Moffitt Researchers Identify Molecular Characteristics of Leptomeningeal Melanoma Metastases

On January 10, 2020 Moffitt Cancer Ctr reported that patients with advanced melanoma who develop metastases in the leptomeninges, the fluid filled membranes surrounding the brain and spinal cord, have an extremely dismal prognosis (Press release, Moffitt Cancer Ctr, JAN 10, 2020, View Source [SID1234553269]). Most patients only survive for 8 to 10 weeks after diagnosis. One reason for this poor prognosis is that very little information is known about the molecular development of leptomeningeal melanoma metastases (LMM), making it difficult to develop effective therapies. Researchers in Moffitt Cancer Center’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence and the Department of Neuro-Oncology sought to change this by performing an extensive analysis of the molecular characteristics of the cerebrospinal fluid of patients with LMM. Their findings were published in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Cancer development and progression are highly regulated by intricate interactions between cancer cells and the surrounding environment. Melanoma cells that invade and metastasize into the leptomeninges interact with the surrounding cerebrospinal fluid. Moffitt researchers wanted to improve their understanding of the development of LMM by analyzing the protein and RNA composition of cerebrospinal fluid from patients with LMM. They compared the molecular profiles of 8 control patients without LMM to 8 patients with LMM, including one LMM patient who had an extraordinary response to treatment and was still alive more than 35 months after diagnosis.

They discovered that the cerebrospinal fluid from LMM patients was enriched for proteins involved in innate immunity, proteases and the IGF-signaling pathway. The most commonly altered protein was TGF-β1. Interestingly, the one patient who had an extraordinary response to treatment displayed high levels of these proteins at baseline, but expression levels decreased as the patient responded to treatment. However, the protein expression patterns in the remaining LMM patients who had poor responses to treatment were high at baseline and remained high throughout treatment and disease progression.

The researcher team, led by Keiran Smalley, Ph.D., director of the Donald A. Adam Melanoma and Skin Cancer Center of Excellence and Peter Forsyth, M.D., Chair of the Department of Neuro-Oncology, hypothesized that the cerebrospinal fluid of LMM patients could impact melanoma cells by modulating their molecular profile. They confirmed this hypothesis by incubating cerebrospinal fluid from the LMM patients with melanoma cells and discovered that the fluid was able to induce activation of proteins and signaling pathways involved in malignant progression, including the PI3K/AKT pathway, integrins, B cell signaling, mitotic cell cycle progression, TNFR, TGF-β and oxidative stress.

Their findings demonstrate that the cerebrospinal fluid from LMM patients who did not respond to treatment promoted survival of melanoma cells, while the cerebrospinal fluid from the extraordinary responder did not promote survival. These observations suggest that molecules exist within the cerebrospinal fluid that can stimulate melanoma cell survival and prevent cell death. The researchers reported that one of these survival molecules is TGF-β. The patient who responded well to treatment had very low to undetectable levels of cerebrospinal fluid TGF-β, while those patients who did not respond to treatment had much higher levels of TGF-β.

The researchers hope that their data will provide important knowledge about LMM and offer insights into potential therapeutic targets. "It is likely that the environment of LMM is a key regulator of both disease progression and therapeutic response. Improved knowledge about the microenvironment of LMM may allow novel therapeutic strategies to be developed that can delay disease progression," explained Smalley.

This study was supported by grants from the National Institutes of Health, the Department of Defense and the State of Florida.

Tyra Biosciences raises $50M to develop therapies targeting acquired resistance in oncology

On January 10, 2020 Tyra Biosciences reported a Series A financing of $50M to discover and develop new small molecule therapies targeting acquired resistance in oncology (Press release, Tyra Biosciences, JAN 10, 2020, View Source [SID1234552976]). Patients are devastated by the emergence of drug resistance after initially responding to targeted therapies, often leaving them and their physicians scrambling for options. Tyra Biosciences is a purpose-built company – with a founding team optimized for tackling this high-impact problem – aiming to develop very specific compounds targeting drug resistant cancer cells and populations.

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The financing round was co-led by Alta Partners, RA Capital, Boxer Capital of Tavistock Group, and Canaan. The funds raised will be used to advance next-generation compounds targeting acquired resistance to current therapies towards clinical trials.

"We are thrilled to have the backing of a strong syndicate, which includes early-stage and crossover firms representing tremendous experience and expertise in the industry," said Todd Harris, co-founder and CEO of Tyra Biosciences. "We are eager to deliver solutions for patients who desperately need additional treatment options. The financing round provides sufficient funding to reach a clinical inflection point, maximizing options for the company."

Targeted oncology – and tyrosine kinase inhibitors (TKIs), specifically – have made significant advancements for cancer patients over the last 20 years. These therapies are able to target discrete proteins involved in signaling pathways that drive tumor growth. In that time, over 40 TKIs have been approved, driving value for patients and investors alike. But as compounds have become more selective and potent, resistance has become a major limitation. Tyra Biosciences is combining insights from structure-based drug design (SBDD), kinase biology, computational chemistry and smart clinical development to discover and develop next-gen small molecule therapies that are active against both wild type and mutant targets.

"The need from patients and the demand from the market for therapies that address acquired resistance has never been stronger," said Isan Chen, Board Member of Tyra Biosciences. "Not only can these medicines be used as the immediate response when resistance emerges but they can also move to front-line treatments with the promise of better efficacy and much longer duration of response than first-generation agents."

"Our approach to drug discovery and development is highly focused and disciplined" said Daniel Bensen, co-founder and COO of Tyra Biosciences. "Leveraging key insights into the molecular basis of acquired resistance, we generate validating translational toolkits and rapidly iterate with SBDD to advance next-generation compounds."

Co-Founders Todd Harris & Daniel Bensen

Co-Founded by Todd Harris, Chief Executive Officer, and Daniel Bensen, Chief Operating Officer, and incubated by Alta Partners, Tyra Biosciences has formed a small cross-functional team, aiming to outpace others in the market by being focused, creative, fast and iterative. Key drug development professionals and scientific advisors include:

— Ronald V. Swanson, Ph.D., Chief Scientific Officer;

— Robert L. Hudkins, Ph.D., Vice President, Chemistry;

— Jane Arboleda, Associate Director of Cell Biology;

— Esther van den Boom. Chief Financial Officer;

— Jeffrey Hager, Ph.D., Scientific Advisor;

— William Hahn, M.D. Ph.D., Scientific Advisor; and

— Jason Sheltzer, Ph.D, Scientific Advisor.

The company’s board members have an extensive history of successful drug development in oncology and life sciences company-building:

— Bob More, Chairman and Managing Director, Alta Partners;

— Isan Chen, M.D., Chief Medical Officer, Mirati Therapeutics;

— Gilla Kaplan, Ph.D., formerly at Gates Foundation, Rockefeller University, and Celgene;

— Jake Simson, Ph.D., Principal, RA Capital Management

— Sid Subramony, Ph.D., Vice President, Boxer Capital of Tavistock Group; and

— Nina Kjellson, General Partner, Canaan.

"As a nimble company with a singular focus on acquired resistance in oncology, Tyra Biosciences is well positioned to deliver solutions for patients," said Gilla Kaplan, Board Member of Tyra Biosciences and pioneering scientist who re-invented thalidomide as an immune modulator, thereby spurning the Celgene success story. "The company has the benefit of a world-class team of drug developers and advisors to help them efficiently and effectively advance new therapies into the clinic."

Fusion Pharmaceuticals To Present at The 38th Annual J.P. Morgan Healthcare Conference

On January 10, 2020 Fusion Pharmaceuticals Inc., a privately-held, clinical-stage precision oncology company developing next-generation radiopharmaceuticals, reported that Chief Executive Officer John Valliant, Ph.D., will present an overview of the Company at the 38th Annual J.P. Morgan Healthcare Conference in San Francisco, California (Press release, Fusion Pharmaceuticals, JAN 10, 2020, View Source [SID1234552993]). The presentation will take place on Thursday, January 16, 2020 at 11:00am PST.

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Rakuten Medical to Present at the 38th Annual J.P. Morgan Healthcare Conference

On January 10, 2020 Rakuten Medical, Inc. (RMI) a clinical-stage, global biotechnology company developing precision-targeted cancer therapies based on its proprietary, anti-cancer treatment platform, Illuminox, reported that will present at the 38th Annual J.P. Morgan Healthcare Conference being held January 13-16, 2020, in San Francisco (Press release, Rakuten Medical, JAN 10, 2020, View Source [SID1234552977]).

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Rakuten Medical’s Chairman and CEO, Hiroshi "Mickey" Mikitani, will present at 4:30 p.m. PST, Monday, Jan. 13 at the Westin St. Francis Hotel, Elizabethan Room C/D.

The annual J.P. Morgan Healthcare Conference is the largest and most informative healthcare investment symposium in the industry, bringing together industry leaders, emerging fast-growth companies, innovative technology creators and members of the investment community.

Indapta Therapeutics and Lonza Announce Strategic Partnership to Advance a Next-generation, Off-the-shelf, Allogeneic Immuno-oncology Therapy

On January 10, 2020 Indapta Therapeutics, Inc., a biotechnology company focused on developing and commercializing a proprietary, first-in-class, off-the-shelf, non-engineered, allogeneic G-NK (FcRγ-deficient Natural Killer) cell therapy to treat multiple cancers, and Lonza reported a strategic partnership (Press release, Indapta Immuno Therapeutics, JAN 10, 2020, View Source [SID1234552994]). Indapta also announced its founding leadership team and scientific advisors.

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Under the terms of the agreement, Lonza will manufacture Indapta’s off-the-shelf, allogeneic G-NK cell therapy under current good manufacturing practices (cGMP) for use in clinical studies. Indapta will leverage Lonza’s process development capabilities and expertise to ensure a robust, reproducible and scalable cGMP process. Process development and manufacturing will take place in Lonza’s state-of-the-art cell and gene therapy manufacturing facility in Houston.

"We believe our first-in-class, off-the-shelf, allogeneic G-NK cell therapy will drive the next critical phase in the evolution of cancer therapies following CAR T-cell therapies," said Guy DiPierro, founder and chief executive officer of Indapta Therapeutics. "Current autologous CAR T-cell therapies have proven efficacy in various hematologic cancers but have been beset with serious clinical and manufacturing challenges. By providing an off-the-shelf solution with our G-NK cell therapy, we can eliminate the need for a patient-specific therapy. Additionally, because our investigational cell therapies are not engineered, they are likely to be more effective, less costly and have a simpler regulatory pathway."

"Lonza, with its demonstrated expertise in cell therapy manufacturing, is the ideal strategic partner to help us advance our clinical program and scale the production of our G-NK cell therapy," said Ronald Martell, co-founder and executive chairman of Indapta Therapeutics. "We are currently completing Investigational New Drug-enabling studies and plan to submit an IND application in late 2020 and initiate a first-in-human Phase 1/2 study in early 2021."

"Indapta’s world-class team of NK cell scientists and clinicians and cell therapy experts has created an innovative off-the-shelf immuno-oncology therapy based on a subset of cancer-killing NK cells that could make a truly meaningful impact in the treatment of hematologic malignancies and solid tumors," said Scott Waldman, chief strategy officer at Lonza.

Alberto Santagostino, senior vice president, head of Cell & Gene Technologies at Lonza, added, "with our long-standing experience in cell therapy manufacturing, we are committed to providing Indapta with the expertise, resources and services it needs for cGMP manufacturing to advance its promising program into the clinic and beyond."

About Indapta’s G-NK Cell Therapy

Indapta Therapeutics is developing off-the-shelf, allogeneic FcεRIγ-deficient NK cells, known as G-NK cells.i,ii,iii These proprietary cells are a specific and potent subset of NK cells with specialized anti-tumor activity when used in combination with a monoclonal antibody. G-NK cells are NK cells that have undergone an epigenetic change after coming into contact with cytomegalovirus (CMV)-infected cells. As a result, they lack the FcεRIγ signaling adapter and, instead, use a different adapter protein, which predisposes them to a far more activated state of antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of a monoclonal antibody. When the monoclonal antibody binds to the tumor target and to the Fc receptor on G-NK cells, it initiates the release of dramatically more immune-stimulating cytokines and cell-killing enzymes than conventional NK cells, causing the direct killing of tumor cells and driving tumor cell death. G-NK cells have been demonstrated to be safe; in vivo studies demonstrate they do not cause graft-vs-host disease or cytokine release syndrome, which can occur with CAR-T cell therapies.

Preclinical research, conducted under NIH grants by scientists at the University of California, San Francisco (UCSF), demonstrated the safety and efficacy of G-NK cells administered in combination with a therapeutic monoclonal antibody. Clinical models of multiple myeloma and lymphoma demonstrated improved survival, a statistically significant decrease in tumor growth, and a statistically significant increase in the activity of the monoclonal antibody without causing graft-vs-host disease. When administered in combination with a monoclonal antibody, G-NK cells have been shown to be highly persistent (lasting four to nine months), to have the ability to preferentially bind to a therapeutic monoclonal antibody in the presence of a tumor cell, and to demonstrate superior ADCC function compared with conventional NK cells. Under a second Indapta NIH grant, researchers at Stanford University will be conducting in vivo studies in additional tumor models.

Indapta’s off-the-shelf G-NK cell therapy is differentiated from an autologous therapy in that it is not necessary to collect cells from each individual patient and produce a unique therapy for every patient. Rather, it is derived from cells from healthy volunteers, which are highly functional and persistent. Indapta’s process for producing G-NK cell therapy for use as an immunotherapy involves taking blood from CMV-seropositive donors, identifying and sorting G-NK cells from these samples, and expanding G-NKs cells using the company’s proprietary, patented expansion method, which preferentially expands and activates GNK cells. Indapta has also developed a proprietary method for freezing and storing the G-NK cells in a GMP master cell bank for use as off-the-shelf allogeneic outpatient immunotherapy in cancer patients.

Developing off-the-shelf G-NK cells may sidestep some of the clinical and financial challenges presented by other, more customized and engineered immuno-oncology approaches, which involve time-consuming and costly manufacturing processes and often can only be delivered in specialized centers. The manufacturing COGS for Indapta’s program will be relatively inexpensive compared to CAR-T or engineered NK cell therapies. Additionally, the regulatory approval process for Indapta’s program may be more straightforward than that for autologous CAR-T cell therapy or engineered NK cells because it does not involve complicated cell engineering.

Not only are G-NK cells widely available from multiple sources, they have the potential to be used in combination with multiple monoclonal antibodies to treat numerous types of cancer (e.g., multiple myeloma, lymphoma, leukemia, melanoma, ovarian, colorectal, renal, liver, breast and lung).

Indapta’s Founding Management Team

Guy DiPierro, Founder and Chief Executive Officer, has over 15 years of experience founding, building, funding and attracting world-leading talent to specialty pharma companies. Prior to Indapta, he was the founder, CEO, chairman and inventor at Chrono Therapeutics. Earlier in his career, he served as Executive Vice President and General Counsel of AMGI Capital. Before that, he was a corporate M&A and technology licensing attorney at Brown and Wood (now Sidley Austin) and Squadron Ellenoff (now Hogen Lovells). He is the inventor on 11 granted U.S. patents and over 36 global and pending patents.
Ronald Martell, Co-Founder and Executive Chairman, has founded, led, built and/or managed a number of unique businesses in the biotech industry during the last 30 years. They include Encellin, ORCA BioSystems, Cetya Therapeutics, HAVAH Therapeutics, Achieve Life Sciences, Sevion Therapeutics, KaloBios, NeurogesX, Poniard Pharmaceuticals, and ImClone Systems. He is currently the president and CEO of Nuvelution Pharma.
Catherine Polizzi, Chief Intellectual Property (IP) Counsel, is a partner at Morrison Foerster, where she assists emerging and established companies in obtaining patents, provides strategic portfolio counseling and management around breakthrough therapies in a variety of areas, including cancer immunotherapy, and offers strategic advice regarding freedom of operation and other forms of IP assessment. She was head IP attorney for Juno Therapeutics, which was acquired by Celgene for $9 billion in part on the strength of the patent portfolio that she crafted.
Austin Bigley, Ph.D., Acting Director of Research and Development, is a member of the Department of Health and Human Performance at the University of Houston. He is an NK cell expert, particularly in how CMV infection modulates NK cell activity against hematologic malignancies; NK cell expansion; ADCC; and the monoclonal antibody-NK cell cytotoxicity domain.
Kathy Leach, Ph.D., Chemistry, Manufacturing & Controls (CMC) and Quality Advisor, was formerly a director of CMC Quality & Analytics at Juno Therapeutics, where she was responsible for the quality strategy and management of key CMC programs for the company’s cell therapy products. Earlier in her career, she was a product quality director at Amgen and a formulation/analytical research scientist at Immunex.
Indapta’s Scientific Advisors

Nina Shah, M.D., Associate Professor, Department of Medicine, UCSF. A hematologist specializing in the treatment of multiple myeloma, Dr. Shah treats patients at the Hematology and Blood Marrow and Transplant Clinic at UCSF. She has expertise in the intersection of immunology and oncology and helping patients fight multiple myeloma by boosting their immune system.
Sungjin Kim, Ph.D., Scientific Founder of Indapta; Inventor and Associate Professor, Department of Medical Microbiology and Immunology, University of California, Davis
John Sunwoo, M.D., Scientific Founder of Indapta; Professor, Stanford University School of Medicine
Todd A. Fehniger, M.D., Ph.D., Associate Professor of Medicine, Washington University School of Medicine
Vaughn Smider, M.D., Ph.D., Associate Professor, Molecular Medicine, The Scripps Research Institute
Arun Witta, M.D., Ph.D., Associate Professor, Department of Laboratory Medicine, UCSF