On January 14, 2015, Boehringer Ingelheim reported that it has established a research alliance with Vanderbilt University and the cancer drug discovery laboratory of Professor Stephen W. Fesik, Ph.D., the Orrin H. Ingram, II Chair in Cancer Research and Professor of Biochemistry, Pharmacology, and Chemistry (Press release Boehringer Ingelheim, JAN 13, 2015, View Source [SID:1234501343]). The aim of the new collaboration is the research and development of small molecule inhibitors of oncogenic Ras for the treatment of cancer. Ras is the most frequently mutated oncogene known in cancer with K-Ras being the most commonly mutated form occurring in pancreas, colon, biliary tract and lung adenocarcinomas. Mutations in the Ras family (comprised of H-Ras, N-Ras and K-Ras) are very common, and found in 20 to 30 percent of all human tumors. Ras has been a particularly difficult protein to target since its discovery in human cancers more than 30 years ago.

Under the terms of the agreement, the research capabilities of Vanderbilt University and Boehringer Ingelheim will be brought together in a multi-year research programme focusing on the development of small molecule inhibitors of Ras. Further details of the agreement are not disclosed.

“We are looking forward to working together with Professor Fesik and his team at Vanderbilt University to discover new medicines for the Ras protein family,” said Michel Pairet, M.D., Senior Corporate Vice President of Research and Non-clinical Development at Boehringer Ingelheim. “We believe that our combined strengths and philosophies in drug discovery will go a long way in addressing what has up to now been a very difficult drug target.”

“Dr. Fesik is a pioneer in the discovery of small molecules that bind to and inhibit challenging drug target proteins. The combination of his lab’s novel techniques and the resources and expertise of Boehringer Ingelheim will result in a powerful drug discovery team,” said Lawrence J. Marnett, Ph.D., the Mary Geddes Stahlman Professor of Cancer Research, University Professor of Biochemistry and Chemistry, and newly appointed associate vice chancellor for Research for the Vanderbilt University Medical Center.

On January 13, 2015 Intrexon and its oncology partner, ZIOPHARM Oncology reported a broad exclusive licensing agreement with The University of Texas MD Anderson Cancer Center, including an exclusive sublicensing agreement through MD Anderson for intellectual property developed at the University of Minnesota for the development of non-viral adoptive cellular cancer immunotherapies (Press release Intrexon, JAN 13, 2015, View Source [SID:1234501340]).

The licensed technologies arise from the laboratory of Laurence Cooper, M.D., Ph.D., professor of pediatrics at MD Anderson and Perry Hackett, Ph.D., professor within the College of Biological Sciences at Minnesota. The Cooper and Hackett laboratories have pioneered the design and clinical investigation of novel chimeric antigen receptor (CAR) T cell therapies using non-viral gene integration platforms. MD Anderson has built on this technology to deliver patient-derived T cells, as well as innovative approaches to generating products for universal off-the-shelf applications. When combined with Intrexon’s technology suite and ZIOPHARM’s clinically tested RheoSwitch Therapeutic System interleukin-12 modules, the resulting proprietary methods and technologies may help realize the promise of genetically modified CAR T cells by tightly controlling cell expansion and activation in the body, minimizing off-target effects and toxicity while maximizing therapeutic efficacy.

“Genetically engineering our patients’ immune-system T cells to efficiently attack and destroy cancer cells represents one of the most exciting approaches with curative potential in oncology today,” MD Anderson President Ron DePinho, M.D., said. “We believe coupling MD Anderson’s unique CAR T cell approach with the powerful technologies of ZIOPHARM and Intrexon will allow us to build T cells that hit cancer harder, with greater precision, under tighter control and with potentially fewer side effects for patients. This agreement ranks as one of MD Anderson’s most substantial collaborations and will provide significant resources to fuel its mission of Making Cancer History.”

“We are proud to see Perry Hackett’s discovery and development work on Sleeping Beauty, a non-viral DNA plasmid-based gene transfer system, in conjunction with Dr. Cooper’s expertise in immunotherapies, provide this breakthrough in oncology” said Brian Hermann, Vice President of Research at the University of Minnesota.

Employing novel cell engineering techniques and multigenic gene programs, the collaboration will implement next-generation non-viral adoptive cellular therapies based on designer cytokines and CARs under control of RheoSwitch technology targeting both hematologic and solid tumor malignancies. The synergy between the platforms will be leveraged to accelerate a promising synthetic immunology pipeline, with up to five CARs expected to enter the clinic in 2015 and off-the-shelf programs initiating in 2016.

“It is a shared vision to maximize the speed and breadth of multigenic innovation for patients through the use of nimble, non-viral DNA cell manufacturing strategies that can further overcome viral packaging constraints and economic limitations,” stated Gregory Frost, Ph.D., Senior Vice President and Head of Intrexon’s Health Sector. “Collectively, this will assemble the most advanced set of technologies to empower the strongest adoptive cell therapy pipeline that can drive innovation through multiple horizons and patient populations.”

Cooper, Hackett and colleagues developed a non-viral DNA plasmid-based gene transfer system to modify T cells by creating a CAR that recognizes and binds to a specific cell surface protein on targeted malignant cells. The testing of this system at MD Anderson in humans paves the way for the rapid design and implementation of modified T cells that can be infused into patients with many types of malignancies.

Work continues in conjunction with MD Anderson’s Moon Shots Program, an ambitious initiative to accelerate the conversion of scientific discoveries into clinical advances and significantly reduce cancer deaths, first targeting eight types of cancer. Cooper leads the Applied Cellular Therapeutics platform for the moon shots, providing expertise and new cellular therapy capabilities for both blood and solid tumor cancers. Clinical trials using non-viral adoptive cellular therapies are either under way or planned for specific moon shot cancers.

The shared infrastructure between MD Anderson, Intrexon and ZIOPHARM enables two approaches to deliver these commercially viable T cells to the bedside. The first develops a point-of-care approach with rapid assembly and infusion of autologous T cells. The second arises from the universal donor platform to infuse off-the-shelf T cells using innovative activation and targeting gene programs that precisely recognize and systemically combat malignancies. The collaboration will advance these platforms in parallel with the most effective CAR-T products tested at MD Anderson graduating to multicenter trials.

“The promise of controlled, cell-based immuno-oncology therapy is that we can achieve dramatic, long duration anti-cancer results while keeping patients out of intensive care during treatment. As importantly, we can reproduce these results in a globally scalable and economically viable way,” remarked Jonathan Lewis, M.D., Ph.D., Chief Executive Officer of ZIOPHARM Oncology. “The MD Anderson Cancer Center has long been a leader in cancer therapy, in terms of innovation, patient care, and the highest quality research. As part of our commitment to this important partnership and the acceleration of translational medicine, ZIOPHARM will build a base of operations in Houston to join and collaborate with the academic and medical community around this world-class institution.”

“The human application of T cell therapies provides cancer patients with new hope, and the alignment of MD Anderson’s immunotherapy and translational programs with Intrexon and ZIOPHARM will help make that hope a reality,” Cooper said. “These two interconnected companies have first-in-class genetic tools and systems to reprogram cells and the management and regulatory expertise to undertake development of potent and focused cell-based immunotherapies.”

Under the terms of the agreement, MD Anderson shall receive consideration of $100 million; $50 million from each Intrexon and ZIOPHARM, payable in shares of their respective common stock, as well as a commitment of $15 to $20 million annually over three years for researching and developing the technologies. The parties will enter into additional collaboration and technology transfer agreements to accelerate technology and clinical development. Further details on the terms of the transaction will be available within the current reports on Form 8-K filed today by Intrexon and ZIOPHARM.

On January 13, 2015 Merck and Eli Lilly and Company reported an oncology clinical trial collaboration to evaluate the safety, tolerability and efficacy of KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with Lilly compounds in multiple clinical trials:

Merck will conduct a Phase 2 study examining the combination of pembrolizumab with pemetrexed in first-line non-squamous, non-small cell lung cancer (NSCLC) (Press release Eli Lilly, JAN 13, 2015, View Source [SID:1234501339]). This study is currently enrolling.
Lilly will conduct a multiple-arm Phase 1/2 study examining the combination of ramucirumab with pembrolizumab in multiple tumors. This study is anticipated to begin in 2015.
Lilly will conduct a Phase 1/2 study examining the combination of necitumumab with pembrolizumab in NSCLC. This study is anticipated to begin in 2015.

The agreement is between Lilly and Merck, through a subsidiary. Additional details of the collaboration were not disclosed.

“Cancer is not one disease but rather more than 200 diseases, all of which have different causes and treatments,” said Richard Gaynor, M.D., senior vice president, product development and medical affairs, Lilly Oncology. “Therefore research into combinations of immune-based therapies with other agents that could address these different tumor types is important. This collaboration between Lilly and Merck represents each company’s strong commitment to patients fighting these devastating diseases.”

“Our understanding of the immune system’s role and its impact in the treatment of cancer continues to grow,” said Eric Rubin, M.D., vice president, global clinical development, oncology, Merck Research Laboratories. “Collaborations such as this one are important in advancing the investigation of novel immuno-oncology combinations in different cancers, and to achieving our shared goal of bringing meaningful benefits to patients facing cancer.”

On January 13, 2015 Bristol-Myers Squibb and Eli Lilly and Company reported a clinical trial collaboration to evaluate the safety, tolerability and preliminary efficacy of Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab) in combination with Lilly’s galunisertib (LY2157299) (Press release Bristol-Myers Squibb, JAN 13, 2015, View Source [SID:1234501334]). The Phase 1/2 trial will evaluate the investigational combination of Opdivo and galunisertib as a potential treatment option for patients with advanced (metastatic and/or unresectable) glioblastoma, hepatocellular carcinoma and non-small cell lung cancer.

Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. Galunisertib (pronounced gal ue” ni ser’tib) is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body. This collaboration will address the hypothesis that co-inhibition of PD-1 and TGF beta negative signals may lead to enhanced anti-tumor immune responses than inhibition of either pathway alone.

“Advanced solid tumors represent a serious unmet medical need among patients with cancer,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “Our clinical collaboration with Lilly underscores Bristol-Myers Squibb’s continued commitment to explore combination regimens from our immuno-oncology portfolio with other mechanisms of action that may accelerate the development of new treatment options for patients.”

“Combination therapies will be key to addressing tumor heterogeneity and the inevitable resistance that is likely to develop to even the most promising new tailored therapies,” said Richard Gaynor, M.D., senior vice president, Product Development and Medical Affairs, Lilly Oncology. “To that end, having multiple cancer pathways and technology platforms will be critical in an era of combinations to ensure sustainability beyond any single asset.”

The study will be conducted by Lilly. Additional details of the collaboration were not disclosed.