On April 18, 2016 Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, reported that data from several ZFP Therapeutic programs will be presented at the 19th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) to be held in Washington, D.C. from May 4-7, 2016 (Press release, Sangamo BioSciences, APR 18, 2016, View Source [SID:1234511044]).

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Sangamo BioSciences, Inc. (PRNewsFoto/Sangamo BioSciences, Inc.)
Eight oral and seven poster presentations will be given by Sangamo scientists and their academic collaborators. These presentations will detail data from Sangamo’s therapeutic and research programs and will focus on lysosomal storage disorders and other monogenic diseases, hemoglobinopathies, HIV/AIDS, cancer immunotherapy and advancements in technology, including improvements in modification efficiency. In addition, Sangamo scientists have been invited to present in two scientific symposia focused on clinical applications of genome editing and gene and cell therapeutics targeting the liver.

"The data to be presented at this year’s ASGCT (Free ASGCT Whitepaper) Annual Meeting from our therapeutic and research programs cover a wide range of applications and demonstrate the versatility of our zinc finger nuclease genome editing platform and the expertise of our research and development teams," said Edward Lanphier, Sangamo’s president and chief executive officer. "Sangamo continues to lead the clinical development of therapeutic genome editing and ASGCT (Free ASGCT Whitepaper) offers an opportunity for us to present the broad capabilities of our highly leverageable technology platform in multiple therapeutic areas."

The following presentations are scheduled at the ASGCT (Free ASGCT Whitepaper) Meeting sessions:

Invited Presentations at Scientific Symposia

Genome Editing in Primary Human Cells and Organs: Toward the Goal of Engineering Genetic Cures – Michael C. Holmes, Ph.D., Sangamo BioSciences
Special Symposium on Concepts and Clinical Applications of Genome Editing
Invited Talk – Wednesday, May 4, 2016

ZFN-Mediated Genome Editing in the Liver – Towards Correcting Hemophilias and Lysosomal Storage Diseases – Thomas Wechsler, Ph.D., Sangamo BioSciences
Scientific Symposium: Targeting the Liver with Gene and Cell Therapeutics
Invited Talk – Wednesday, May 4, 2016

Lysosomal Storage Disorders

In Vivo Zinc-Finger Nuclease Mediated Iduronate-2-Sulfatase (IDS) Target Gene Insertion and Correction of Metabolic Disease in a Mouse Model of Mucopolysaccharidosis Type II (MPS II) – Abstract #484
Session: Targeted Genome Editing: In Vivo Genome Editing
Oral Presentation – Friday, May 6, 2016

ZFN-Mediated Liver-Targeting Gene Therapy Corrects Systemic and Neurological Disease of Mucopolysaccharidosis Type I – Abstract #485
Session: Targeted Genome Editing: In Vivo Genome Editing
Oral Presentation – Friday, May 6, 2016
HIV/AIDS

CCR5 Gene Edited Hematopoietic Stem Cells Engraft in Diverse Anatomical Locales and Undergo SHIV-Dependent Positive Selection in Nonhuman Primates – Abstract #38
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

In Vivo Inhibition of HIV-1 in NSG Mice After Transduction of Primary Human T Cells with CXCR4 Conjugated to an HR2 Peptide – Abstract #427
Session: Immunological Aspects of Gene Therapy I
Poster Presentation – Thursday, May 5, 2016

Pre-Clinical Development and Qualification of ZFN-Mediated Disruption of CCR5 Gene Sequences in Human Hematopoietic Stem and Progenitor Cells – Abstract #734
Session: Targeted Genome Editing: Methods and Technology
Oral Presentation – Saturday, May 7, 2016
Hemoglobinopathies

Targeted Gene Addition in CD34+ Cells from Healthy Donors and Fanconi Anemia Patients – Abstract #558
Session: Targeted Genome Editing III
Poster Presentation – Friday, May 6, 2016
Cancer Immunotherapy

Single Chain TCR Gene Editing in Adoptive Cell Therapy for Multiple Myeloma – Abstract #752
Session: Cancer-Immunotherapy, Cancer Vaccines III
Oral Presentation – Saturday, May 7, 2016
Monogenic Diseases

Towards Clinical Translation of Hematopoietic Stem Cell Gene Editing for the Correction of SCID-X1 Mutations – Abstract #37
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

Correction of SCID-X1 by Targeted Genome Editing of Hematopoietic Stem/Progenitor Cells (HSPC) in the Mouse Model – Abstract #42
Session: Targeted Genome Editing: Gene Editing in Hematopoietic Cells
Oral Presentation – Wednesday, May 4, 2016

Technology Developments and other Applications

Highly Efficient Homology-Driven Genome Editing in Human T Cells with Combined Zinc-Finger Nuclease mRNA and AAV6 Donor Delivery and Improved Efficiency Under Serum-Free Conditions – Abstract #133
Session: Targeted Genome Editing I
Poster Presentation – Wednesday, May 4, 2016

Valproic Acid Treatment Enhances Hematopoietic Stem and Progenitor Cell Multipotency Ex Vivo for Enhanced Long-Term Engraftment of Gene-Modified Cells – Abstract #432
Session: Immunological Aspects of Gene Therapy I
Poster Presentation – Thursday, May 5, 2016

Highly Efficient, ZFN-Driven Knockout of Surface Expression of the T-Cell Receptor and HLA Class I Proteins in Human T-Cells for Enhancing Allogeneic Adoptive Cell Therapies – Abstract #641
Session: Cancer-Immunotherapy, Cancer Vaccines III
Poster Presentation – Friday, May 6, 2016

Enhanced FVIII AAV Vector Cassette Produces Improved Virus Yields and Supraphysiological FVIII Levels In Vivo – Abstract #684
Session: Hematologic & Immunologic Diseases II
Poster Presentation – Friday, May 6, 2016

Genome Editing of Inducible Cell Lines for Scalable Production of Improved Lentiviral Vectors for Human Gene Therapy – Abstract #286
Session: Vector and Cell Engineering/Manufacturing
Oral Presentation – Thursday, May 5, 2016

Characterization of Chromosomal Alterations Using a Zinc-Finger Nuclease Targeting Both the Beta- and Delta-Globin Gene Loci in Hematopoietic Stem/Progenitor cells – Abstract #118
Session: Targeted Genome Editing I
Poster Presentation – Wednesday, May 4, 2016

All abstracts for the ASGCT (Free ASGCT Whitepaper) meeting are available online at 2016 ASGCT (Free ASGCT Whitepaper) Annual Meeting Abstracts.

On April 18, 2016 Infinity Pharmaceuticals, Inc. (NASDAQ: INFI) reported new preclinical data for IPI-549, an orally administered immuno-oncology development candidate that selectively inhibits phosphoinositide-3-kinase gamma (PI3K-gamma) (Press release, Infinity Pharmaceuticals, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2157820 [SID:1234510975]). Preclinical data in multiple solid tumor models demonstrate that IPI-549 targets immune cells and alters the immune-suppressive microenvironment, promoting an anti-tumor immune response that leads to tumor growth inhibition. Data also demonstrate that IPI-549 enhances the effects of checkpoint inhibitors, resulting in improved survival in murine models. These data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana. A Phase 1 clinical study is under way to explore the safety and activity of IPI-549 both as a monotherapy and in combination with anti-PD-1 antibody therapy, a type of checkpoint inhibitor.

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"While advances in our understanding of the immune response to cancer have resulted in new therapies for patients, additional treatments are needed that can offer even more patients the chance for prolonged survival," stated Jedd Wolchok, M.D., Ph.D., chief of Melanoma and Immunotherapeutics Service, Lloyd J. Old/Ludwig Chair in Clinical Investigation Department of Medicine and Ludwig Center, at Memorial Sloan Kettering Cancer Center and lead investigator for the Phase 1 clinical study of IPI-549. "Emerging data from our collaboration with Infinity’s discovery team provide additional rationale for combining IPI-549 with checkpoint inhibitors, and I am pleased to be leading the Phase 1 study for this program."

Preclinical Data for IPI-549 Presented at the AACR (Free AACR Whitepaper) Annual Meeting 2016 (Abstract #554)
Infinity researchers, in collaboration with researchers at Memorial Sloan Kettering Cancer Center, presented preclinical data for IPI-549 in a poster entitled, "Checkpoint blockade therapy is improved by altering the immune suppressive microenvironment with IPI-549, a potent and selective inhibitor of PI3K-gamma, in preclinical models."

In preclinical models, treatment with IPI-549 leads to a decrease in tumor-associated immune suppressive myeloid cells. IPI-549 treatment also leads to a decrease in FOXP3 T-regulatory cells, which have immune-suppressive effects, and an increase in intratumoral CD8+ T-cells, which are known to play a role in inhibiting tumor growth. Taken together, these data suggest that through its effect on myeloid cells and T-cells, IPI-549 has the potential to disrupt the immune-suppressive microenvironment and enable a heightened anti-tumor immune response.

Preclinical data in murine models show that treatment with IPI-549 in combination with anti-CTLA4 or anti-PD-L1, two types of checkpoint inhibitors, results in greater tumor growth inhibition compared to monotherapy treatment. Additionally, IPI-549 in combination with anti-PD-1 increased the number of complete responses and improves survival. Re-implantation of tumor cell lines into mice that had achieved complete responses revealed low or no tumor engraftment, suggesting sustained tumor-specific immune protection.

These data provide additional preclinical rationale for the ongoing Phase 1 clinical study designed to explore the safety and activity of IPI-549 as a monotherapy and in combination with anti–PD-1 antibody therapy in patients with selected solid tumors, including non-small cell lung cancer and melanoma (ClinicalTrials.gov identifier NCT02637531).

Infinity is also developing duvelisib, an investigational, oral, dual inhibitor of PI3K-delta and PI3K-gamma. The PI3K pathway is also known to play a critical role in regulating the growth and survival of certain types of blood cancers. Duvelisib is being evaluated in registration-focused studies, including DYNAMOTM, a Phase 2 study in patients with refractory indolent non-Hodgkin lymphoma (iNHL), BRAVURA, a Phase 3 study in patients with relapsed iNHL, and DUOTM, a Phase 3 study in patients with relapsed/refractory chronic lymphocytic leukemia. For additional information about clinical studies of duvelisib, please visit www.infi.com or www.clinicaltrials.gov.

About IPI-549
IPI-549 is an orally administered immuno-oncology development candidate that selectively inhibits PI3K-gamma. In preclinical studies, IPI-549 inhibits immune-suppressive macrophages within the tumor microenvironment, whereas other immunotherapies such as checkpoint modulators more directly target immune effector cell function. As such, IPI-549 may have the potential to treat a broad range of solid tumors and represents a potentially complementary approach to restoring anti-tumor immunity in combination with other immunotherapies such as checkpoint inhibitors.

Duvelisib and IPI-549 are investigational compounds and their safety and efficacy have not been evaluated by the U.S. Food and Drug Administration or any other health authority.

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 Onxeo S.A. (Euronext Paris, Nasdaq Copenhagen: ONXEO), an innovative company specializing in the development of orphan oncology therapeutics, reported the final data from a study aiming to confirm the mechanism of action of Livatag, a doxorubicin loaded nanoparticle formulation based on Onxeo’s Transdrug technology in overcoming cellular resistance in hepatocellular carcinoma (HCC) (Press release, Onxeo, APR 18, 2016, View Source [SID:1234511024]). Livatag is currently being evaluated in a Phase III trial (ReLive) in patients with advanced HCC, or primary liver cancer.

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Results, presented today in a poster (Abstract #2143 / Poster #13) by Dr. Graham Dixon, PhD, Onxeo’s Chief Scientific Officer, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, demonstrated that the bio-distribution of doxorubicin Transdrug (Livatag) nanoparticles showed a preferential affinity for the liver and an increased exposure in plasma compared to free doxorubicin, together supporting the use of Livatag in the treatment of patients suffering from advanced HCC.

While evaluating the mechanism of action the study showed that the nanoparticle formulation of doxorubicin Transdrug (Livatag) entered into HCC cell lines via passive diffusion and avoided recognition by certain multi-drug resistance (MDR) proteins, (P glycoprotein 1, or Pgp) leading to major accumulation of the drug in the cells and a dramatic increase in cytotoxicity in HCC cell lines compared to free doxorubicin.

Further investigations will be performed to test if doxorubicin Transdrug (Livatag) also overcomes resistance induced by other MDR-related proteins expressed by HCC cells as well as the involvement of the Livatag nanoparticle "ion pair" in overcoming the efflux-mediated resistance.

Graham Dixon, PhD, Chief Scientific Officer of Onxeo, commented, "These are important findings as they confirm that the underlying mechanism of action of Livatag’s nanoformulation effectively accumulates doxorubicin specifically in the liver and evades tumor cell resistance mediated by multiple drug resistance MDR efflux pumps, enabling an efficacious and safe approach to cancer treatment. These results further support our ongoing Phase 3 ReLive study of Livatag for the treatment of patients with advanced HCC, for which we anticipate preliminary data readout mid-2017."

On April 18, 2016 Nektar Therapeutics (NASDAQ: NKTR) reported new preclinical data for the company’s investigational immuno-stimulatory cytokine therapy, NKTR-214, which demonstrate both its activity as a single-agent and its synergistic activity with checkpoint blockade (Press release, Nektar Therapeutics, APR 18, 2016, View Source [SID:1234510977]). In a TCR repertoire analysis conducted to assess both anti-tumor T cell clonality and T cell tumor infiltration (TIL clonality and infiltration), the combination of NKTR-214 and a checkpoint inhibitor resulted in dramatically higher increases for both parameters as compared to dual checkpoint inhibition. These data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA on April 17, 2016.

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TIL clonality establishes the frequency of T cells with a specific TCR Vβ and TCR Jβ chain usage at the tumor site, which suggests increased CD8-positive effector T cell function against the specific tumor.1 The concomitant presence of both TIL clonality and infiltration has been significantly correlated with clinical response and better survival outcomes in patients.1 In a CT26 colon carcinoma model, sequencing for TCRs in the tumor was conducted using Adaptive Biotechnologies’ ImmunoSEQ platform. Measurements of TIL clonality and infiltration were assessed seven days after treatment. NKTR-214 as a single-agent led to superior increases in TIL clonality and infiltration as compared to either anti-CTLA-4 or anti-PD-1 therapy alone. The combination of NKTR-214 with either mode of checkpoint inhibition led to superior increases in both TIL clonality and infiltration relative to the combination of CTLA-4 and PD-1 inhibitors. The highest increases occurred when NKTR-214 was added to an anti-PD-1 therapy.

"We are particularly excited by these new preclinical data for the combination of NKTR-214 with a checkpoint inhibitor which show an induced oligoclonal T cell response along with high TIL infiltration, "said Dr. Jonathan Zalevsky, Vice President of Biology at Nektar Therapeutics. "These data demonstrate that the addition of NKTR-214 to either an anti-CTLA-4 or anti-PD-1 agent could improve T cell clonality differences over checkpoint blockade therapies."

NKTR-214 is an investigational CD122-biased agonist currently in Phase 1/2 clinical development. NKTR-214 is designed to stimulate the patient’s own immune system to kill tumor cells by preferentially activating production of specific immune cells which promote tumor killing, including CD8-positive T cells and Natural Killer (NK) cells, within the tumor micro-environment. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these types of T cells.2

In studies conducted in multiple established tumor models presented at AACR (Free AACR Whitepaper), NKTR-214 demonstrated activity as both a single-agent and when co-dosed with either an anti-PD-1 agent or an anti-CTLA-4 agent. In a tumor re-challenge study conducted in an EMT6 colon carcinoma model, sequential dosing of anti-CTLA-4 followed by NKTR-214 resulted in durable immunity, with complete responders resisting a tumor re-challenge. Following a second re-challenge, 100% of the animals remained tumor-free without additional treatment.

"Our latest preclinical findings continue to show that treatment with NKTR-214 either as a single-agent or in combination with checkpoint blockade is superior to single or dual checkpoint inhibition in multiple models," added Steve Doberstein, PhD, Senior Vice President and Chief Scientific Officer of Nektar Therapeutics. "These new data emphasize the cellular mechanisms underlying the remarkable efficacy of NKTR-214 in our preclinical models of cancer."

The data presentation at AACR (Free AACR Whitepaper) entitled, "Durable antitumor activity of the CD122-biased immuno-stimulatory cytokine NKTR-214 combined with immune checkpoint blockade," can be accessed at View Source

In preclinical studies, NKTR-214 demonstrated a highly favorable mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells relative to regulatory T cells.3 Furthermore, the pro-drug design of NKTR-214 enables an antibody-like dosing regimen for an immuno-stimulatory cytokine.4

About the NKTR-214 Phase 1/2 Clinical Study

A Phase 1/2 clinical study is underway to evaluate NKTR-214 in patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer. The first stage of this study, which is expected to be complete in the second half of 2016, is evaluating escalating doses of single-agent NKTR-214 treatment in approximately 20 patients with solid tumors. The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214 and to identify a recommended Phase 2 dose. In addition, the study will also assess the immunologic effect of NKTR-214 on tumor-infiltrating lymphocytes (TILs) and other immune cells in both blood and tumor tissue, and it will also include TCR repertoire profiling. Dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.

The NKTR-214 clinical study is being conducted initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz. Patients and physicians interested in the ongoing NKTR-214 Study can visit the "Clinical Trials" section of www.mdanderson.org using identifier 2015-0573 or visit View Source