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.