On January 11, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that its European regional headquarters Eisai Europe Ltd. (Location: U.K.) has submitted a new application to the European Medicines Agency (EMA) for its in-house developed novel anticancer agent lenvatinib mesylate (generic name, "lenvatinib") for use in the treatment of advanced or metastatic renal cell carcinoma (Press release, Eisai, JAN 11, 2016, View Source [SID:1234508771]). As a new medicine that is expected to be of major public health interest, particularly from the viewpoint of therapeutic innovation, lenvatinib has been granted an accelerated review by the EMA.

The number of patients with renal cancer in Europe is estimated to be 115,000,1 and renal cell carcinoma comprises more than 90% of all malignancies of the kidney.2 For advanced or metastatic renal cell carcinoma that is difficult to treat with surgery, the standard treatment method is molecular targeted drug therapy, however with low 5-year survival rates, this remains a disease with significant unmet medical need.

This application was based on a Phase II clinical study (Study 205)3 which compared the efficacy and safety among three groups including a combination of lenvatinib (18 mg) plus everolimus (5 mg), lenvatinib alone (24 mg) and everolimus alone (10 mg) in unresectable advanced or metastatic renal cell carcinoma following one prior vascular endothelial growth factor targeted therapy. From the results of the study, the combination of lenvatinib plus everolimus group demonstrated a significant extension in progression free survival (PFS), the study’s primary endpoint, compared to the everolimus alone group. Additionally, the lenvatinib alone group demonstrated an extension in PFS compared to the everolimus alone. Both the lenvatinib plus everolimus group and the lenvatinib alone group showed an improvement in objective response rate compared to the everolimus alone group. The most common treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher were diarrhea, hypertension and fatigue.

Currently lenvatinib has been launched in the United States, Japan and Europe under the product name Lenvima as a treatment for refractory thyroid cancer. In addition, lenvatinib has received a breakthrough therapy designation from the U.S. Food and Drug Administration for the potential indication of advanced and/or metastatic renal cell carcinoma, and an application seeking approval for an indication covering advanced or metastatic renal cell carcinoma was submitted in the United States in November 2015. Eisai intends to discuss further steps regarding potential submission strategies for this indication with the regulatory authorities in Japan as well.

Eisai is committed to exploring the potential clinical benefits of lenvatinib in order to further contribute to patients with cancer and their families.

On January 11, 2016 Cellectis (Paris:ALCLS) (NASDAQ:CLLS) (Alternext: ALCLS – Nasdaq: CLLS) reported the publication of a study in Scientific Reports, a Nature Publishing Group journal, describing the design and development of a new CAR architecture with an integrated switch-on system that permits control over CAR T-cell functions (Press release, Cellectis, JAN 11, 2016, View Source [SID:1234508770]). This integrated switch-on system offers the advantages of controllable CAR T-cells for safety while allowing for the possibility of multiple cytotoxicity cycles using a small molecule drug.

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The possibility to control spatially and temporally the CAR T activity is very desirable to mitigate potential unwanted risks, such as cytokine-release syndrome1 (CRS) and the "on-target, off-tumor" effect2. To date, few strategies are available and mostly rely on suicide mechanisms that ultimately lead to a complete eradication of the engineered T-cells, thus resulting in a premature end of the treatment. Consequently, implementing non-lethal, spatio-temporal control of gene edited CAR T-cells represents an important advancement in improving the CAR T-cell technology.

In this report, Alexandre Juillerat, Ph.D., and his collaborators engineered a system directly integrated within the CAR architecture. In particular, they showed that such system turns a CAR T-cell from an off-state to an on-state upon addition of a small molecule, inducing the cytolytic properties of the gene edited T-cell. Overall, this non-lethal system not only offers the advantage of a temporal control of activation to mitigate the risk of CAR-induced toxicities but also enables opportunities for spatial activation of the engineered CAR T-cells using local targeted drug delivery.

Alexandre Juillerat, Ph.D. Innovation Senior Scientist

Dr. Alexandre Juillerat, Ph.D., graduated in Chemistry of the University of Lausanne, Switzerland. After receiving in 2006 his Ph.D. in protein engineering from the École Polytechnique Fédérale de Lausanne (EPFL, Switzerland), he moved to the laboratory of Structural Immunology at the Institut Pasteur in Paris, France, performing structure-function studies on a major adhesin of plasmodium falciparum. In 2010, he joined the R&D department of Cellectis in Paris, France, working on the development and implementation of sequence specific designer nucleases including the transcription activator-like effector nucleases (TALEN). He then joined the Cellectis facility based in New York, NY, USA, leading projects associated with the development of the T-cell chimeric antigen receptor (CAR) technology.

Design of chimeric antigen receptors with integrated controllable transient functions

Alexandre Juillerat, Alan Marechal, Jean-Marie Filhol, Julien Valton, Aymeric Duclert, Laurent Poirot and Philippe Duchateau
View Source

On January 6, 2016 TetraLogic Pharmaceuticals Corporation (Nasdaq: TLOG), a clinical-stage biopharmaceutical company focused on discovering and developing novel small molecule therapeutics in oncology and infectious diseases, reported the results of the interim analyses of two clinical studies (Filing, 8-K, TetraLogic Pharmaceuticals, JAN 11, 2016, View Source [SID:1234508768]).

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In a placebo controlled Phase 2 study of birinapant co-administered with azacitidine in first line higher risk patients suffering from myelodysplastic syndromes (MDS), birinapant did not demonstrate any clinical benefit over placebo on the primary endpoint of response rate after four months of therapy and met the bounds for futility. This interim analysis included the first 62 patients randomized in the trial. This study will now be terminated.

TetraLogic has undertaken an interim analysis of a randomized Phase 2 clinical study of SHAPE, the company’s proprietary topical HDAC inhibitor. The clinical trial was designed to investigate the safety and efficacy of three different dosing regimens of SHAPE in patients suffering from earlier stage cutaneous T-cell lymphoma (CTCL). All patients in the study had received prior therapy either in the form of topical steroids, UV light therapy, topical nitrogen mustard, or some other agent. Twenty-eight of 34 patients were evaluable for response at the 6 month time point. After six months of treatment, 8 of 34 patients exhibited a response to treatment as assessed by CAILS, the primary endpoint, and a further 18 had stable disease. Using the mSWAT, a secondary endpoint in the study, 11 of 34 patients responded and a further 14 patients had stable disease at the 6 month endpoint.

SHAPE also showed improvement in pruritus (itch), a significant symptom associated with CTCL. Thirty-eight percent of patients demonstrated a clinically meaningful decrease in pruritus during the study as measured by a Visual Analog Scale. The drug was well tolerated by patients in the study. The 60 patient study is now fully enrolled, and the company expects that final results will be available in mid-2016.

"Whilst the results of the birinapant study in MDS are disappointing, the results we achieved with SHAPE provide an interesting product profile with activity observed on both the CAILS and mSWAT endpoints and the potential to reduce pruritus, one of the more difficult symptoms to treat in CTCL," said J. Kevin Buchi, TetraLogic CEO. "We are exploring our strategic alternatives based upon the results seen in these studies."

On January 11, 2016 Juno Therapeutics, Inc. (Nasdaq: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported that it has acquired AbVitro, Inc., a privately held biotechnology company based in Boston, Massachusetts (Press release, Juno, JAN 11, 2016, View Source [SID:1234508765]). The acquisition provides Juno with a leading next-generation single cell sequencing platform that will augment Juno’s capabilities to create best-in-class engineered T cells against a broad array of cancer targets. Juno and Celgene Corporation have agreed in principle to enter into an agreement to license Celgene a subset of the acquired technology and to grant Celgene options to certain related potential product rights emanating from the acquired technology.

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AbVitro’s technology allows for the identification of fully-human, natively paired T cell receptors (TCRs) and chimeric antigen receptor (CAR) T binders directly from cancer patients. This capability, which allows for the interrogation of millions of single cells per experiment, enables the generation of binders that recognize known targets as well as the discovery of novel cancer antigen targets. Juno will also use the technology for translational assays to provide a better understanding of the natural immune response to cancer as well as to interrogate and monitor the immune system of cancer patients during treatment.

Juno intends to relocate the AbVitro scientists to Seattle and incorporate this platform into its therapeutic discovery process. In connection with the transaction, AbVitro co-founder and Harvard Medical School Professor George Church will become a scientific consultant to Juno. Jeffrey Ostrove, Ph.D., former CEO of AbVitro, will also become a consultant to Juno.

"High throughput, single cell sequencing will meaningfully accelerate our research process in finding both novel antigen targets and appropriate TCR and CAR T cell binders. We remain highly encouraged by the potential of our engineered T cell technology to impact the lives of cancer patients, and this technology improves our capabilities to extend our platform to a broader array of cancer types including solid tumors," said Hy Levitsky, M.D., Juno’s Chief Scientific Officer. "We are highly impressed with the quality of the science at AbVitro, and we are delighted to welcome this world-class team to Juno."

"The technology platform we built at AbVitro represents an exciting, novel approach to the understanding of immune responses and the discovery of tumor-infiltrating lymphocytes and their antigen targets. The synergy with Juno’s goals in the field of TCR and CAR T cell therapies is a perfect match for our team and technology," said Francois Vigneault, Ph.D., co-Founder and former Chief Scientific Officer of AbVitro, and now Juno’s Vice President, Research.

"Juno’s newly acquired high throughput, single cell sequencing capabilities have the potential to expand their current pipeline and Celgene is excited by the opportunity to access some of these potential new drugs," said Rob Hershberg, M.D., Ph.D., Celgene’s Chief Scientific Officer. "This transaction is another example of the Celgene and Juno collaboration providing benefits to both partners as we pursue therapies benefiting patients across the globe."

The consideration for the AbVitro acquisition was approximately $78 million in cash and 1,289,193 shares of Juno stock. Juno and Celgene have agreed in principle to enter into an agreement to license Celgene a subset of the acquired technology and to grant Celgene options to certain related potential product rights emanating from the acquired technology.

On January 11, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, reported that its Sleeping Beauty non-viral gene transfer technology was featured in a perspectives article in the January 2016 issue of the journal Nature Medicine (Volume 22, Number 1, 26—36), titled "Prospects for gene-engineered T cell immunotherapy for solid cancers" (Press release, Ziopharm, JAN 11, 2016, View Source [SID:1234508761]).

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The article describes how adoptive transfer of receptor-engineered T cells has produced "impressive results in treating B-cell leukemias and lymphomas," but that effective treatment of solid cancers using a similar approach based upon pursuing shared tumor antigens is unlikely. It suggests that the success of cell-based immunotherapies for solid tumors may come from the "arduous task of targeting the unique set of mutations that cause each patient’s cancer." Because of the challenges of achieving this goal, the authors note that nonviral integration systems can be considerably cheaper to manufacture and easier to implement for single-use applications compared with viral vectors and that, among these, Sleeping Beauty has advanced farthest in clinical development.

The Sleeping Beauty transposon-transposase is a unique non-viral system for introducing genes encoding T-cell receptors and chimeric antigen receptors into lymphocytes that was exclusively licensed to ZIOPHARM and its collaboration partner, Intrexon Corporation (NYSE:XON), through an agreement with the MD Anderson Cancer Center.

"Implementing immunotherapy for solid tumors goes hand-in-hand with generating individualized T-cell therapies. To move beyond shared targets on the cell surface of liquid tumors to more complex, multifaceted targets within solid tumors requires a robust set of technologies to take advantage of antigen discovery," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "Sleeping Beauty is a clinical platform unlike any other, both in its stage of development and flexibility for the implementation of low cost, personalized T-cell therapies. Along with other technologies developed with our partners and collaborators, it has the potential to play a key role accessing tumor-associated antigens at the individual level thereby translating the enormous promise of adoptive cell therapy to all cancers."