On June 25, 2020 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported positive preclinical findings published in Frontiers in Immunology regarding the prospect of MN-166 (ibudilast) as an adjunct treatment for glioblastoma (Press release, MediciNova, JUN 25, 2020, View Source [SID1234561500]).

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The publication, entitled "Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression", was a collaborative effort between MediciNova and the Cleveland Clinic, led by Tyler Alban (doctoral candidate) and Dr. Justin Lathia, Co-Director of the Brain Tumor Research and Therapeutic Development Center of Excellence at the Lerner Research Institute, Cleveland Clinic, and Associate Professor, Department of Molecular Medicine at Case Western Reserve University. Dr. Lathia, Dr. Michael Vogelbaum (previously at the Cleveland Clinic, now at Moffitt Cancer Center in Tampa, FL) and colleagues previously reported on findings that GBM patients had higher levels of immune suppressive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and they tended to be resistant to and dependent on macrophage migration inhibitory factor (MIF). In this research publication, in collaboration with Dr. Richard Bucala (Yale University), they report the monocytic subset of MDSCs (M-MDSCs) expressed high levels of the MIF cognate receptor CD74 in the tumor microenvironment. This finding is meaningful in that targeting M-MDSCs with ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, resulted in decreased MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. They note that clinical trial results to date suggest that treatment with an immune stimulatory therapy alone is not effective in treating GBM and hypothesized that better clinical outcomes will be seen when an immune stimulatory therapy is combined with ibudilast, which has been shown to reverse tumor-induced immune suppression.

Dr. Justin Lathia commented, "We found that the receptor CD74 may play a greater role in GBM MDSC biology because the subset of MDSCs primarily found in the tumor microenvironment were M-MDSCs, which predominantly express CD74 as a MIF receptor. These findings are significant for treating patients diagnosed with GBM. Among multiple anti-MIF agents we tested, ibudilast was most potent with reducing M-MDSCs. Ibudilast readily crosses the blood-brain barrier, an advantage over other agents, and has a strong safety profile. Our hope is that combining ibudilast and immune stimulatory therapy will translate to decreased disease progression in clinical trials."

Yuichi Iwaki, MD, PhD, President and Chief Executive Officer of MediciNova, Inc., commented, "We have an ongoing clinical trial evaluating MN-166 in combination with temozolomide for the treatment of GBM at the Dana-Farber Cancer Institute, Harvard Medical School. Recently, we expanded our target population to include patients with either recurrent or newly diagnosed GBM. A recently published GBM animal model study showed that median survival was longer in the group treated with MN-166 plus temozolomide than in the group treated with temozolomide alone. The new findings reported by Dr. Lathia and his colleagues may lead to the use of MN-166 as combination therapy with immune stimulatory treatment and may offer a new treatment option to patients with GBM, one of the most serious refractory cancers."

About Glioblastoma

According to the American Association of Neurological Surgeons, glioblastoma is an aggressive brain cancer that often results in death within 15 months of diagnosis. Glioblastoma develops from glial cells (astrocytes and oligodendrocytes), grows rapidly, and commonly spreads into nearby brain tissue. Glioblastoma is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that glioblastoma represents about 15% of all primary brain tumors and approximately 10,000 cases of glioblastoma are diagnosed each year in the U.S. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with glioblastoma. Median survival is approximately 11-15 months for adults with more aggressive glioblastoma (IDH-wildtype) who receive standard treatment of surgery, temozolomide, and radiation therapy.

About MN-166 (ibudilast)

MN-166 (ibudilast) is a first-in-class, orally bioavailable, small molecule macrophage migration inhibitory factor (MIF) inhibitor and phosphodiesterase (PDE) -4 and -10 inhibitor that suppresses pro-inflammatory cytokines and promotes neurotrophic factors. Our earlier human studies demonstrated significant reductions of serum MIF level after treatment with MN-166 (ibudilast). It also attenuates activated glial cells, which play a major role in certain neurological conditions. MN-166 (ibudilast)’s anti-neuroinflammatory and neuroprotective actions have been demonstrated in preclinical and clinical studies, which provide the rationale for treatment of amyotrophic lateral sclerosis (ALS), progressive multiple sclerosis (MS) and other neurological diseases such as glioblastoma (GBM), and substance abuse/addiction. MediciNova is developing MN-166 for ALS, progressive MS and other neurological conditions such as degenerative cervical myelopathy (DCM), glioblastoma, substance abuse/addiction, and chemotherapy-induced peripheral neuropathy. MediciNova has a portfolio of patents which covers the use of MN-166 (ibudilast) to treat various diseases including ALS, progressive MS, and drug addiction.

On June 25, 2020 Intensity Therapeutics, Inc., a clinical-stage biotechnology company pioneering a novel, immune-based drug approach to treat solid tumor cancers through direct tumor injection, reported the publication of results from the Company’s nonclinical research in the International Journal of Molecular Sciences (IJMS) (Press release, Intensity Therapeutics, JUN 25, 2020, View Source [SID1234561467]). The paper titled, "Intratumoral Administration of a Novel Cytotoxic Formulation with Strong Tissue Dispersive Properties Regresses Tumor Growth and Elicits Systemic Adaptive Immunity in In Vivo Models," was published in IJMS as part of a Special Issue titled The Immune Landscape in Solid Tumors. The Special Issue addresses various aspects of the molecular and cellular biology of immune cells in the context of tumors and invites experts in the field to contribute an original research article or a comprehensive review. The paper is available online (doi.org/10.3390/ijms21124493).
The paper describes the Company’s lead product candidate, INT230-6, a novel combination of cisplatin and vinblastine formulated with a unique amphiphilic diffusion enhancer molecule (SHAO) that non-covalently interacts with payloads to increase intratumoral (IT) drug dispersion when injected into solid tumors. The data reported demonstrated that INT230-6 achieved greater inhibition of tumor growth and improved survival compared to the same drugs without enhancer given intravenously or IT. INT230-6 treatment increased the number of immune infiltrating cells within injected tumors. Animals demonstrating complete responses developed systemic immunity to the cancer. INT230-6 when combined with anti-programmed cell death protein 1 (PD-1), antibodies resulted in improved survival and increased rate of complete responses. INT230-6 induced significant tumor necrosis, which induced a systemic immune-based anti-cancer attack. This research demonstrates a novel, local treatment approach for cancer that minimizes systemic toxicity while stimulating adaptive immunity.

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"The results reported in the paper provided the pre-clinical rationale to advance INT230-6 into clinical development," said Lewis H. Bender Founder, President and CEO of Intensity Therapeutics and lead author on the paper. "Our clinical research conducted to-date is consistent with the results of this paper; data suggests that the dispersion, tumor-killing and immune activation properties of INT230-6 observed in mice are translating to humans. We are looking forward to initiating phase 2 clinical cohorts later this year combining INT230-6 with our partners’ products, Merck’s pembrolizumab and Bristol Myers Squibb’s ipilimumab, in cancers with high unmet medical need."

About INT230-6

INT230-6, Intensity’s lead proprietary product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRxSM technology platform. The drug is comprised of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule that helps disperse the drugs throughout tumors for diffusion into cancer cells. In preclinical studies, INT230-6 eradicated tumors by a combination of direct tumor killing, release of tumor antigens and recruitment of immune cells to the tumor. Results generated by both the Company and the National Cancer Institute (NCI) showed treatment with INT230-6 in in vivo models of severe cancer resulted in substantial improvement in overall survival compared to standard therapies. Further, INT230-6 provided complete responses in animals with long-term protection from multiple re-challenges of the initial cancer and resistance to other cancers. The Company’s research published in the International Journal of Molecular Sciences and jointly with the NCI as part of Intensity’s collaborative research, published in July 2019 in the Journal OncoImmunology, also showed strong synergy when INT230-6 was combined with anti-PD-1 and anti-CTLA-4 antibodies. INT230-6 is being evaluated in a Phase 1/2 clinical study (NCT03058289) in patients with various advanced solid tumors. There have been no dose limiting adverse events observed in patients to date, even when dosing into deep tumors in the lung and liver. Several patients demonstrated tumor shrinkage, symptomatic improvement, and evidence of cancer cell death and immune cell activation on tumor biopsy. In combination cohort with pembrolizumab the Company reported the safety of combination was comparable to INT230-6 monotherapy.

On June 25, 2020 NantHealth, Inc. (NASDAQ: NH), a next-generation, evidence-based, personalized healthcare company, reported the publication of a study in JCI Insight, a peer-reviewed journal dedicated to biomedical research from preclinical to clinical studies (Press release, NantHealth, JUN 25, 2020, View Source [SID1234561468]). This research looked into the discordance between genomic sequencing and transcriptome analysis, and how this may reflect a mechanism of resistance to therapy in tumors that has previously been under-recognized and should be subject to further investigation.

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Next-generation sequencing (NGS) of DNA has not revealed all the mechanisms underlying resistance to genomically matched drugs. This study was designed to discover another potential mechanism. Researchers evaluated data from 1,417 tumors whole-exome tumor (somatic)/normal (germline) NGS and whole-transcriptome sequencing in order to examine transcriptomic silencing of putative driver alterations. Drivers are significant in this context, compared to passenger mutations, which are not linked to targeted drug therapies. Thus the data is particularly clinically relevant because it pertains to mutations that are commonly used to prescribe drug therapies. In this large-scale study, they also determined the frequency of tumor mutations being germline, rather than somatic, in these and an additional 462 tumors with tumor and normal exomes. They found there was a high risk of germline mutations being falsely reported as somatic. In that event, clinicians may prescribe a treatment that would actually target the normal healthy germline cells in addition to tumor cells and result in greater toxicity. In examination of a set of 50 genes highly associated with cancer and targeted therapies, at least 13% of variants detected in DNA were unexpectedly not expressed.

The research confirmed that both the frequency of silenced variant transcription and the risk of falsely identifying germline mutations as somatic are important. Therefore, transcriptomics is critical in conjunction with genomics when interrogating patient tumors for actionable alterations, and to ultimately reduce the risk of therapeutic resistance.

"Exploring another mechanism of resistance to therapy and thus helping bring about a deeper understanding around the interrogation of patients’ tumors brings with it hope and excitement for the success of future therapeutics," said Dr. Sandeep "Bobby" Reddy, Chief Medical Officer, NantHealth. "NantHealth is dedicated to the fight against cancer, devoting much time to finding effective personalized cancer treatments. The recognition of transcriptomic silencing means that we may be giving targeted therapies to up to 13% of patients in whom the target is actually missing."

JCI Insight publishes well-executed, high-quality, insightful research in all biomedical specialties, including autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, vascular biology and many others. JCI Insight builds on the editorial leadership of the JCI, one of the oldest and most respected biomedical research journals, and is self-published by the American Society for Clinical Investigation (ASCI). JCI Insight serves to fulfill the ASCI’s objective to advance medical science through the publication of clinically relevant research reports.

NantHealth is focused on using data to close the loop – connecting payers, providers, and patients. Through its software, it facilitates the delivery of precise and timely data for creating efficiency, personalized treatment, and collaboration across healthcare.

On June 25, 2020 NeoImmuneTech, Inc., a clinical-stage T cell-focused biopharmaceutical company, reported the first patient has been dosed at The University of Texas MD Anderson Cancer Center in the Phase 1b/2a clinical trial of NT-I7 (efineptakin alfa) in combination with KEYTRUDA, a leading checkpoint inhibitor (CPI), for the treatment of patients with relapsed/refractory advanced solid tumors (Press release, NeoImmuneTech, JUN 25, 2020, View Source [SID1234561486]).

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"We’re very pleased to further progress this critically important clinical program quickly, despite the challenges due to the COVID-19 pandemic. Dosing the first patient in this study marks a major milestone in the development of NT-I7 for the treatment of patients with advanced solid tumors," said NgocDiep Le, M.D., Ph.D., Executive VP and Chief Medical Officer of NeoImmuneTech. "We will investigate clinically NT-I7’s potential to augment the already proven anti-tumor activity of pembrolizumab in CPI-responsive tumors. Additionally, we will also explore whether the combination can overcome CPI resistance. We hope that NT-I7 in combination with KEYTRUDA can improve the lives of cancer patients with various solid tumors."

The goal of the Phase 1b portion of the study, which will enroll up to 18 patients, is to establish a recommended dosing regimen. The Phase 2a portion will enroll up to 150 patients and will explore the preliminary anti-tumor activity of the combination therapy both in patients who have been treated with a CPI and patients who are CPI-naïve. The results of this study will be used to guide further clinical development of this combination in select tumor types.

More information can be found at www.neoimmunetech.com or www.clinicaltrials.gov, identifier: NCT04332653

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA.

About NT-I7

NT-I7 (efineptakin alfa) is the only clinical-stage long-acting human IL-7, and is being developed in oncologic and immunologic indications, where T cell amplification and increased functionality may provide clinical benefit. IL-7 is a fundamental cytokine for naïve and memory T cell development and for sustaining immune response to chronic antigens (as in cancer) or foreign antigens (as in infectious diseases). NT-I7 exhibits favorable PK/PD and safety profiles, making it an ideal combination partner. NT-I7 is being studied in multiple clinical trials in solid tumors and as vaccine adjuvant. Studies are being planned for testing in hematologic malignancies, additional solid tumors and other immunology-focused indications.

On June 25, 2020 TAE Technologies Inc. of Foothill Ranch races to solve the world’s energy problems via nuclear fusion,reported that its 3-year-old biologically-targeted radiation therapy offshoot is inching closer to its own world-changing target: treating and curing cancer patients (Press release, TAE Life Sciences, JUN 25, 2020, View Source [SID1234561517]).

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TAE Life Sciences LLC recently announced a $30 million investment to support its drug development program, which when combined with its neutron beam accelerator technology could unlock a new generation of targeted cancer therapy.

The Series B initial funding is among the largest in Orange County in the first half of the year.

The amount of funding is indicative of the company’s high expectations, officials tell the Business Journal.

"TAE Technologies doesn’t shy away from some pretty ambitious goals. We have the same culture at our company," said Bruce Bauer, chief executive of TAE Life Sciences, or TLS.

"We believe we have a technology that is going to change the world of cancer therapy. That’s an ambitious goal and a challenging area, but we have a culture of solving big problems. We’re not shying away from the magnitude of it."

Tumors Targeted

TLS publicly launched in March 2018 with some $40 million in funding at a $100 million valuation. Its combined $70 million of reported investments to date is a relatively small amount of funding compared to the $700 million its parent company has raised over the past 18 years; TAE Technologies backers have included Google and the late Paul Allen, co-founder of Microsoft Corp.

The PhD-heavy parent company, which is aiming to commercialize its space-age fusion technologies in the next three years or so, is reported to have a $3 billion valuation.

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TLS exclusively licensed its parent company’s accelerator technology, built on more than two decades of research that originated at the University of California-Irvine. The parent company’s goals are to provide an abundant source of energy that produces fewer pollutants.

TLS is using that same base of technology for medical applications: it aims to build a neutron delivery system for an emerging type of radiation therapy called Boron Neutron Capture Therapy or BNCT. BNCT is a radiation therapy technique that offers noninvasive treatment options for cancers of the head and neck, brain tumors and other aggressive and recurrent cancers.

TLS’ delivery system, called the AlphaBeam, produces low-energy neutrons that neutralize tumors containing accumulated boron-10, a nontoxic type of isotope that when given to a patient via a drug collects in tumor cells.

The radiation therapy is designed to spare healthy tissue. Because the boron-10 carrier drug is highly targeted to accumulate cancer cells, a patient could in theory be treated in just one or two treatment sessions, without many of the side effects of traditional radiation therapy.

Testing Underway

The technology is still in the testing phase.

The company’s first commercial system is currently on its way to a site in China, where its partner Neuboron Medtech Ltd. plans to launch Phase II clinical trials with TLS’ accelerator-based neutron system and a boron-10 target drug called BPA, which has been used to treat about 2,000 patients to date.

In the meantime, TLS is finalizing construction plans with an Italian-based partner, which will kick off clinical trials for CE markings in 2022. U.S. clinical trials will follow with at least three or more clinical sites.

On the drug development side, Bauer said research will continue for several years before clinical trials can begin.

"We’re bringing together everything from particle acceleration technology to pharmaceutical development. It takes time and perseverance, and that’s what we’re bringing to the table."

$100M Mission

TLS announced the $30 million initial close of its Series B round of financing on June 2.

More’s in store. Bauer—whose résumé includes stints in the private equity and medical imaging industries—said TLS ultimately wants to raise $100 million in its Series B round.

San Francisco-based Artis Ventures, which led TLS’ $40 million Series A round in 2018, participated in the deal.

R&D

Funds from the latest funding round will support drug development, which takes place at the company’s new R&D facility in Santa Monica. The building was previously occupied by Japan’s Stella Pharma Corp., which has experience in creating boron compounds for BNCT.

TLS subleased the 16,000-square-foot lab and recruited a core team of researchers from Stella, Bauer said.

The new round of funding will also support growing teams in R&D, manufacturing, quality control, software and systems engineering in Foothill Ranch.

TLS currently has 30 employees, though more than 70 people including contractors and TAE Technologies employees are working on the project, Bauer said.

Bauer declined to comment on future job openings, saying the subsidiary is "performing very well" occupying one of the four buildings at TAE Technologies’ Foothill Ranch headquarters.

Bright Future

Amid COVID-19, Bauer said TLS has transitioned to work from home and, he joked, "given everyone a chance to catch up on their paperwork, given the regulatory environment we operate in."

Joking aside, "we’ve had very productive continuity on the device side and drug development side."

The biggest challenge for the business has been maintaining its international partnerships amid travel restrictions, which have prevented teams from traveling to sites in Russia and China.

"The good news is we have strong partnerships in these locations and we’ve been relying on local assets to continue our work. It’s slowed us down a bit, but we’re working it out. Our teams will travel when they can."

Bauer is no stranger to patience and persistence, and he’s keeping his ambitions high.

"OC has a history of companies that have undertaken big challenges in healthcare, and succeeded, and really made an impact.