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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Mogamulizumab (Mog), a humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) that mediates antibody-dependent cellular cytotoxicity (ADCC) using FcγR IIIa (CD16)-expressing effector cells, has recently been approved for treatment of CCR4-positive adult T-cell leukemia (ATL) in Japan. However, Mog failure has sometimes been observed in patients who have accompanying chemotherapy-associated lymphocytopenia. In this study, we examined whether adoptive transfer of artificial ADCC effector cells combined with Mog would overcome this drawback.
We lentivirally gene-modified peripheral blood T cells from healthy volunteers and ATL patients expressing the affinity-increased chimeric CD16-CD3ζ receptor (cCD16ζ-T cells). Subsequently we examined the ADCC effect mediated by those cCD16ζ-T cells in the presence of Mog against ATL tumor cells both in vitro and in vivo.
cCD16ζ-T cells derived from healthy donors killed in vitro Mog-opsonized ATL cell line cells (n=7) and primary ATL cells (n=4) depending on both the number of effector cells and the dose of the antibody. cCD16ζ-T cells generated from ATL patients (n=3) also exerted cytocidal activity in vitro against Mog-opsonized autologous ATL cells. Using both intravenously disseminated model (n=5) and subcutaneously inoculated model (n=4), co-administration of Mog and human cCD16ζ-T cells successfully suppressed tumor growth in xenografted immunodeficient mice, and significantly prolonged their survival (p<0.01 and p=0.02, respectively).
These data strongly suggest clinical feasibility of the novel combined adoptive immunotherapy using cCD16ζ-T cells and Mog for treatment of aggressive ATL, particularly in patients who are ineligible for allo-HSCT.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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