The FDA designates Ziopharm Oncology's (ZIOP +4.2%) gene therapy candidate, Ad-RTS-hIL-12, an Orphan Drug for the treatment of malignant glioma, a brain tumor that originates in the brain or spine. Gliomas represent 30% of all brain and CNS tumors and 80% of brain tumors.
Ziopharm (NASDAQ:ZIOP) has presented clinical and pre-clinical data for its Ad-RTS-IL-12 gene therapy candidate at a a cancer immunotherapy conference taking place in NYC from Sep. 16-19.One presentation, titled "Demonstration of Systemic Antitumor Immunity via Intratumoral Regulated Expression of IL-12 in Advanced Breast Cancer and Melanoma Patients," is said to highlight "additional evidence of systemic immune activation with AD-RTS-hIL-12 and veledimex in advanced melanoma and breast cancer patients."Another presentation, titled "Demonstration of Systemic Antitumor Immunity via Intratumoral Regulated Expression of IL-12 as a Gene Therapy Approach to Treatment of Cancer," is said to demonstrate "the anti-tumor effects and tolerability of Ad-RTS-mIL-12 in murine models of glioblastoma (brain cancer), colon cancer and melanoma."Shares are up 1.5% after hours to $12.78, after rising 5.7% in regular trading.
ZIOPHARM Announces Presentation of Data From CD19-Specific CAR+ T-Cell Therapy Programs at ASH Annual Meeting Mon December 7, 2015 5:15 PM|GlobeNewswire | About: ZIOP Results demonstrate survival benefit in long-term follow-up infusing autologous genetically modified T cells after HSCT
Results demonstrate survival benefit in follow-up infusing donor-derived genetically modified T cells after allogeneic HSCT, including haploidentical HSCT
BOSTON, Dec. 7, 2015 (GLOBE NEWSWIRE) -- ZIOPHARM Oncology, Inc. (ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, today announced that results from its CD19-specific CAR T-cell therapy programs were presented at the 57thAmerican Society of Hematology (ASH) Annual Meeting in Orlando, Florida. The presentation (Abstract 862), titled "Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies" was presented by lead author Partow Kebriaei, M.D., Associate Professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an oral session, and is available at www.ziopharm.com. The investigational therapies infusing T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR), described in the presentation, were exclusively licensed to ZIOPHARM and its collaboration partner, Intrexon Corporation (NYSE:XON), through an agreement with MD Anderson.
"This study, which was initially designed to test the safety and tolerability of the Sleeping Beauty platform, a system for the non-viral genetic modification of cells, appears to show a survival benefit with a doubling of overall survival compared to historical controls," said Dr. Richard Champlin, Chair, Department of Stem Cell Transplantation and Cellular Therapy at MD Anderson. "This is the measure of clinical success for a post-transplant therapy, where the contribution of either treatment is difficult to discern in early follow-up. Also promising was the absence of GvHD among HLA-mismatched CAR+ T-cell recipients, even at large doses, which supports infusing third-party T cells."
In the two separate trials described in Dr. Kebriaei's presentation, patient-derived (autologous) or donor-derived (allogeneic) CAR-modified T cells targeting CD19 were administered to recipients with advanced CD19+ malignancies after hematopoietic stem-cell transplantation (HSCT). The studies employed the Sleeping Beauty system, a cost-effective non-viral two plasmid electroporation method to stably express CAR in T cells.
Seven patients with advanced non-Hodgkin lymphoma (NHL) were treated with autologous cells, all of whom remained alive and six of whom remained in complete remission at a median 25.5 months of follow-up translating to a three-year progression free survival (PFS) of 83% and a three-year overall survival (OS) of 100%.
Nineteen patients with advanced acute lymphoblastic leukemia and NHL were treated with allogeneic T cells. One-year PFS among these patients was 53% and one-year OS was 63%. Among eight patients who received donor-derived T cells after haploidentical HSCT, all remained alive and six remained in complete remission after a median of 5.2 months of follow up, translating to a one-year PFS of 75% and OS of 100%.
No infusion related or late toxicity was observed in any recipients. A mild elevation in cytokines was observed, without cytokine storm. Autologous and allogeneic cells survived an average of 201 and 51 days, respectively.
A graft-versus-host disease (GvHD) rate of 11% was observed among recipients receiving donor-derived CAR+ T cells which did not differ from controls. Because of this low rate of GvHD, a complication associated with allogeneic HSCT, administration of up to 108/m2 genetically modified haploidentical T cells was possible. This lays the groundwork for infusing HLA-mismatched CAR+ T cells as an off-the-shelf broadly-accessible therapeutic.
"Sleeping Beauty, which is among the fastest technologies to go from bench to bedside, was a critical innovation of this trial," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "In addition to demonstrating safety and durable responses, it provides us a pathway for testing new CARs, co-expressing CAR with other molecules, and to do so at relatively low cost in the setting of both patient-derived and third-party derived products. We look forward to the new trial initiated at MD Anderson using Sleeping Beauty-modified T cells expressing a next-generation CD19-specific CAR in active CD19+ lymphoid malignancies."
Results from the haploidentical population were also presented separately in an oral presentation, titled "Donor-derived CD19-specific CAR+ T-cell therapy after haploidentical hematopoietic stem-cell transplantation," by Dr. Cooper, at the Haplo2015 Symposium, December 3, 2015, in Orlando, Florida. The presentation is available at www.ziopharm.com
Ziopharm has four presentations scheduled for the American Society of Hematology annual meeting that will be held December 3 - 6. Herein we discuss the technological progress and its significance. The Company has shown the Sleeping Beauty transposon system can very rapidly produce CAR T cells by avoiding the need for T cell activation and prolonged ex vivo tissue culture. The technology described will support the manufacture and delivery of CAR T cells at multiple points of care. Indeed, this technological breakthrough is central to the creation of personalized immunotherapies at the point of care and it should obviate the need for a central manufacturing facility and minimize production costs. A high-throughput platform has been created to identify tumor-specific TCRs for personalized cancer therapies. This was accomplished using next generation sequencing to identify TCR genes of interest and a cell reporter system to assess the specificity and affinity of the related TCRs for the antigen of choice. The success here will figure importantly creating personalized TCR-T cells at the point of care. A CAR that mimics a TCR offers an alternative approach to targeting cytoplasmic antigens. Ziopharm demonstrated an ability to use a Sleeping Beauty transposon to create a CAR T cell that recognizes a cytoplasmic antigen presented by the HLA system. This approach offers an alternative to a TCR T cell. A Sleeping Beauty transposon was also used to create a complementary cell, specifically an antigen presenting T cell with membrane-bound IL-15. This cell enhanced the persistence and activity of the aforementioned CAR T cell. The technique was demonstrated with a multiple myeloma therapy tested in a preclinical model. CD33-CAR T cells greatly extend survival in an AML preclinical model. This is a proof-of-concept experiment that sets the stage for the CD33-CAR T cell therapy to enter clinical development in the near future. We are impressed with Ziopharm¡¯s innovations and we look forward to the related presentations at ASH and to learning its IL-12 clinical results at the Society for Neuro-Oncology meeting on November 17 - 20. We are affirming our BUY recommendation and $21 price target. INVESTOR CONSIDERATIONS We believe Ziopharm has already laid the groundwork for the development of numerous immunotherapies in collaboration with Intrexon Corporation. A presentation on its interleukin-12 (IL-12) gene therapy for glioblastoma should set the stage for a pivotal trial in 2017. And the abstracts for the American Society for Hematology meeting indicate that the Company has made major advances toward its goal of creating personalized immunotherapies at the point of care. In addition, it has offered two sets of preclinical proof-of-concept data related to myeloid malignancies. One was a used to illustrate how a CAR may be used to target cytoplasmic proteins and the other was intended specifically to support clinical development of its CD33-CAR T cell therapy for acute myeloid leukemia. But then, the Company has several other clinical programs that include off-the-shelf NK cells and combination therapies set to commence, as shown in its R&D pipeline chart.
Overall, we think Ziopharm has an exciting mix of therapies to compete in the emerging immune-oncology market. Moreover, its focus on point-of-care production will limit its capital investments and yield cost savings in the preparation and delivery of the therapies. We are maintaining our BUY recommendation on ZIOP shares and our $21 price target. A REVIEW OF ASH ABSTRACTS Ziopharm has four abstracts for presentations at the American Society of Hematology conference that will be held December 3 - 7. While all of them are highly innovative, we consider two of particular importance because they demonstrate techniques that will underpin the creation of CAR- and TCR-T cells at the point of care. The Sleeping Beauty transposon system figures importantly in both procedures. A METHOD TO RAPIDLY PRODUCE CAR-T CELLS The new approach to rapidly producing CAR-T cells avoids the need for T-cell activation before or after gene transfer. Accordingly, the duration of the ex vivo tissue culture is minimized and the memory and sustained persistence of CAR+ T cells is preserved. This shortened culture is the cornerstone in the Company¡¯s point-of-care strategy. The experiment that was used to demonstrate this technique involved two modifications: One caused the expression of membrane-bound interleukin-15, which is known to significantly enhance in vivo T cell persistence, and the other added a CD19-CAR to the T cell. These modifications were accomplished via two Sleeping Beauty transposons. The therapeutic cells were tested in immunodeficient mice with an established CD19+ leukemia. The T cell therapy was cultured for only two days before 7.5 x 105 CAR+ T cells or an equivalent dose of CARneg T cells were infused. As illustrated in Figure 1, the results clearly show a potent anti-tumor effect of the CAR+ T cells even at a much lower dose of cells than is customary A HIGH-THROUGHPUT PLATFORM TO IDENTIFY TUMOR-SPECIFIC T CELL RECEPTORS Ziopharm has created a streamlined process to identify and characterize T cell receptors (TCRs) based on their specificity and avidity to a selected antigen. This system, which is able to generate neoantigen-specific TCRs, will be employed to produce TCR-T cell therapies for solid tumors. Proof-of-concept studies were conducted with two well-defined antigens, NY-ESO-1 and a cytomegalovirus peptide. The process has two basic components, the use of next-generation sequencing to identify genes specifying T cell receptor chains A and B and a reporter cell to test the specificity of the receptors and their affinity for the target molecule. The sequencing focused on the complementary determining region 3, or CDR3, of the genome, which defines the binding region of the receptor's two chains. The sequenced CDR3 regions were then coded into DNA plasmids of the Sleeping Beauty transposons and incorporated into reporter cells that expressed the TCRs. The reporter cells were also imparted with the ability to produce a green fluorescent marker protein in proportion to the affinity of the TCR for the target molecule. Thus, the system permits a rapid analysis of hundreds of antigen-specific TCRs for their binding properties. The abstract of the presentation includes an example of the results comparing a wild-type TCR against the one selected and produced via the high-throughput platform targeting the tumor antigen NY-ESO-1. As shown in Figure 2, the selected TCR (Mut TCR) shows a significantly stronger response to the antigen than the wild type (Wt TCR) in reporter cells.
ENHANCING CAR T-CELL EFFICACY WITH A T-CELL VACCINE Ziopharm examined the effect of combining two types of T cells, one that was modified to serve as an antigen presenting cell and the other that was an effector T cell expressing a CAR mimicking a TCR. This approach offers an alternative to developing a TCR against an intracellular tumor antigen. The antigen chosen for this proof-ofconcept study was NY-ESO-1, which is a normal testis protein that is aberrantly expressed in the cytoplasm by some cancers, including myeloid malignancies. The antigen presenting cells were created by transferring DNA plasmids from the Sleeping Beauty system coding for the NY-ESO-1 antigen and membrane-bound interleukin-15 to T cells. The CAR was designed to function as a mimetic of a TCR to recognize NY-ESO-1 presented by the appropriate HLA system. The NY-ESO-1-specific CAR T cells were tested alone and in combination with the antigen-presenting T cells in a mouse model of multiple myeloma. Though the abstract does not include the actual data, the conclusion was that the NY-ESO-1-specific CAR T cells were effective against the disease when compared against control T cells (i.e., CD19-CAR T cells). However, the combination of the two experimental cells exhibited an improved anti-tumor effect that was attributed to better persistence of the NY-ESO-1-specific CAR T cells. Thus, Ziopharm has created an alternative approach to a TCR that successfully targets an intracellular antigen expressed by the HLA system. CD33-CAR T CELLS FOR ACUTE MYELOID LEUKEMIA One of the clinical trials that is scheduled to commence in the near future is a CD33-CAR T cell therapy for acute myeloid leukemia (AML). A presentation at ASH provides preclinical proof-of-concept data on this therapy. As shown in Figure 3, the CD33 targeted T cells improved the survival of immunocompromised mice bearing established CD33+(CD19neg) AML cells compared against mice that received either saline or two control CAR T cells (i.e., untransduced T cells and CD19-CAR T cells). The CD33-CAR T cells also included a "kill switch" comprised of an epidermal growth factor receptor that could be activated with cetuximab to protect against any serious on-target-off-malignancy toxicities.
Under: Been on the sidelines for a bit holding (building) cash. Now that "BIGLEY" has rolled out the tax plan its time to jump in.
Dec 21, 2017 19:06:02 GMT -6
martyc: Looks like you are buying Msft again!
Dec 15, 2017 11:23:29 GMT -6
martyc: The news that Trump called Rupert to congratulate him sure seems to indicate that this is heading to approval
Dec 15, 2017 11:22:23 GMT -6
Under: DIS finally getting some traction.?
Dec 14, 2017 17:08:45 GMT -6
martyc: I took an entry level position in DIS. Will add eventually to overweight when it becomes clearer that the deal will go thru. Can't believe how well positioned they will be. 60% Hulu. 20% of content watched on NFLX they can pull. More in thread
Dec 14, 2017 11:05:16 GMT -6
Under: Great posts on $DIS
Dec 13, 2017 17:50:49 GMT -6
Under: $ROKU Citron on a war path.
Nov 28, 2017 15:11:20 GMT -6
Under: $HAS takeover bid for $MAT?
Nov 10, 2017 16:16:07 GMT -6
martyc: Not looking like the market will provide any discounted opp for SGMO. Call was just too professional and all signs indicate they are on a great path for commercialization. Happy with core but wish I had some trading shs
Nov 10, 2017 9:04:05 GMT -6
martyc: For anyone looking to find an entry point into SGMO, I'm almost hoping is sells off in next few days so I can add more. They are really clicking but the fact they haven't signed new deals might cause some to exit. Watching as I have room for trading shs
Nov 9, 2017 18:28:09 GMT -6
martyc: Been an interesting ride so far. I figured the Bears would be about this good but hoped the O wouldn't look so lame. Another building yr but still possible to get to 8-8 IMO
Nov 9, 2017 18:26:08 GMT -6
Under: whats up with your Bears this year Marty?
Nov 9, 2017 17:35:25 GMT -6
martyc: Hope you were long ROKU. I wanted to see Q first so missed out
Nov 9, 2017 7:08:53 GMT -6