On February 12, 2018 MabVax Therapeutics Holdings, Inc. (Nasdaq: MBVX), a clinical-stage biotechnology company focused on the development of antibody-based products to address unmet medical needs in the treatment of cancer, reported positive interim results from the Company’s ongoing Phase 1 trial evaluating MVT-5873 in combination with standard of care chemotherapy in patients newly diagnosed with pancreatic and other CA19-9 positive malignancies (Press release, MabVax, FEB 12, 2018, View Source [SID1234523919]). At the dose tested, all six patients in the cohort had meaningful reductions in tumor volume by RECIST.

In the Phase 1 study, MabVax’s MVT-5873, a fully human antibody, was given in combination with nab-paclitaxel and gemcitabine to patients newly diagnosed with CA19-9 positive pancreatic cancer. MVT-5873 at a dose of 0.125 mg/kg when added to first-line chemotherapy was generally well tolerated by all subjects. The Company reported that all six patients had measurable tumor reductions, with four patients meeting the criteria for partial response (PR) and two patients meeting the criteria for stable disease (SD). These results help confirm results reported from a group of patients treated earlier. Patient CA19-9 levels, which are a prognostic indicator of the disease state, were markedly reduced in all subjects with this combination therapy. The Company plans to enroll additional patients at this dose to further explore safety and potential response.

"We are highly encouraged by the continued positive response across all of the initial patients at this dose of MVT-5873. We are enrolling additional patients at this dose level to confirm our early clinical results with a goal to determine if these clinically meaningful initial results can continue to be replicated in a larger patient population. With additional confirmatory data, we could establish the potential of combining MVT-5873 with first line therapy in very difficult to treat cancer patients," commented David Hansen, MabVax’s President and Chief Executive Officer.

This Phase 1 clinical trial is an open-label, multi-center nonrandomized study evaluating the safety and recommended Phase 2 dose of MVT-5873 in combination with a standard of care chemotherapy in subjects with pancreatic and other CA19-9 positive malignancies. Secondary objectives include evaluating tumor response rate by RECIST 1.1, duration of response, and to determine pharmacokinetics. This study utilizes a conventional 3+3 design to identify the recommended Phase 2 dose. Dr. Eileen O’Reilly, Associate Director of the David M. Rubenstein Center for Pancreatic Cancer Research, attending physician, member at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College is the lead investigator in the MVT-5873 Phase 1 clinical trial.

For additional information about the Phase 1 MVT-5873 clinical trial, please visit clinicaltrials.gov, and reference Identifier NCT 02672917.

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On February 12, 2018 EUSA Pharma (EUSA), reported that the National Institute for Health and Care Excellence (NICE) has published a Final Appraisal Determination (FAD) recommending tivozanib as a first-line treatment option for advanced renal cell carcinoma (aRCC) in line with its licensed indication (Press release, EUSA Pharma, FEB 12, 2018, View Source [SID1234523911]). Tivozanib was licensed by the European Commission (EC) in August 20171 and is an oral, once-daily, potent selective vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI). VEGFR-TKIs work by reducing the supply of blood to the tumour – denying it the food and oxygen it would need to grow in size.2

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In arriving at its positive recommendation, NICE considered data from the global, open-label, randomised, multi-centre Phase III trial (TiVO-1)3 which evaluated the efficacy and tolerability of tivozanib compared to a currently available comparator VEGFR-TKI (sorafenib) in the treatment of 517 patients with aRCC. Patients treated with tivozanib experienced superior progression-free survival (PFS) (11.9 vs. 9.1 months in the overall population and 12.7 vs. 9.1 months in treatment naïve patients) versus sorafenib.3 There was also an improved side effect profile with tivozanib, with only 14% (versus 43% with sorafenib) requiring a dose reduction due to adverse events (AEs).3 In addition, fewer people on tivozanib experienced burdensome side effects, such as diarrhoea (23% vs 33%), and hand-foot syndrome (14% vs 54%).3

Dr Lisa Pickering, Consultant Medical Oncologist at St George’s Hospital, London, commented: This is excellent news for patients with aRCC. A key treatment goal is to enable patients to live without their cancer progressing for longer periods of time – we cannot cure their cancer but we can help to preserve normal living for as long as possible. That is why I’m delighted that NICE has recommended tivozanib as a treatment option."

Around 12 people in the UK die every day of kidney cancer, with more than 40% of cases in England diagnosed at a late (advanced) stage. Kidney cancer is expected to be one of the fastest increasing cancers over the next 10 years, as a result of the UK’s ageing population, and with smoking and a rise in obesity also playing a part.4

Nick Turkentine, Chief Executive of Kidney Cancer UK, said: "With over 12,500 new cases of kidney cancer being diagnosed every year this is a great result for people with aRCC and the overall fight with the disease. It is vitally important patients have access to effective, well-tolerated treatments, so they can spend more precious time with their families and loved ones. We applaud EUSA Pharma, NICE and NHS England for making this happen."

Patients with advanced renal cell carcinoma (aRCC) who may benefit from treatment with tivozanib will be able to access it from today as the final guidance is published, and should be able to have immediate access through the CDF.

Lee Morley, EUSA Pharma’s Chief Executive Officer commented "We are very pleased that NICE are recommending the use of Fotivda for the first line treatment of advanced Renal Cell Carcinoma and that Fotivda will be funded immediately in England and Wales, meaning physicians and patients can experience the benefits of Fotivda. Fotivda has the potential to become an important new first-line therapy and the recommendation by NICE is a great achievement for the EUSA team delivering on their mission to improve the lives of those patients suffering from cancer."

On February 12, 2018 Ziopharm Oncology, Inc. (Nasdaq:ZIOP), a biotechnology company focused on development of next generation immunotherapies utilizing gene- and cell-based therapies to treat patients with cancer, reported data demonstrating point-of-care (P-O-C) manufacturing of human T cells expressing chimeric antigen receptor (CAR) that persist and have an anti-tumor effect in preclinical models were presented at the Keystone Symposia Emerging Cellular Therapies: T Cells and Beyond in Keystone, Colorado (Press release, Ziopharm, FEB 12, 2018, View Source [SID1234523928]).

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The data presented showed T cells expressing CD19-specific CAR with membrane-bound IL-15 (mbIL15) were generated with the non-viral Sleeping Beauty system in less than two days and did not require ex vivo activation or propagation. T cells designed to express mbIL15 showed greater persistence and more potent antitumor activity than comparator T cells without mbIL15 in these studies.

Lenka V. Hurton, Ph.D., a researcher in the Division of Pediatrics at the University of Texas MD Anderson Cancer Center, presented the findings in a talk entitled, "Rapid production of T cells co-expressing CAR and membrane-bound IL-15 potentiates antitumor activity and promotes in vivo memory." She also presented a poster under the same title during the Keystone Symposia.

Ziopharm is advancing its non-viral Sleeping Beauty platform towards using its point-of-care, or P-O-C, technology, a very rapid manufacturing process of genetically modified CAR+ T cells co-expressing mbIL15, with the first in-human trial utilizing this approach expected to commence in 2018. Ziopharm believes that manufacturing under P-O-C has the potential to reduce the costs associated with T-cell therapies and the potential to broaden application based on avoiding the need for centralized manufacturing as is the case when using a virus to genetically modify T cells.

Dr. Hurton’s poster and presentation slides are based on research conducted in collaboration with The University of Texas MD Anderson Cancer Center and Precigen Inc., a wholly-owned subsidiary of Intrexon Corporation (NYSE:XON). The poster is available in the Presentations and Publications section of the Company’s website, www.ziopharm.com.

On February 12, 2018 ERYTECH Pharma (Euronext: ERYP- Nasdaq: ERYP), a clinical-stage biopharmaceutical company developing innovative therapies by encapsulating therapeutic drug substances inside red blood cells, reported the selection of Triple Negative Breast Cancer as the next target indication for broadening the scope of eryaspase (GRASPA) development in solid tumors (Press release, ERYtech Pharma, FEB 12, 2018, View Source;p=RssLanding&cat=news&id=2332012 [SID1234523923]).

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L-asparaginase is a cornerstone treatment in acute lymphoblastic leukemia (ALL), especially for pediatric patients, but the excessive toxicity of conventional L-asparaginase formulations has limited its use in other indications.

The positive Phase 2b result of eryaspase (L-asparaginase encapsulated in red blood cells) in metastatic pancreatic cancer, reported in 2017, represents, to our knowledge, the first-ever evidence of clinical benefit of an asparaginase-based product in a solid tumor indication. In this 141-patient randomized Phase 2b study, eryaspase in combination with chemotherapy demonstrated a 40% reduction in risk of death rate (HR=0.60; p=0.009) compared to chemotherapy alone.

Following these very encouraging results, ERYTECH conducted a comprehensive evaluation to determine other potential solid-tumor indications for developing eryaspase. Metastatic Triple-Negative Breast Cancer (TNBC) has now been selected as the next indication to expand the potential use of eryaspase in solid tumors. TNBC is an aggressive and metabolically active form of breast cancer with high rates of symptomatic metastases. A recent publication in Nature1 supports the hypothesis that restricting availability of asparagine can reduce metastatic progression of cancer cells in breast cancer. One of the most striking observations from our Phase 2b trial in pancreatic cancer was the 40% reduction of new lesions in the eryaspase arm compared to the control arm.

"TNBC is a heterogenous subgroup of breast cancer associated with poor patient outcome and high risk of recurrence compared to other breast cancer subtypes. Aside from BRCA1/2 mutation status, treatment options for TNBC remain limited," commented Iman El-Hariry, MD, PhD, Chief Medical Officer of ERYTECH. "There is growing evidence of altered metabolism in TNBC. The evaluation of eryaspase in metastatic TNBC provides a promising new therapeutic approach, which capitalizes on reprogramming of the metabolic pathways in this disease."

Gil Beyen, Chairman and CEO of ERYTECH, added, "The selection of TNBC as the second solid tumor indication for evaluating eryaspase anti-tumor activity brings hope for improving the health of these women. The safety profile of eryaspase provides additional rationale for combination with currently existing therapies to increase treatment options in TNBC."

The development in TNBC complements ERYTECH’s pipeline of programs, which focus on the development of therapies that target amino acid metabolism of tumor cells. Set-up activities of a Phase 2 proof-of-concept clinical study have started and ERYTECH expects to enroll the first patient in Q3 2018.

About Triple-Negative Breast Cancer (TNBC)

Breast cancer is the most commonly diagnosed cancer in women globally with nearly 1.8 million new cases diagnosed annually2. It is estimated that over 600,000 women each year are diagnosed with breast cancer in the United States and Europe in aggregate3. Approximately 10-20% of breast cancers are TNBC, a form of breast cancer that lacks expression of estrogen receptor (ER), progesterone receptor (PR) and does not overexpress HER24. TNBC is associated with a poorer prognosis when compared to other breast cancer subtypes. As commonly utilized hormone therapy and HER2 targeting agents are not treatment options for women with TNBC, there is significant unmet need for novel therapeutic approaches in this subtype of breast cancer.

On February 12, 2018 Cellectis (Euronext Growth: ALCLS – Nasdaq: CLLS), a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic CAR T-cells (UCART), reported the issuance of two U.S. patents – US 9,855,297 and US 9,890,393 – for the invention of certain uses of RNA-guided endonucleases, such as Cas9 or Cpf1, for the genetic engineering of T-cells (Press release, Cellectis, FEB 12, 2018, View Source [SID1234523922]). The patents came into force on January 2nd, 2018 and February 13th, 2018, respectively.

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Both patents claim methods by which T-cells are gene edited using transient expression of CRISPR/Cas9 components. These inventions are based on the early work initiated by inventors at Cellectis when the CRISPR technology first came to light.

These therapeutic-focused patents follow the grant by the European Patent Office of patent No. EP3004337 for similar inventions and previous intellectual property that Cellectis has obtained over the last two decades for major gene editing technologies including meganucleases, TALEN, MegaTAL and CRISPR.

"Cellectis is a pioneering gene editing company that has always been keen to be at the forefront of all gene editing technologies," said Dr. André Choulika, Cellectis Chairman & CEO. "We have been the first to explore the potential of CRISPR in its early days in various applications, including therapeutics and plants. These early findings ultimately led to the grant of this set of new patents. As such, these patents only reinforce Cellectis’ leadership position in the gene editing industry."

Convinced of their strong value for the future development of engineered CAR T-cells, Cellectis will make these patents available for licensing to companies that are willing to use CRISPR technologies in T-cells. The technical knowledge in these patents could, for example, help users engineer allogeneic CAR T-cells while suppressing genes involved in checkpoint inhibitions, such as PD-1, engineer drug resistance, or remove MHC (Major Histocompatibility Complex) related genes. The technology could also be used to insert a DNA CAR construct by gene targeting a specific locus in the genome of T-cells.

The inventors of these patents are Dr. André Choulika, Chairman & CEO of Cellectis and one of the pioneers in the development of nuclease-based genome editing technologies; Dr. Philippe Duchateau, Cellectis Chief Scientific Officer and seasoned gene editing expert; and Dr. Laurent Poirot, Cellectis Head of Early Discovery and expert of gene functions in immune cells.

Claims 1 and 2 of US 9,855,297:

1. A method of preparing genetically modified primary T-cells for immunotherapy comprising the steps of: (a) transfecting mRNA encoding an RNA-guided endonuclease into the primary T-cells, wherein the RNA-guided endonuclease is expressed from the transfected m RNA; (b) introducing a DNA vector that encodes a specific guide RNA, wherein the specific guide RNA directs the RNA-guided endonuclease to at least one targeted locus in the T-cell genome into the primary T-cells; (c) cleaving at least one targeted locus in the T-cell genome with the RNA-guided endonuclease; (d) generating a genetic modification at the site of the cleavage; and (e) expanding the resulting genetically modified T-cells.

2. The method of claim 1, wherein the RNA-guided endonuclease is Cas9.

Claim 1 of US 9,890,393:

1. A method of preparing T-cells for immunotherapy comprising the step of:

(a) genetically modifying primary T-cells by introduction and/or expression into the cells of at least:

– a RNA-guided endonuclease; and

– a specific guide RNA that directs said endonuclease to at least one targeted locus in the T-cell genome,

wherein said RNA-guided endonuclease is expressed from transfected mRNA;

wherein said RNA-guided endonuclease comprises the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2; and

(b) expanding the resulting cells.