On March 26, 2019 BioInvent International AB (OMXS: BINV), a biotech company focused on the discovery and development of novel immuno-regulatory antibodies to treat cancer and Transgene (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapies for the treatment of solid tumors, reported the extension of their collaboration to co-develop multi-functional oncolytic viruses (OV) encoding for undisclosed antibodies sequences capable of treating a broad range of solid tumors (Press release, Transgene, MAR 26, 2019, View Source [SID1234534629]).

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Under the terms of the extension agreement, Transgene will contribute its industry-leading OV design and engineering expertise, some non-antibody transgenes, as well as its proprietary engineered vaccinia virus (TK-, RR-) backbone, which forms the basis of its Invir.IO platform. BioInvent will provide its cancer biology and antibody expertise to the collaboration as well as one or more antibodies sequences, generated through its proprietary n-CoDeR/F.I.R.S.T. platforms. Certain sequences for an undisclosed target will be selected for encoding within Transgene’s Invir.IO backbone to create a multi-functional OV.

In November 2018, Transgene and BioInvent presented positive data from their initial collaboration at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper). These initial data covered the collaboration’s work on an anti-CTLA-4 antibody-armed oncolytic vaccinia virus, based on Transgene’s proprietary vaccinia virus (TK-, RR-) backbone. This enhanced oncolytic vaccinia virus demonstrated its ability to ensure the expression of BioInvent’s anti-CTLA-4 antibody in the tumor with low systemic exposure. It also showed improved efficacy and a better safety profile when compared to the combination of the antibody and the non-armed corresponding oncolytic virus given individually in pre-clinical models.

Consistent with the initial collaboration, research and development costs as well as revenues and royalties from the multifunctional OVs generated as a result of the new collaboration will be shared 50:50.

Encoding BioInvent’s antibodies sequences in Transgene’s proprietary Invir.IO platform, for a direct expression into the tumor, promises to optimize the efficacy and tolerability of these antibodies. Both Transgene and BioInvent believe that these novel multifunctional OVs could be significantly more effective than co-administering an OV and an antibody together.

Commenting on the agreement, Martin Welschof, CEO of BioInvent, said: "The extension of our collaboration with Transgene opens up further opportunities for both companies to combine their expertise and knowledge to develop antibody oncolytic virus combinations capable of treating a broad range of solid tumors. By leveraging BioInvent’s unique and proprietary n-CoDeR/F.I.R.S.T. platforms, we will be able to develop a number of novel first-in-class antibodies that could be delivered directly into the tumor via Transgene’s vaccinia viral backbone, potentially enhancing their efficacy and improving their side effect profile."

Philippe Archinard, PhD, Chairman and CEO of Transgene, said: "We are pleased to extend the scope of our highly productive collaboration with BioInvent. We believe that the next generation of multi-functional oncolytic viruses expressing BioInvent’s highly targeted immune modulators directly in the tumor micro-environment will deliver much improved overall survival outcomes in patients with solid tumors. This agreement further expands Transgene’s broad portfolio of oncolytic viruses in development, the first of which is expected to enter the clinic in 2020."

On March 26, 2019 Charles River Laboratories International, Inc. (NYSE: CRL) reported that its team of oncology experts will attend the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, with 19 scientific posters and two oral presentations to highlight its enhanced oncology portfolio (Press release, Charles River Laboratories, MAR 26, 2019, View Source [SID1234534645]). The meeting is taking place from March 29-April 3, 2019, at the Georgia World Congress Center in Atlanta, Georgia.

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Charles River’s team of industry-leading oncology experts have been named as co-inventors on more than 60 patents secured by clients for compounds with an oncology indication, including one launched product, and have produced numerous development candidates in this therapeutic area. Additionally, the Company worked on over 85 percent of all oncology therapies approved by the FDA in 2018. At the AACR (Free AACR Whitepaper) Annual Meeting, researchers will present recent work utilizing emerging tools and approaches for cancer research.

Combination Therapies for Breast Cancer

PARP inhibitors have shown promise when used in combination with immunotherapy in women with breast and ovarian cancers who carry the BRCA mutations. In an oral presentation at the AACR (Free AACR Whitepaper) Annual Meeting, Julia Schueler, DVM, PhD, Research Director at Charles River, will discuss the crosstalk identified between PARP inhibitors and immune checkpoint inhibitors in cell and research models expressing the BRCA mutation. The crosstalk suggests this drug combination might be effective in women suffering from BRCA1-driven malignancies.

Monday, April 1, 3:35-3:50 p.m.: Modulation of the tumor infiltrating lymphocyte population by PARP inhibitor Talazoparib in combination with anti-PD1 treatment significantly enhances overall survival in a murine BRCA1-/- breast cancer model
Collaboration in Pediatric Oncology

Cancer remains the leading cause of death from disease among children, making a continued focus on research in this field extremely important. Charles River has partnered with Meds4Kids Pharma (M4K), an organization using open science to revolutionize how affordable new treatments are discovered and developed.

Since 2017, Charles River has donated drug discovery services to M4K, including medicinal and synthetic chemistry. Working collaboratively with M4K and their open science partners, the team has made progress towards the identification of potent, selective, brain-penetrant ALK2 inhibitors.

At the AACR (Free AACR Whitepaper) Annual Meeting, Sue Cramp, PhD, Team Leader, Chemistry at Charles River, will give an oral presentation on work conducted with M4K, the Ontario Institute for Cancer Research, and the Structural Genomics Consortium. She will discuss their combined efforts to generate an orally-available, brain-penetrant therapeutic to treat Diffuse Intrinsic Pontine Glioma (DIPG), a rare, aggressive, and uniformly fatal childhood brain cancer.

Tuesday, April 2, 3:00-5:00 p.m.: Open science medicinal chemistry: Towards a treatment for DIPG
Additionally, Charles River is a part of the Innovative Therapies for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform (ITCC-P4), a public-private partnership with 21 members focused on establishing 400 new patient-derived xenografts (PDX) of high-risk pediatric tumors. By establishing and characterizing these PDXs, the consortium, funded under IMI2 Grant Agreement No. 116064, aims to build a sustainable, comprehensive platform for more translational drug testing.

Tuulia Huhtala, PhD, Head of Biomarkers and Molecular Imaging at Charles River, will present a poster based on the work done in characterizing these PDXs, which demonstrates the essential role of imaging in both clinical diagnosis and monitoring therapy response. The presentation will review volumetric, metabolic, and functional changes in an orthotopic PDX brain tumor model using MRI, MRS, and PET imaging.

Monday, April 1, 1:00-5:00 p.m.: Translational imaging findings in a pediatric patient-derived orthotopic xenograft brain tumor model
Charles River Launches New Drug Discovery Platforms

At the AACR (Free AACR Whitepaper) Annual Meeting Charles River is also launching a new model for oncology research. The HuPBMC-NCG Humanized Model is a humanized, PBMC-engrafted NCG mouse. This study-ready model eliminates the time, energy, and resources spent validating and humanizing a model, enabling researchers to quickly initiate short-term in vivo studies.

Humanized mice, which harbor human immune cells, can be utilized to test the safety and efficacy of compounds that manipulate the immune system to fight cancer. The HuPBMC-NCG Humanized Model will be commercially available in April 2019.

In addition, Distributed Bio scientists will join the Charles River team to highlight their recently announced partnership. A combination of Distributed Bio’s antibody discovery platform and Charles River’s extensive drug development expertise creates an elite end-to-end solution for therapeutic antibody discovery and development. With access to the Distributed Bio’s SuperHuman, AbGenesis, and Tumbler technologies, clients can discover, analyze, and engineer therapeutic antibodies with unprecedented speed.

A full schedule of Charles River’s activities during AACR (Free AACR Whitepaper) 2019 is available online. Reprints of each poster will be available in Booth 2914 during the conference, and Charles River experts will be available for meetings to discuss how an integrated approach can support drug discovery and development programs from hit identification to IND (Investigational New Drug) filing.

Throughout the conference, Charles River will be providing live updates on the Eureka Blog, including reviews of scientific sessions and input on the research being presented.

Approved Quotes

"Cancer remains a leading cause of death by disease across the globe. Our researchers are committed to finding novel treatments by harnessing innovative tools and methodologies." – Birgit Girshick, Corporate Executive Vice President, Discovery & Safety Assessment, Biologics Testing Solutions, and Avian Vaccine Services at Charles River
"The AACR (Free AACR Whitepaper) Annual Meeting affords us a unique opportunity to share our research in oncology and learn from our peers. I am hopeful that our presentation on the use of combination therapies in breast cancer treatment will inspire continued research in this promising area." – Julia Schueler, DVM, PhD, Research Director at Charles River
"For pediatric cancer patients, time is essential. I am proud that Charles River is part of collaborative groups, like M4K and ITCC-P4, that unite the best minds in the industry to focus on finding the most promising targets." – Ian Waddell, PhD, Executive Director, Biology at Charles River

On March 26, 2019 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage biotechnology company focused on discovering and developing novel small molecule drugs for the treatment of cancer and other life-threatening diseases, reported that the first patient has been treated in the Phase 1/2 open-label clinical trial of the glutaminase inhibitor telaglenastat (CB-839) in combination with Pfizer’s poly adenosine diphosphate ribose polymerase (PARP) inhibitor talazoparib, also known as Talzenna , in patients with advanced or metastatic solid tumors (Press release, Calithera Biosciences, MAR 26, 2019, View Source [SID1234535225]).

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"The initiation of this clinical trial of telaglenastat in combination with talazoparib marks the first of two clinical trials that will evaluate telaglenastat with approved Pfizer therapeutics as part of this collaboration," said Susan Molineaux, PhD, president and chief executive officer of Calithera. "We believe these new combination trials have the potential to broaden the opportunities for telaglenastat to improve patient outcomes."

Preclinical studies have shown that telaglenastat synergizes with PARP inhibitors to impair DNA synthesis, enhance DNA damage and block cancer cell proliferation. The combination of telaglenastat with PARP inhibitors has demonstrated synergistic activity in a number of preclinical cancer models, including renal cell carcinoma (RCC), triple negative breast cancer (TNBC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), ovarian cancer and prostate cancer. In October 2018, Calithera entered into a clinical trial collaboration agreement with Pfizer to evaluate telaglenastat in two clinical trials. The first trial is a combination of telaglenastat with talazoparib and the second trial is a combination of telaglenastat with palbociclib, also known as Ibrance. As part of this agreement, Pfizer will provide palbociclib and talazoparib, as well as financial support.

The Phase 1/2 trial (NCT03875313) will evaluate the safety and efficacy of the combination of telaglenastat plus talazoparib in patients with locally advanced/metastatic RCC, TNBC and CRC that are refractory or intolerant to standard therapies. The trial will evaluate the potential of telaglenastat to sensitize tumors to talazoparib in patients regardless of mutations in the BRCA gene.

Telaglenastat is an investigational, novel glutaminase inhibitor specifically designed to block glutamine consumption in tumor cells. Tumors commonly exhibit metabolic alterations that increase their dependence on glutamine. In preclinical studies, telaglenastat produced synergistic antitumor effects when used in combination with standard-of-care therapies.

On March 26, 2019 NANOBIOTIX (Euronext: NANO – ISIN: FR0011341205 – the ‘‘Company’’), a clinical-stage nanomedicine company pioneering new approaches to the treatment of cancer, reported that the Company has clarity on its regulatory pathway in the treatment of Head and Neck cancers for first-in-class radioenhancer NBTXR3 (Press release, Nanobiotix, MAR 26, 2019, View Source [SID1234534630]).
The announcement follows pre-IND feedback from the US FDA received on March 18, 2019.

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Stage III and IV Head and Neck cancers include large primary tumors which may invade underlying structures and/or spread to regional nodes. Treatment of these locally advanced forms of the disease—which makes up more than 50% of all Head and Neck cancers—requires aggressive, concerted measures that often remain a clinical challenge with an estimated 5-year survival rate of 50% with the current standard of care.

Within the Stage III and IV Head and Neck cancers patient population, the Company targets a subpopulation of patients, who have a higher risk of recurrence, or a poorer prognosis as they have an inability to receive cisplatin, the frontline chemotherapy drug for advanced Head and Neck cancers. Additionally, the localization of the tumor focuses on oropharynx, hypopharynx, and oral cavity – representing the majority of Head and Neck cancers.

Based on US FDA feedback, the Company plans to design an Overall Survival (OS)-based, randomized, event-driven Phase II/III clinical trial. 50% of patients will receive standard of care radiotherapy combined with NBTXR3 while the other 50% will receive radiotherapy in combination with cetuximab. The expected total number of patients to participate in this global clinical trial is approximately 600, and an efficacy interim analysis is planned.

Notably, the US FDA has not objected to the use of the data from the dose-escalation phase of the Company’s European Phase I clinical trial in elderly and frail patients with locally advanced Head and Neck cancers as well as the Company’s current CMC (chemical, manufacturing and control) development plan.

The Company plans to initiate its global clinical trial authorization process with US FDA in 2H2019.-Ends

About NBTXR3

NBTXR3 is a first-in-class product candidate designed to destroy tumors and metastasis when activated by radiotherapy. NBTXR3 has a high degree of biocompatibility and requires one single administration before the whole radiotherapy treatment. Nanobiotix believes NBTXR3 has the ability to fit into current worldwide standards of radiation care. Nanobiotix’s broad clinical program includes 7 clinical trials. In June 2018, Nanobiotix established human proof of concept for this first-in-class product candidate in its Soft Tissue Sarcoma (STS) Phase III clinical trial. 2 NBTXR3 is actively being studied in head and neck cancer with locally advanced squamous cell carcinoma of the oral cavity or oropharynx in elderly and frail patients who are unable to receive chemotherapy or cetuximab and have very limited therapeutic options. Promising results from these clinical studies have been observed from the ongoing Phase I/II trial regarding the local control of tumors. Nanobiotix is also running an Immuno-Oncology development program. In the United States, Nanobiotix has received approval from the US FDA to launch a clinical study of NBTXR3 activated by radiotherapy in combination with anti-PD1 antibodies in lung, and head and neck cancer patients (head and neck squamous cell carcinoma and non-small cell lung cancer). The other ongoing NBTXR3 trials are treating patients with liver cancers (hepatocellular carcinoma and liver metastasis), locally advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with concurrent chemotherapy, and prostate adenocarcinoma. The first market authorization process (CE Marking) is ongoing in Europe in the STS indication.

On March 26, 2019 Abcuro, Inc., a biopharmaceutical company developing first-in-class immunomodulatory therapeutics, reported the publication of proof-of-concept data describing KLRG1 as a promising new target for cancer immunotherapy (Press release, Abcuro, MAR 26, 2019, View Source [SID1234534646]). The article, published in Oncotarget ( link ), reports the anticancer activity of KLRG1 antibody blockade in syngeneic mouse models of breast cancer, colon cancer and melanoma. The study also highlights the expression of KLRG1 in human tumor infiltrating lymphocytes (TILs) and its role in adaptive resistance to immunotherapies.

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KLRG1 was identified as a critical immune inhibitory receptor by datamining expression profile databases with the aim of finding immune checkpoint receptors that align with the state of T cell differentiation. This analysis showed that KLRG1 is, genome wide, the immune inhibitory receptor that best aligns with degree of T cell differentiation. Compared to other clinical targets that are active in early and intermediate stages of T cell differentiation (such as CTLA-4 and PD-1), KLRG1 functions as the ultimate break on the most differentiated and cytotoxic T cells. Furthermore, KLRG1 expression on a differentiated subset of T cells and the high cytotoxic potential of these cells strongly suggests a beneficial therapeutic combination with existing treatments.

The results presented in the publication show in vivo proof-of-concept for the anti-cancer action resulting from KLRG1 blockade in mouse syngeneic models and highlight KLRG1 as an important driver of adaptive resistance to immunotherapy in humans. Abcuro has discovered KLRG1 blocking antibodies and is developing first-in-class new immunotherapy agents for treatment of cancer.