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Cyclacel’s Second-Generation CDK2/9 Inhibitor, CYC065, is an Effective Inducer of Cell Death in B-cell Lymphoma and Synergizes With Bcl-2 or BET Inhibitors

On April 18, 2016 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), reported the presentation of preclinical data demonstrating therapeutic potential of CYC065, the Company’s second-generation, cyclin-dependent kinase (CDK) 2/9 inhibitor, as a targeted anti-cancer agent (Press release, Cyclacel, APR 18, 2016, View Source [SID:1234510969]). The data show that CYC065 can induce cell death and combined beneficially with anti-cancer drugs from the Bcl-2 and BET inhibitor classes, in in vitro models of B-cell lymphoma, including double-hit lymphomas. The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016, April 16 – 20, 2016, in New Orleans.

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"CYC065 is currently in a Phase 1 clinical trial to evaluate its safety, pharmacokinetic and pharmacodynamic activity in patients with solid tumors and lymphomas," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "Data presented at AACR (Free AACR Whitepaper) highlights its potential as an agent to treat hematological malignancies, such as B-cell lymphoma. Data from this study are particularly important as they validate the mechanism of action of CYC065, which is reducing MYC and Mcl-1 levels, both of which can be elevated in B-cell lymphoma. The study also suggests that CYC065 may be used effectively in combination with other targeted anti-tumor agents in lymphomas. In parallel with collecting preclinical data, we continue to enroll patients in the Phase 1 trial and look forward to reporting initial results from the clinical study."

Double‐hit B-cell lymphomas, defined by concurrent MYC and BCL2 rearrangements, have poor prognosis compared to standard‐risk diffuse large B-cell lymphomas (DLBCL). There is a need for novel treatments specifically exploiting molecular features of the disease. DLBCL show frequent overexpression of Mcl‐1, 50% in ABC and 30% in GCB subtypes respectively. MYC‐driven lymphomas are highly sensitive to depletion of Mcl‐1. MYC overexpression and CDK inhibition have shown synthetic lethality.

The preclinical study evaluated both single-agent activity of CYC065 and combinations of CYC065 with the Bcl-2 inhibitor, venetoclax (ABT-199, Venclexta), and BET (Bromodomain and Extra-Terminal) inhibitors in B-cell lymphoma cell lines. Short exposure to CYC065 was sufficient to downregulate MYC, an oncogene aberrantly expressed in many cancers, and Mcl-1, an anti-apoptotic member of the Bcl-2 family, and to induce cell death. CYC065 treatment had no impact on Bcl-2 levels. Combinations of CYC065 with venetoclax or BET inhibitors were both synergistic. CYC065 targets key oncogenic and survival pathways in double-hit B-cell lymphomas suggesting a therapeutic rationale for this indication.

Abstract: 1309
Title: CYC065, a novel CDK2/9 inhibitor, is an effective inducer of cell death and synergizes with BCL2 and BET inhibitors in B-cell lymphoma, including double-hit lymphomas
Date/Time: Monday, April 18, 2016 8 a.m. – 12 p.m. CDT
Location: Section 18, Poster Board 28
Session Title: Regulation of Anticancer Drug Effects
Authors: Sheelagh M. Frame, Elizabeth Pohler, Craig MacKay, Daniella Zheleva, David Blake, Cyclacel Limited, Dundee, UK

The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.

About CDK Inhibition

CDK enzymes, in particular CDK2, 4, 6 and 9, play pivotal roles in cancer cell growth, survival, metastatic spread and repair of DNA damage. Pharmacological inhibition of CDK2/9 has been shown to have potent anticancer effects in certain cancer types, including some that are resistant to approved treatments. CDK2/9 inhibitors have been shown to induce apoptosis, or programmed death of cancer cells, whereas CDK4/6 inhibitors, such as palbociclib (Ibrance), induce senescence or dormancy of cancer cells. Senescence may be associated with emergence of resistance.

About CYC065 (second generation CDK inhibitor)

CYC065 is a highly-selective, orally- and intravenously-available, second generation inhibitor of CDK2 and CDK9 and causes apoptotic death of cancer cells at sub-micromolar concentrations. Antitumor efficacy has been achieved in vivo with once a day oral dosing at well tolerated doses. Evidence from published nonclinical studies show that CYC065 may benefit patients with adult and pediatric hematological malignancies, including certain Acute Myeloid Leukemias (AML), Acute Lymphocytic Leukemias (ALL), Chronic Lymphocytic Leukemias (CLL), B-cell lymphomas, multiple myelomas, and certain solid tumors, including breast and uterine cancers. Independent investigators published nonclinical evidence that CYC065 as a single-agent can induce tumor growth delay to HER2-positive breast cancer cells addicted to cyclin E, the partner protein of CDK2, and resistant to trastuzumab (Herceptin), while administration of CYC065 in combination with trastuzumab resulted in regression or sustained tumor growth inhibition.

CYC065 is mechanistically similar but has much higher dose potency, in vitro and in vivo, improved metabolic stability and longer patent protection than seliciclib, Cyclacel’s first generation CDK inhibitor. Translational biology data support development of CYC065 as a stratified medicine for solid and liquid cancers. CYC065 has been shown to reverse drug resistance associated with the addiction of cancer cells to cyclin E and may inhibit CDK9-dependent oncogenic and leukemogenic pathways, including malignancies driven by certain oncogenes and mixed lineage leukemia rearrangements (MLL-r). CYC065 causes prolonged down regulation of the Mcl-1-mediated pro-survival pathway in cancer cells.

A grant of approximately $1.9 million from the U.K. government’s Biomedical Catalyst has supported IND-directed development of CYC065.

ChemoCentryx Announces Immuno-Oncology Data Presentation at the American Association for Cancer Research (AACR) Annual Meeting

On April 18, 2016 ChemoCentryx, Inc., (Nasdaq:CCXI), a clinical-stage biopharmaceutical company developing orally-administered therapeutics to treat autoimmune diseases, inflammatory disorders, and cancer, reported the presentation of data from its immuno-oncology program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2016 Annual Meeting, being held April 16-20, 2016 in New Orleans, Louisiana (Press release, ChemoCentryx, APR 18, 2016, View Source [SID:1234510968]). The preclinical data highlight the synergistic effect of employing an antibody against the checkpoint inhibitor PD-L1 in conjunction with CCX9588, in a model of triple negative breast cancer. CCX9588 is a small molecule inhibitor of the chemokine receptor known as CCR1 and is currently in preclinical development for certain oncology indications targeting both solid and liquid tumors.

The preclinical results were presented in a poster titled, "Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates anti-tumor effects in a murine model of breast cancer" (Abstract #3298, April 17, 1:00 to 5:00 p.m. ET, Session: Immune Modulating Agents 1, Convention Center, Halls G-J, Poster Section 26).

The presentation from the Company’s ongoing preclinical research investigating the effects of combining CCX9588 with an anti-PD-L1 antibody includes the following results and data:

The combination of CCX9588 and the anti-PD-L1 antibody ("Combination Treatment") significantly decreased circulating and tumor infiltrating granulocytic myeloid-derived suppressor cells, or G-MDSC’s.
G-MDSCs are known to be responsible for the induction of an immunosuppressive environment around the growing tumor, as well as a metastatic phenotype in primary tumors which can lead to the early dissemination of cancer cells.
G-MDSCs were demonstrated to be attracted by chemokines produced by the breast cancer cells, and directed migration of the G-MDSCs were shown to be specifically blocked by inhibiting CCR1 with CCX9588.
Combination Treatment increased the number of effector T cells in the tumor infiltrate, which is known to have an anti-cancer effect.

Overall tumor size and progression was also significantly reduced by the Combination Treatment.
"These results suggest that an orally-administered CCR1 inhibitor, such as CCX9588, combined with an antibody against the checkpoint inhibitor PD-L1, may be of utility in treating triple negative breast cancer, which we modeled in these experiments," said Pirow Bekker, MD, PhD, Chief Medical Officer, ChemoCentryx. "These data reveal an important role for the chemokine receptor CCR1 in modulating the suppressive nature of the tumor microenvironment, and suggest that blocking CCR1 could significantly help to unleash the potential of the body’s own immune system to attack cancer."

About the ChemoCentryx Immuno-Oncology Program

Myeloid derived suppressor cells (MDSCs) are thought to possess an immunosuppressive behavior, effectively helping tumors hide from the body’s natural cytotoxic immune response to tumor cells. These cells are thought to express chemokine receptors such CCR1 and CCR2 and are guided to the tumor microenvironment by the action of these receptors. Inhibiting CCR1 and CCR2 may lead to a reduction of MDSCs in the tumor microenvironment, and the concomitant liberation of the cytotoxic immune response against tumor cells, reduced tumor burden, and potentially lead to improved patient survival.

The Company currently has an ongoing clinical trial of CCX872, an inhibitor of the chemokine receptor known as CCR2, in patients with non-resectable pancreatic cancer. In addition, the Company is conducting preclinical research with various chemokine receptor inhibitors in combination with checkpoint inhibitors, such as those inhibiting the PD-L1 pathway, which may result in a greater anti-tumor effect than with checkpoint inhibition alone. CCX9588 is a small molecule inhibitor of CCR1 and is currently in preclinical development for certain oncology indications targeting both solid and liquid tumors.

Celator® Pharmaceuticals Announces Positive Data for VYXEOS™ in FLT3-ITD Mutated Acute Myeloid Leukemia (AML) Cells Derived from Patients with Newly Diagnosed AML

On April 18, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that positive data for VYXEOS (cytarabine:daunorubicin) Liposome for Injection (also known as CPX-351), its lead product candidate, were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, April 16-20, 2016 (Press release, Celator Pharmaceuticals, APR 18, 2016, View Source [SID:1234510967]).

The presentation, titled "CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes," was based on research conducted in the laboratory of Jeffrey Tyner, Ph.D. at Oregon Health & Science University and examined the ex vivo sensitivity of AML cells derived from newly diagnosed patients to VYXEOS.

The profile of ex vivo AML blast sensitivity to VYXEOS mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from VYXEOS treatment. The increased sensitivity of FLT3-ITD+ (internal tandem duplication) blasts to VYXEOS is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation.

FLT3-ITD mutant expression has historically been a predictor of poor patient outcomes to conventional treatment regimens. A notable result from this research was the observation that AML cells exhibiting the FLT3-ITD mutation were approximately five times more sensitive to VYXEOS than AML cells with normal FLT3. In addition, there was evidence that increased sensitivity to VYXEOS is associated with increased uptake of the drug-laden liposomes by leukemia cells.

"Testing cell killing activity against fresh AML cells outside the body allows us to identify specific AML cell-VYXEOS interactions that could be exploited clinically," said Dr. Tyner. "We are particularly excited about the marked increase in sensitivity of FLT3-ITD cells to VYXEOS and are working to better understand the mechanism underlying this phenomenon."

"VYXEOS continues to deliver positive efficacy read-outs," said Lawrence Mayer, Ph.D., President and Chief Scientific Officer at Celator. "The encouraging activity of VYXEOS against AML cells harboring the FLT3-ITD mutant phenotype opens exciting opportunities to test VYXEOS in this AML patient population. We will submit data from patients exhibiting this mutation, who were treated in the recently completed Phase 3 trial, to an upcoming medical conference."

The poster will be available on Celator’s website (www.celatorpharma.com) at the conclusion of the AACR (Free AACR Whitepaper) meeting.

Late Breaking Data at AACR Annual Meeting from Advaxis Phase 2 Study of AXAL Highlights Potential of the Company’s Lm Technology™ Platform

On April 18, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported immunological and pathologic data from the Company’s ongoing Phase 2 study of its lead immunotherapy candidate, axalimogene filolisbac (AXAL), in patients with late-stage HPV-associated oropharyngeal cancer (HPVOPC) (Press release, Advaxis, APR 18, 2016, View Source [SID:1234510966]). This phase 2 "window of opportunity" trial was designed to evaluate the effect of AXAL on anti-tumor immunity in the tumor immune microenvironment (TME) of patients with HPVOPC by conducting an analyses and comparison of the TME between pre-treatment tumor biopsy and post-treatment resected tumor tissue, as well as pre and post AXAL treatment blood samples.

The data were selected for "Late Breaking Abstract" status and will be presented in the poster session of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 18, 2016 from 8:00 AM to 12:00 PM CT in Hall H of the New Orleans Memorial Convention Center in New Orleans, Louisiana. The poster (abstract LB-095) titled "HPV E7 antigen-expressing Listeria-based immunotherapy (AXAL) prior to robotic surgery for HPV-positive oropharyngeal cancer enhances HPV-specific T cell immunity" will be available at www.advaxis.com on Monday, April 18 at 9:00 AM ET.

The Phase 2 study, led by Andrew G. Sikora, M.D., Associate Professor of Otolaryngology and Co-Director of the Head and Neck Cancer Program in the NCI Comprehensive-Designated Dan L. Duncan Cancer Center at Baylor College of Medicine, supported by key investigators Brett Miles, M.D. and Marshall Posner, M.D. at the Icahn School of Medicine at Mount Sinai, and presented at AACR (Free AACR Whitepaper) by Rosemarie Krupar, M.D. from Baylor College of Medicine, evaluates the immunogenicity and differential mechanism of AXAL as preoperative treatment prior to robot-assisted surgery in patients with HPVOPC.

The trial has enrolled eight AXAL-treated patients and six no-treatment observational patients to date, with stage II-IV HPVOPC. The trial uniquely leveraged a 5-6 week "window of opportunity" between diagnosis and TORS (trans-oral robotic surgery) with curative intent, to administer two doses of AXAL treatment at 1x109CFU 2 weeks apart. This unique clinical setting or "window of opportunity", makes it possible to analyze and compare changes to the TME after the compressed regimen of AXAL treatment as well as pre and post treatment blood samples. In this limited timeframe, patients received two doses of AXAL separated by only two weeks, followed by TOR surgery 1-2 weeks after the second dose.

The data presented showed that HPV E7- and/or E6-specific T cell responses increased in the peripheral blood in five of the study patients. Increased infiltration of both CD4+ and CD8+ T cells were observed in the TME of four patients, with a reduction of FOXP3+ regulatory T cells within the tumors of 3/6 patients. Increased T cell responses to HPV E6 supports enhanced immune activity against additional tumor targets. Changes to the TME included cytotoxic T cell infiltration into the post-resection tumor, increased immune activation, a reduction of regulatory T cells, infiltration of cytotoxic T cells, and increased expression of inflammatory activation markers. In addition, fluctuations of circulating serum cytokine (IL-15, IL-9, TNfa, IL-2 and MIP-1b) levels were observed potentially suggesting consumption by activated T cells and migration of T cells to the TME.

"While our data is preliminary, in several patients we saw increased T cell response, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells into the tumor. We also saw trends towards a reduction in immuno-suppressive Tregs. Importantly, in several patients when compared to pre-treatment tumor tissue, post-treatment tissue analysis showed conversion of the TME into a site of active inflammation characterized by infiltration of activated T cells, and increased expression of activation markers including PD-1, PD-L1," said Andrew Sikora, M.D., Ph.D., Associate Professor of Otolaryngology at the Baylor College of Medicine. "The fact that we are seeing these trends at this preliminary point in the study is very encouraging, and suggests that AXAL has the potential to generate beneficial immunologic responses in patients with HPV+ head and neck cancer."

"The biggest challenge for an effective cancer immunotherapy is to overcome the mechanisms tumors use to protect themselves from immunological attack and destruction. Researchers refer to this as ‘immunosuppression in the tumor microenvironment (or TME).’ It has been demonstrated and published in peer review journals that Advaxis’ Lm Technology enables cytotoxic T cells to infiltrate into the TME. The late breaking AXAL data shows – for the first time in a human clinical trial – the potential of the Lm Technology platform to elicit a targeted anti-cancer immune response with clear infiltration into the TME by cytotoxic T cells," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.

"This is the first human clinical data that replicates the multiple beneficial immunologic and tumor microenvironment-modifying aspects of treatment with Advaxis’ immunotherapies that have been consistently demonstrated in several research models. It’s impressive that these changes occurred so consistently despite being obliged to use a shortened treatment schedule without the usual follow-up period to fit within the ‘window.’ Immunotherapies are generally understood to work better over time, and we would expect these early beneficial effects to deepen and contribute to tumor-controlling immunity over time," said Robert Petit, Chief Scientific Officer and EVP of Advaxis. "These data points are the first clear demonstration of the reduction of Tregs in human tumors associated with Advaxis’ immunotherapy. Inhibition of Tregs has been clearly associated with the Advaxis tLLO fusion peptide in many publications. Immune activation through TLRs and PAMPS, including STING and the subsequent infiltration of tumor fighting T cells into the TME along and simultaneous reduction in tumor protection by Tregs, are the cornerstones of successful immunotherapies. Every Advaxis immunotherapy product candidate, including AXAL, has these elements built into it."

The study received a three-year $1.1 million grant from the U.S. Food and Drug Administration’s Office of Orphan Products Development, which funds research for the development of products for rare diseases.

For additional information, Advaxis will host a Research Reception at AACR (Free AACR Whitepaper) at 6:30 PM CT on April 18, 2016 at the Sheraton New Orleans Hotel in New Orleans, Louisiana.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology. Axalimogene filolisbac has Orphan Drug Designation in the U.S. for the treatment of anal cancer.

Varian Medical Systems Supports Trial on Lung Cancer Radiosurgery

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, InfiMed, APR 18, 2016, View Source [SID:1234510962]).

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."

Learn more about the Stablemates Trial at View Source