On April 5, 2017 Heat Biologics, Inc. (Nasdaq:HTBX), a leader in the development of immunotherapies designed to activate a patient’s immune system against cancer, reported that it presented new preclinical data from its collaboration with OncoSec Medical Incorporated (Nasdaq:ONCS), focused on evaluating the combination of Heat’s immunotherapy platforms with intratumoral electroporation (EP), at the AACR (Free AACR Whitepaper) Annual Meeting (Press release, Heat Biologics, APR 5, 2017, View Source [SID1234518484]). In the poster entitled "Combined Intratumoral Electroporation and Allogenic Vaccination of Gp96-Ig/Fc-OX40L Stimulates CD8+ T cell Cross Priming to Tumor-Specific Neoantigens and Enhances Anti-Tumor Response," (abstract #5617) researchers combined EP of ComPACT DNA (expressing Gp96-Ig and FC-OX40L) directly into a tumor, with cell-based ComPACT vaccination, to explore the effects of an intratumoral plus vaccination approach in a preclinical mouse model of melanoma. Results confirmed that this combination approach led to increased antigen-specific CD8+ T cells, enhanced anti-tumor response and improved overall survival compared to individual treatments.

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"This proof-of-principal study shows there may be benefit in combining our vaccines with an intratumoral approach to deliver the vaccine directly into the tumor to increase the coverage of tumor-specific shared- and neo-antigen presentation," said Jeff Hutchins, Ph.D., Heat’s Chief Scientific Officer and Senior Vice President of Preclinical Development. "It opens up the possibility of pairing our ImPACT and ComPACT platform technologies with intratumoral approaches, which aligns with our strategy to advance new, synergistic immuno-oncology combinations to improve patient outcomes."

A copy of the abstract is available and can be viewed online through the AACR (Free AACR Whitepaper) website at www.aacr.org. The poster will be made available in the Publications section of Heat’s corporate website

About Heat Biologics, Inc.
Heat Biologics, Inc. (Nasdaq:HTBX) is an immuno-oncology company developing novel therapies that are designed to activate a patient’s immune system against cancer utilizing an engineered form of gp96, a protein that robustly activates the immune system. Heat’s highly specific T cell-stimulating therapeutic vaccine platform technologies, ImPACT and ComPACT, in combination with other therapies, such as checkpoint inhibitors, are designed to address three distinct but synergistic mechanisms of action: robust activation of CD8+ "killer" T cells (one of the human immune system’s most potent weapons against cancer); reversal of tumor-induced immune suppression; and T cell co-stimulation to further enhance patients’ immune response. Currently, Heat is conducting a Phase 2 trial with HS-110 (viagenpumatucel-L) in combination with an anti-PD-1 checkpoint inhibitor to treat patients with non-small cell lung cancer (NSCLC) and a Phase 2 trial with HS-410 (vesigenurtacel-L) in patients with non-muscle invasive bladder cancer (NMIBC).

Heat’s wholly-owned subsidiary, Zolovax, Inc., is developing therapeutic and preventative vaccines to treat infectious diseases based on Heat’s gp96 vaccine technology, with a current focus on the development of a Zika vaccine in conjunction with the University of Miami.

For more information, please visit www.heatbio.com.

On April 5, 2017 Geron Corporation (Nasdaq:GERN) reported a poster presentation by Janssen Research & Development, LLC describing non-clinical data on the telomerase inhibitor imetelstat at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in Washington, D.C. from April 1-5, 2017 (Press release, Geron, APR 5, 2017, View Source [SID1234518483]). The poster presentation is available on Geron’s website at www.geron.com/presentations.

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"These data from preclinical studies presented at AACR (Free AACR Whitepaper) this year provide further insight into the mechanisms by which inhibiting telomerase with imetelstat may impact cancer cells," said John A. Scarlett, M.D., Geron’s President and Chief Executive Officer. "These studies also build on previously published reports that suggest the potential application of imetelstat in the treatment of multiple hematologic myeloid malignancies, including acute myeloid leukemia, and reflect the ongoing work by our colleagues at Janssen to advance the imetelstat program for patients in need of new therapies."

Poster Presentation

Title: Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia (Abstract #1101)

Prior research by others has shown that telomerase and BCL-2 are overexpressed in acute myeloid leukemia (AML) cells and are involved in blocking apoptotic signals. Therefore, Janssen designed preclinical studies to test whether inhibiting telomerase expression and/or activity and BCL-2 could enhance cell killing and result in a greater anti-tumor effect in AML through the combined administration of imetelstat and venetoclax, a selective BCL-2 inhibitor, as compared to either treatment alone.

Janssen presented data of imetelstat’s activity in combination with venetoclax in AML cell lines, patient samples and a mouse xenograft model. In AML cell lines, telomerase expression and activity were decreased by imetelstat and further reduced in combination with venetoclax. In addition, imetelstat enhanced apoptosis induced by venetoclax in AML cell lines and AML patient samples. Combining imetelstat with venetoclax in an AML mouse model prolonged survival, with four of ten mice alive approximately 80 days after treatment was stopped.

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting malignant progenitor cell clones associated with hematologic malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies include fatigue, gastrointestinal symptoms and cytopenias. Patients in these studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients followed after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc., to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. All regulatory, development, manufacturing and promotional activities related to imetelstat are being managed through a joint governance structure, with Janssen responsible for these activities.

On April 5, 2017 Endocyte, Inc. (NASDAQ:ECYT), a leader in developing targeted small molecule drug conjugates (SMDCs) and companion imaging agents for personalized therapy, reported in a late-breaking poster session the presentation of new research from investigators and faculty at the Purdue University Center for Drug Discovery on the application of Endocyte’s SMDC technology in a chimeric antigen receptor (CAR) therapy setting (Poster #LB-187 – New Methods for Controlling CAR T Cell-mediated Cytokine Storms) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington D.C (Press release, Endocyte, APR 5, 2017, View Source [SID1234518482]).

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"The significant potential of CAR T-cell therapies has been limited by an inability to control the rate and degree of cytokine release, which can cause severe safety issues in patients. The data presented demonstrate approaches that may successfully mitigate these cytokine storms and highlight how Endocyte’s bi-specific SMDC adaptors can potentially improve the safety and tolerability profiles of current CAR T-cell therapies," said Mike Sherman, president and CEO at Endocyte. "This is just one example of how we are continuing to advance our next-generation CAR T-cell therapeutic platform, now also in collaboration with leading experts in the field at Seattle Children’s Research Institute."

This presentation discusses methods in which Endocyte’s bi-specific SMDC adaptors can control the rate and extent of CAR T-cell activation, by using a bispecific adaptor molecule to mediate engagement of the CAR T-cell with the cancer cell. Endocyte’s unique bispecific adaptors are constructed with a fluorescein isothiocyanate (FITC) molecule and a tumor-homing molecule to precisely bridge a universal CAR T-cell with the cancer cells, which causes localized T-cell activation. This approach enables a universal CAR T-cell to bind and kill a cancer cell only when the bispecific adaptor establishes a bridge between the two. The poster explores several novel strategies for regulating cytokine storms, including: 1) interruption of bi-specific adaptor administration, 2) injection of excess folate to block/compete bi-specific adaptor bridging of the CAR T-cell to the cancer cell, 3) use of a very low or very high dose of the bi-specific adaptor and 4) gradual escalation of bi-specific adaptor dose. Since the circulation half-life of most bi-specific adaptors is approximately 30 minutes, unwanted toxicity from CAR T-cell induced cytokine storms can be either pre-emptively prevented or rapidly suppressed following their emergence. Data in this poster demonstrate in pre-clinical models that all of the above strategies mitigate or eliminate cytokine storms.

"We are very pleased with the results of these studies, as they confirm our hypothesis that the use of bi-specific SMDC adaptors can offer a next-generation approach to CAR T-cell therapy. We look forward to continuing our research, including exploring the ability of this approach to more completely target cells in heterogeneous solid tumors," said Phil Low, Ph.D., professor of chemistry and director of the Center for Drug Discovery at Purdue University. Dr. Low is the chief scientific officer, a board member and founder of Endocyte.

Endocyte and Purdue University have exclusive agreements to research, develop and commercialize SMDC therapeutics and companion imaging agents for the treatment of disease through a long-standing partnership with Dr. Low and Purdue University. Those agreements grant Endocyte exclusive rights to the CAR T-cell and SMDC adaptors for all indications. This technology is jointly-owned by Endocyte and Purdue, and covered by pending patent applications.

About Endocyte’s SMDC Bi-Specific Adaptors

Endocyte’s SMDC bi-specific adaptors represent a novel approach that makes possible the engineering of a single universal CAR T-cell, designed to bind with high affinity to FITC. This universal CAR T-cell can be specifically directed to cancer cells through the administration of a tumor targeted FITC-containing SMDC, known as a bi-specific adaptor that acts to bridge the universal CAR T-cell with the cancer cells to cause localized T-cell activation. This approach has been shown pre-clinically to address three key CAR T-cell issues by: (i) avoiding hyper-activation of CAR T-cells leading to a cytokine storm, (ii) enabling termination of CAR T-cell activity upon eradication of the tumor, and (iii) potentially enabling elimination of all cancer cells in heterogeneous solid tumors. In March 2017, Endocyte entered into a research collaboration with Seattle Children’s Research Institute and Dr. Michael Jensen for the development of Endocyte’s SMDC platform in CAR T-cell immunotherapy setting through the use of Endocyte’s proprietary SMDC bi-specific adaptor molecules.

On April 5, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that it has presented three abstracts at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, DelMar Pharmaceuticals, APR 5, 2017, View Source [SID1234518481]). These abstracts are all focused on pre-clinical research to elucidate the mechanism of action (MOA) of DelMar Pharmaceuticals’ lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol), a "first-in-class" small-molecule, DNA-targeting, chemotherapeutic agent.

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The AACR (Free AACR Whitepaper) Annual Meeting is currently ongoing (April 1-5, 2017) in Washington, D.C.

Details of the poster presentations by DelMar and its collaborators from the MD Anderson Cancer Center and the University of British Columbia/BC Prostate Center are as follows:

Abstract #1429 – DNA damage response to dianhydrogalactitol (VAL-083) in p53-deficient non-small cell lung cancer (NSCLC) cells

Chemo-refractory NSCLC cells often demonstrate platinum resistance due to the presence of p53 mutations in these cells. Subsequently, such NSCLC tumors are also rendered resistant to tyrosine kinase inhibitors (TKIs) due to the accumulation of new mutations like T790M and KRAS. In this poster, the activity of VAL-083 is assessed in 11 different NSCLC cell lines. Using cytotoxicity assays (IC50), VAL-083 was found to be active in all 11 cell lines irrespective of p53, KRAS and EGFR status. Furthermore, VAL-083 is active in cells with T790M and KRAS mutations indicating that this agent can overcome TKI-resistance. This poster demonstrates that VAL-083 has a differentiated MOA with a dual signaling pathway (p53 dependent and p53 independent signaling) to cause permanent DNA damage in NSCLC cell lines.

These preclinical results provide the scientific rationale for further assessment of VAL-083 in NSCLC in human clinical trials.

Abstract #2483 – Molecular mechanisms of dianhydrogalactitol (VAL-083) in overcoming chemoresistance in glioblastoma

Glioblastoma multiforme (GBM) is the most common but perhaps the most abysmal CNS tumor with a 5-year survival of ~3%. This poor prognosis is attributable to chemoresistance to the current standard front-line chemotherapy—Temodar (TMZ). The activity of the enzyme O6-methyl guanine methyl transferase (MGMT) protects cancer cells against the activity of TMZ, rendering the GBM cells chemo-resistant to this front-line agent.

In this poster, the authors elucidate the unique MOA of VAL-083 which is a new small molecule, DNA-targeting agent that unlike TMZ is not inhibited by MGMT. By permanently damaging the tumor cell’s DNA resulting in cell-cycle arrest in the G2/S phase, VAL-083 may have synergistic activity with S-phase specific drugs like topoisomerase inhibitors and PARP inhibitors.

Further, the authors support this theory by demonstrating the synergistic activity of VAL-083 with topoisomerase I/II inhibitors camptothecin and etoposide.

Abstract CT#054 – Phase II study of dianhydrogalactitol in patients with MGMT-unmethylated bevacizumab-naive recurrent glioblastoma

This abstract builds on the preclinical observations from Abstract#2483 which showed that compared to TMZ, the tumor cell DNA-damaging activity of VAL-083 is not lost in MGMT expressing GBM tumors. The authors also cite a previously completed VAL-083 Phase I/II study (ASCO 2016) where a meaningful overall survival (OS) of 8.35 months was demonstrated in 22, third-line GBM patients following failure of both TMZ and bevacizumab (Avastin).

Given that VAL-083’s activity is not lost even in MGMT-unmethylated GBM tumors, the authors provide a rationale to conduct a clinical trial of this novel agent as a second line therapy after TMZ failure, and not just as a third line therapy after TMZ and bevacizumab. The authors delineate the design of an ongoing, Phase 2, single arm, biomarker driven, MGMT unmethylated, clinical trial of VAL-083 in 48 GBM patients after their first recurrence, post radio-chemotherapy with TMZ.

Should the set efficacy benchmark be met in this trial, VAL-083 will be positioned to change the treatment paradigm in GBM by emphasizing biomarker testing for MGMT and the use of VAL-083 (perhaps even in lieu of TMZ) in all MGMT-unmethylated GBM patients.

The Company’s presentations from the 2017 AACR (Free AACR Whitepaper) Annual Meeting can be viewed via the scientific-publications page on DelMar’s website.

About VAL-083

VAL-083 is a "first-in-class," small-molecule DNA-targeting agent that demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institute. DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details can be found at www.delmarpharma.com/scientific-publications.html.

VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas, and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.

DelMar has also announced plans to advance VAL-083 into a pivotal randomized multi-center Phase 3 clinical trial for the treatment of bevacizumab-failed GBM. A separate Phase 2 trial for MGMT-unmethylated recurrent GBM is currently open for enrollment at the University of Texas MD Anderson Cancer Center and an international trial for newly diagnosed MGMT-unmethylated GBM is expected to commence enrollment upon receipt of required government approval.

DelMar believes that data from its clinical trials, if successful, will form the basis of a new treatment paradigm for the vast majority of GBM patients whose tumors exhibit features that make them unlikely to respond to currently available therapies.

On April 5, 2017 Cascadian Therapeutics, Inc. (NASDAQ:CASC), a clinical-stage biopharmaceutical company, reported data highlights from presentations of preclinical data for the Company’s investigational orally bioavailable, potent and selective checkpoint kinase 1 (Chk1) inhibitor known as CASC-578 (Press release, Cascadian Therapeutics, APR 5, 2017, View Source [SID1234518480]). An additional abstract highlights data from the first public presentation on the Company’s preclinical antibody program targeting the immune checkpoint receptor TIGIT. These data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington, DC from April 1-5, 2017.

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"The research presented at AACR (Free AACR Whitepaper) illustrates why we believe CASC-578 is well positioned for IND-enabling studies," said Scott Peterson, Ph.D., Chief Scientific Officer of Cascadian Therapeutics. "CASC-578 has demonstrated anti-tumor activity as a single agent or in combination with a Wee1 inhibitor in preclinical models of acute leukemia, mantle cell lymphoma and non-small cell lung cancer. Furthermore, a recent GLP safety pharmacology study indicated CASC-578 has an acceptable safety profile with no apparent effects on QTc interval or cardiac contractility."

Dr. Peterson added, "Our TIGIT antibody program presentation profiles the discovery of highly potent, fully human TIGIT antibodies, which are active as a single agent in a mouse tumor model that is resistant to PD-1 antibody blockade."

A summary of data highlights presented at AACR (Free AACR Whitepaper) follows. To access these poster presentations, please visit www.cascadianrx.com.

CASC-578, a novel Chk1 inhibitor, is active as a single agent in solid tumors and displays synergistic anti-tumor activity in combination with Wee1 inhibition (Abstract #295)

CASC-578 is a highly selective, picomolar inhibitor of Chk1 that is active as a single agent and in combination with chemotherapeutic agents in a variety of solid tumor and hematological tumor derived cell lines. Chk1 is a protein kinase that regulates cell cycle progression in response to DNA damage response (DDR) signaling.

CASC-578 is active as a single agent in non-small cell lung cancer (NSCLC) tumor models and has shown enhanced activity with Wee1 inhibitor in vitro and in NSCLC tumor xenograft.
The novel orally available sub-nanomolar potent and selective checkpoint kinase 1 inhibitor CASC-578 is highly active in mantle cell lymphoma as a single agent and in combination with Wee1 inhibition (Abstract #297)

Targeting the DNA Damage Response (DDR) axis with CASC-578, alone or in combination with Wee-1 inhibition, presents a promising therapeutic approach to treating mantle cell lymphoma and other hematological cancers.
CASC-478 showed compelling single agent activity on mantle cell lymphoma cell lines — both in vitro and in vivo, including complete tumor regression in a Jeko-1 xenograft model.
Preclinical pharmacokinetics of CASC-578, a novel selective potent and orally bioavailable small molecule checkpoint kinase 1 inhibitor (Abstract #4090)

CASC-578 has desirable drug-like properties, including good oral availability and ADME/PK properties, sub-nanomolar Chk1 inhibition, limited off-target kinase activity (>1000x selective vs. Chk2) and balanced pharmacokinetics, potency and in vivo efficacy.
Discovery and characterization of novel antagonistic antibodies that bind with high affinity to human, cynomolgus and murine TIGIT, an immune checkpoint receptor (Abstract #578)

TIGIT is an emerging immune checkpoint target that regulates the induction of adaptive (T cell) and innate (natural killer or NK) cells. CASC-TIGIT antibodies represent a potentially attractive approach to immune checkpoint inhibition.

Novel, high-affinity, fully human antibodies have been identified that block TIGIT function.
Lead antibody binds with sub-nM affinity to human, cynomolgus monkey and mouse TIGIT and blocks ligand interactions and signaling in T cells
Potent single-agent activity in mouse model that is resistant to PD-1 antibody.