) incorporating a single point mutation display high affinity for IL13Rα2 and reduced binding to IL13Rα1 in order to reduce healthy tissue targeting.

We are developing an optimized CAR-T product incorporating enhancements in CAR design and T-cell engineering to improve antitumor potency and T-cell persistence. We include a second generation hinge optimized CAR containing mutations in the IgG4 linker to reduce off target Fc interactions, as well as the 41BB (CD137) co-stimulatory signaling domain for improved survival and maintenance of memory T-cells, and extracellular domain of CD19 as a selection/safety marker. In order to further improve persistence, memory T-cells are enriched and genetically engineered using a manufacturing process that limits ex vivo expansion in order to reduce T-cell exhaustion and maintain a memory T-cell phenotype.

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