On April 20, 2016 Checkmate Pharmaceuticals , a clinical-stage biopharmaceutical company focused on developing novel approaches for cancer immunotherapy, reported the appointment of David Mauro, M.D., Ph.D . to the newly created position of Chief Medical Officer. Checkmate also announced the dosing of the first patient in a Phase 1b trial with CMP-001 in combination with pembrolizumab in melanoma patients who have either progressed on or failed to respond to at least 12 weeks of anti -‐ PD1 therapy. CMP -‐ 001 is a first -‐ in -‐ class CpG -‐ A oligonucleotide that activates the innate immune system via Toll -‐ like receptor 9 (TLR9) (Press release, Checkmate Pharmaceuticals, APR 20, 2016, View Source [SID1234516800]). The combination therapy has the potential to increase the proportion of cancer patients who respond to checkpoint inhibitor therapies and to increase the magnitude and duration of the anti -‐ tumor responses , providing added clinical benefit . Industry Veteran with Immun o -‐ Oncology Clinical Development and Leadership Expertise Dr. Mauro brings to Checkmate more than 15 years of experience in early and late stage oncology drug development, clinical and translational research , and medical affairs. Previously he served as Exe cu tive Vice President and Chief Medical Officer at Advaxis , where he was responsible for the strategy and oversight of the company’s clinical programs, including several combination drug programs with checkpoint inhibitor s . "We welcome David to the Checkmate team at this pivotal time ," said Art Krieg, M.D., Chief E xecutive Officer of Checkmate. " His deep knowledge and experience in immuno -‐ oncology , and specifically in the development of checkpoint inhibitor combinations, will be invaluable to Checkmate in the clinical development of CMP -‐ 001 for patients with advanced cancer ." Dr. Mauro has held senior level positions at Merck & Co. and Bristol Myers Squibb Company, where he was involved in the clinical development, trans la tional science , and life cycle management for multiple programs , including Keytruda ( pembrolizumab ), Erbitux (cetuximab), Sprycel (dasatinib), and Sylatron (peginterferon alfa -‐ 2b). He received his Bachelor of Science in Bioch emistry from Cornell University, his medical degree and his doctorate in pharmacology from Temple Univ ersity School of Medicine , and completed his residency training at the National Cancer Institute. A s Chief Medical Officer at Checkmate, Dr. Mauro will oversee the development of the Company’s current and future clinical programs, based on the TLR9 mechani sm of immune activation. " I am excited to be joining Checkmate as it progress es CMP -‐ 001 into the clinic in itially in melanoma patients ," said Dr. Mauro. "I look forward to working with the team to further expand the development of this compound in other indications and checkpoint inhibitor combinations . The immun o -‐ oncology field is evolving rapidly , and I believe that CMP -‐ 001 has the potential to increase the response rates to current checkpoint therapies a nd have a broad impact in the development of new standards of care f or oncology treatment." Initiation of Phase 1b Trial in Advanced Melanoma with a TLR9 Immune Activator Checkmate has dosed the first patient in its Phase 1b clinical study of CMP -‐ 001 . Th e trial is designed as a multi -‐ center, open -‐ label study of CMP -‐ 001 in combination with pembrolizumab for patients with advanced melanoma who have either progressed on an anti -‐ PD1 , or have failed to respond to at least 12 weeks of therapy . Patients will c ontinue on the approved dose and schedule of pembrolizumab, with the addition of intratumoral CMP -‐ 001 therapy. The trial will include a dose escalation study and will enroll patients in an expansion phase , as well as undertake correlative studies to characterize the immune effects of treatment in the blood and tumor. P atients will be monitored for safety and tolerability as well as possible clinical response . " We are excited to begin our clinical development of this new appr oac h of a ltering the tumor microenvironment with intratumoral CMP -‐ 001," said Dr. Krieg. " We believe this treatment should convert "cold" tumors , which lack immune activation and are not likely to respond to checkpoint inhibitors , in to immunologically "hot" tumors which are much more likely to respond to checkpoint inhibition . This has the potential to induce a powerful anti -‐ tumor CD8 + T cell immune response resulting in significantly increased response rates to checkpoint inhibitor therapy in multiple cancer indications ." About CMP -‐ 001 CMP -‐ 001 comprises a CpG -‐ A oligonucleotide packaged within a virus -‐ like particle . It is designed to activate the innate immune system via Toll -‐ like receptor 9 (TLR9) and mediate tumor control by the subsequent induction of both innate and adaptive anti -‐ tumor immune responses . CMP -‐ 001 is the only CpG -‐ A oligonucleotide in clinical development . It differs from the other major classes of TLR9 agonists in development , CpG -‐ B, and CpG -‐ C , by it s induction of much higher levels of type I interferons, without inducing immune suppressive IL -‐ 10. In addition, the virus -‐ like particle nature of CMP -‐ 001 will promote formation of immune complexes within tumors, providing an additional mechanism driving anti -‐ tumor i mmunity. In preclinical models , CMP -‐ 001 shows single agent activity in controlling growth of both local and distant tumors, with increased anti -‐ tumor ac tivity seen in combination with systemic anti -‐ PD -‐ 1 therapy. CMP -‐ 001 was licensed from Kuros Biosciences AG and was formerly known as CYT003. It has previously demonstrated a good safety profile and evidence of immune activity in over 700 patients who participated in clinical trials for non -‐ oncology indications.
About Checkmate
Checkmate Pharmaceuticals is a clinical stage company pursuing a novel approach to specifically activating the innate arm of the immune system to recognize and ultimately destroy tumor cells. The company is leveraging its expertise and the vast body of knowledge in the field of CpG oligonucleotides and is validating a n approach that will combine the ability of CpG DNA to activate an anti -‐ tumor T cell response with checkpoint inhibition to overcome a tumor’s ability to mute the immune response .
Checkmate’s founder and CEO, Dr. Art Krieg, discovered immune stimulatory CpG DNA in 1994 . S ince then , CpG containing DNA therapies have been administered to thousands of patients showing potent immune activation and a n acceptable safety profile. Checkmate is a privately held company headquartered in Cambridge, M A , whose Series A investors include Sofinnova Ventures and venBio

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On April 20, 2016 Immune Therapeutics Inc., (OTC-QB: IMUN), reported that they have signed a binding Letter of Intent to acquire Chinese Chimeric Super Antigen Receptor T cell (CAR-T) cocktail therapy, Immuno-Oncology patents (pending), manufacturing technology, and clinical data of the aforementioned therapies from Super-T Cell Cancer Company ("STCC") a newly formed corporation (Filing, 8-K, TNI BioTech, APR 20, 2016, View Source [SID:1234511271]).

"This CAR-T cell technology licensing further accelerates IMUN’s growth in the Immuno-Oncology field as we evaluate paths to commercialization both in China and other Emerging Markets," commented Christopher Pearce Chief Operating Officer.

CAR-T cell therapy involves engineering cancer patients’ own immune cells to recognize and attack cancer tumors. CAR-T therapy has great potential to improve patient-specific cancer therapy in a profound way. Numerous studies have implicated regulatory T cells as key mediators in the creation of an immunosuppressed microenvironment that enables tumors to escape attack by the host immune system. The Super CAR –T Cocktail therapy has shown promise in early human clinical trials for the treatment of blood cancer, renal, cervical and hepatic cancer.

"We are very impressed by the quality of the work done by Professor Shan and his team, and are excited by the safe and efficacious profile of this novel CAR-T cocktail therapy for cancerous diseases. This is the beginning of a long-term strategic partnership between IMUN and STCC. Together, we will expeditiously continue our quest in developing more affordable, safer, and more effective cancer immunotherapy programs," said Noreen Griffin, Chief Executive Officer of Immune Therapeutics, Inc.

The need in China for new affordable therapies is critical. It is predicted that there will be about 4,292,000 newly diagnosed invasive cancer cases in 2016, corresponding to almost 12,000 new cancer diagnoses on average each day. IMUN believes that once approved it could capture 5% of the market in the first year.

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On April 20, 2016 Syros Pharmaceuticals reported that SY-1365, a first-in-class potent and selective cyclin-dependent kinase 7 (CDK7) inhibitor, was observed to induce durable tumor regression and prolong survival in in vivo models of acute myeloid leukemia (AML) (Press release, Syros Pharmaceuticals, APR 20, 2016, View Source [SID:1234511184]). These data were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans. Based on the strong efficacy and safety data, Syros selected SY-1365 as its development candidate and plans to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration in the second half of 2016 with the goal of initiating a Phase 1/2 clinical study in acute leukemia in the first half of 2017.

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"Up until now, creating medicines to control important disease causing transcription factors has been a major challenge in cancer drug development. SY-1365, our first-in-class CDK7 inhibitor, highlights the potential of our pioneering platform to produce drugs that can selectively modulate these transcription factors," said Nancy Simonian, M.D., Chief Executive of Syros. "Certain hematologic and solid tumor cancers, including AML, are dependent on transcription factors for their growth and survival and have been shown to be particularly dependent on CDK7. Results from preclinical studies demonstrate that SY- 1365 lowers the levels of these disease causing transcription factors and, in so doing, may treat diseases that have eluded other genomics-based approaches and provide a profound and durable benefit for patients with these difficult-to-treat cancers."

In the preclinical studies presented at AACR (Free AACR Whitepaper), SY-1365 was observed to preferentially kill cancer cells over non-cancerous cells and significantly prolong survival in patient-derived xenograft (PDX) models of AML. In the in vitro and in vivo studies, SY-1365 induced:

Tumor regression in 100 percent of treated mice in a cell-line derived xenograft model of AML; tumor regression was maintained through the end of the 38-day study.

Strong survival benefit, with 80 percent of treated mice alive at the end of the 8- week study in a PDX model of treatment-resistant AML; by contrast, none of the untreated mice survived beyond 4-1/2 weeks.

Rapid and dose-dependent apoptosis in AML cell lines treated with SY-1365 while having little to no effect on non-cancerous cells.
Potent and selective inhibition of CDK7, with only six other kinases, none of which are in the CDK family, exhibiting greater than 90 percent binding when profiled across a panel of 468 kinases at a concentration of 1μM.

Minimal effect on blood cell counts in in vivo models, including white blood cells, lymphocytes, neutrophils and reticulocytes, demonstrating a more favorable profile than a non-selective CDK inhibitor.

Reduced expression of cancer-contributing genes associated with specialized regulatory regions of DNA known as super-enhancers, including transcription factors and the oncogenes MYB and MYC, in an AML cell line.

Synergistic activity when combined with other targeted agents in AML, including Flt3, Bcl-2 and pan-Brd inhibitors.

Syros’ selective CDK7 inhibitors, including SY-1365, have been observed to delay tumor progression in additional in vivo models of transcriptionally addicted cancers, including acute lymphoblastic leukemia (ALL), MYCN-amplified neuroblastoma, small cell lung cancer and triple negative breast cancer.

Direct co-operation between sensitiser molecules BAD and NOXA in mediating apoptosis suggests that therapeutic agents which sensitise to BAD may complement agents which sensitise to NOXA. Dynamic BH3 profiling is a novel methodology that we have applied to the measurement of complementarity between sensitiser BH3 peptide mimetics and therapeutic agents. Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells. At the concentrations used, the peptides did not trigger mitochondrial outer membrane permeabilisation in their own right, but primed cells to release Cytochrome C in the presence of an appropriate trigger of a complementary pathway. In KG-1a cells TG02 and ABT-199 synergised to induce apoptosis. In heterogeneous AML patient samples we noted a range of sensitivities to the two agents. Although some individual samples markedly favoured one agent or the other, in the group as a whole the combination of TG02 + ABT-199 was significantly more cytotoxic than either agent individually. We conclude that dynamic NOXA and BAD BH3 profiling is a sensitive methodology for investigating molecular pathways of drug action and complementary mechanisms of chemoresponsiveness.

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Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed the efficacy of the combination treatment of TH-302 and radiotherapy in two preclinical tumor models. The effect of oxygen modification on the combination treatment was evaluated and the effect of TH-302 on the hypoxic fraction (HF) was monitored using [(18)F]HX4-PET imaging and pimonidazole IHC stainings.
Rhabdomyosarcoma R1 and H460 NSCLC tumor-bearing animals were treated with TH-302 and radiotherapy (8 Gy, single dose). The tumor oxygenation status was altered by exposing animals to carbogen (95% oxygen) and nicotinamide, 21% or 7% oxygen breathing during the course of the treatment. Tumor growth and treatment toxicity were monitored until the tumor reached four times its start volume (T4×SV).
Both tumor models showed a growth delay after TH-302 treatment, which further increased when combined with radiotherapy (enhancement ratio rhabdomyosarcoma 1.23; H460 1.49). TH-302 decreases the HF in both models, consistent with its hypoxia-targeting mechanism of action. Treatment efficacy was dependent on tumor oxygenation; increasing the tumor oxygen status abolished the effect of TH-302, whereas enhancing the HF enlarged TH-302’s therapeutic effect. An association was observed in rhabdomyosarcoma tumors between the pretreatment HF as measured by [(18)F]HX4-PET imaging and the T4×SV.
The combination of TH-302 and radiotherapy is promising and warrants clinical testing, preferably guided by the companion biomarker [(18)F]HX4 hypoxia PET imaging for patient selection.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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