On November 5, 2019 Unum Therapeutics Inc. (NASDAQ: UMRX), a clinical-stage biopharmaceutical company focused on developing curative cell therapies for cancer, reported preclinical data for its BOXR1030 program presented at the SITC (Free SITC Whitepaper) meeting being held November 6–10, 2019 in National Harbor, MD (Press release, Unum Therapeutics, NOV 5, 2019, View Source [SID1234550347]).

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"Solid tumors create an unfavorable microenvironment that depletes T cells of critical nutrients and amino acids, drives T cell dysfunction, and inhibits the effectiveness of cellular therapies, and our BOXR platform was specifically developed to discover novel transgenes that can be co-expressed with chimeric-targeting receptors to improve T cell functionality in the solid tumor microenvironment," said Seth Ettenberg, Ph.D., Chief Scientific Officer of Unum. "At this year’s SITC (Free SITC Whitepaper), we present preclinical data on the first product candidate from our BOXR platform, BOXR1030, which contains the GOT2 transgene. In our preclinical studies using stringent animal xenograft models that simulate the solid tumor microenvironment, expression of the GOT2 mitochondrial enzyme in BOXR1030 increased the production of key amino acids and metabolites, improved the anti-oxidant balance of T cells, and prevented their dysfunction and exhaustion. This work extends the increasingly recognized importance of immunometabolism in ensuring proper immune cell function."

Poster presentation title: "Co-expression of the Metabolic Enzyme GOT2 with a GPC3-Targeted CAR-T Overcomes Challenges of the Solid Tumor Microenvironment, Substantially Improving Therapeutic Efficacy in Solid Tumor Xenografts"

BOXR1030 Summary:

BOXR1030 contains a humanized single-chain variable fragment (scFv) 4-1BB CAR targeting GPC3 and separately co-expresses the glutamic-oxaloacetic transaminase 2 (GOT2) transgene from a single viral construct. Unum’s BOXR platform led to the discovery of the utility of GOT2, a critical enzyme involved in cellular metabolism. When co-expressed with a GPC3-targeted CAR-T, GOT2 improved metabolic and transcriptional profiles resulted in greater anti-tumor activity compared with parental CAR-T when tested both in vitro and in vivo under stringent conditions representing the solid tumor microenvironment (TME).

Over one hundred BOXR candidates were generated by cloning a library of literature-derived, hypothesis-driven bolt-on genes into vectors containing a GPC3-targeted CAR-T and were screened through Unum’s novel TME assays. Candidates were selected for their ability to overcome multiple TME challenges, while maintaining specificity and tolerability.

In vitro, BOXR1030 T cells were resistant to suppressive TME-like conditions, showing improved T cell proliferation under both hypoxic and low glucose conditions compared with control GPC3+ CAR-T cells. In vivo, BOXR1030 demonstrated superior activity compared to the parental CAR-T with treated animals achieving complete tumor regressions. Tumor infiltrating lymphocytes isolated from the tumors of treated animals revealed that BOXR1030 cells were more resistant to dysfunction and had fewer markers of exhaustion as compared to the control CAR-T cells.

About Unum’s BOXR platform
Unum’s BOXR platform was established with the aim of discovering novel "bolt-on" transgenes that can be co-expressed with chimeric-targeting receptors to improve the function of T cells in the solid tumor microenvironment. Unum’s BOXR discovery capabilities broadly evaluate T cell phenotype through a rigorous, multi-stage screening strategy that simulates the tumor microenvironment. Unum has discovered and continues to enrich a library of master regulatory genes of T cell biology that regulate pathways essential for cell growth, proliferation, and survival under a variety of conditions. BOXR bolt-on transgenes identified in this platform are designed to address a variety of immunosuppressive mechanisms of solid tumors, including metabolic competition, immune suppressor cells, and exhaustion due to chronic stimulation. Once discovered, BOXR transgenes are designed to be incorporated into several different types of therapeutic T cells, including both ACTR T cells and CAR-T cells, to impart new functionality to T cells. BOXR platform objectives include expanding the scope of biological mechanisms and transgenes in its proprietary BOXR library, enabling BOXR bolt-on applications for a broad range of immune cell therapies, including both autologous and allogeneic approaches, and advancing new BOXR product candidates into the clinic.

On November 5, 2019 IONpath, Inc., a company revolutionizing multiplexed tissue imaging, reported that launched the MIBIscope System, the first commercially available Multiplexed Ion Beam Imaging (MIBI) system (Press release, IONpath, NOV 5, 2019, View Source [SID1234550363]). The MIBIscope enables researchers to image over 40 biomarkers simultaneously at higher sensitivity, resolution, and throughput than existing methods. IONpath is showcasing the platform at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in Maryland from November 6-10.

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To help scientists see deeper into the tissue microenvironment and study the relationships between proteins, cells and their environment in intact tissue samples, IONpath has leveraged secondary ion mass spectrometry and elementally labeled antibodies to create MIBI technology. This method enables higher throughput than existing multiplexed imaging technologies, such as mass cytometry, and is far more sensitive, permitting single-molecule detection. The MIBIscope can image cellular structures as small as 280 nm and visualize over 40 biomarkers simultaneously with a dynamic range of five orders of magnitude.

"Scientists in oncology and translational research will benefit from the unprecedented insights into spatial relationships within the tissue microenvironment by imaging and characterizing tissue samples at subcellular resolution," said Harris Fienberg, chief executive officer and co-founder, IONpath. "After successfully piloting the MIBIscope in leading research and biopharma institutions, we are excited to bring the platform to market."

The MIBIscope System removes only a thin layer of sample during imaging, thus permitting scientists to perform multiple scans on a single sample. Further, by scanning at different levels of depth, researchers can study tissue architecture in three dimensions. The MIBIscope System can be automated to image tissue samples continuously for multiple days, allowing researchers to process hundreds of samples a week and conduct broad cohort studies.

The simple staining process employs a standard immunohistochemistry workflow and is compatible with both FFPE and fresh/frozen tissue. Furthermore, samples are stable for months following staining.

To learn about the MIBIscope, visit IONpath at SITC (Free SITC Whitepaper) booth #326, or attend the company’s symposium on Saturday, November 9 at 12:35 pm in Riverview Ballroom A3, where leading researchers from the Dana-Farber Cancer Institute, Stanford University, and University of Colorado, Denver, will be presenting their research using the MIBIscope to characterize the tumor microenvironment. More information about IONpath’s activities at SITC (Free SITC Whitepaper) can be found at View Source Information about the MIBIscope System can be found at View Source

On November 5, 2019 Immunic, Inc. (Nasdaq: IMUX), a clinical-stage biopharmaceutical company focused on developing best-in-class, oral therapies for the treatment of chronic inflammatory and autoimmune diseases, reported management’s participation in the following industry and investor conferences in November (Press release, Immunic, NOV 5, 2019, View Source [SID1234550379]):

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November 11-13: 25th Annual BIO-Europe International Partnering Conference: Daniel Vitt, Ph.D., Chief Executive Officer and President of Immunic, will present a company overview at the 25th Annual BIO-Europe International Partnering Conference in Hamburg, Germany, on Tuesday, November 12, at 9:30 am CET.

November 19-20: Stifel 2019 Healthcare Conference: Dr. Vitt will present a company overview at the Stifel 2019 Healthcare Conference in New York on Tuesday, November 19, at 8:35 am ET.

November 20-21: Jefferies 2019 London Healthcare Conference: Sanjay Patel, CFA, Chief Financial Officer of Immunic, will host 1×1 meetings at the Jefferies 2019 Healthcare Conference in London on Wednesday, November 20 and Thursday, November 21.

On November 5, 2019 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies for the treatment of cancer, reported that the United States Food and Drug Administration (FDA) has granted AUTO1 orphan drug designation for treatment of acute lymphoblastic leukemia (ALL) patients (Press release, Autolus, NOV 5, 2019, View Source [SID1234550683]).

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According to the National Institute of Health’s National Cancer Institute, in the United States, there will be an estimated 5,930 new cases of ALL and an estimated 1,500 related deaths in 2019. Patients are predominantly children; approximately 60% of cases occur at age < 20 years. ALL occurs when the bone marrow makes too many immature lymphocytes, which are a type of white blood cell. Despite a high rate of response to induction chemotherapy, only 30–40% of adult patients with ALL will achieve long-term remission. Similarly, pediatric patients typically respond well to first-line treatment (combination chemotherapy) but 10 to 20% of total patients relapse with chemotherapy-resistant disease, leading to a significant unmet need in pediatric patients with high-risk relapsed or refractory ALL.

"We are pleased to receive orphan drug designation for AUTO1 for acute lymphoblastic leukemia," said Dr. Christian Itin, chairman and chief executive officer of Autolus. "From the data reported in our ongoing studies, we have seen strong remission rates and excellent CAR T cell expansion and persistence without inducing high-grade CRS, a serious adverse event affecting a significant number of patients on currently available CAR T treatments. We look forward to presenting data on AUTO1 at ASH (Free ASH Whitepaper) at the end of the year."

Orphan drug designation is granted by the FDA Office of Orphan Products Development to drugs and biologics which are intended for the treatment, diagnosis or prevention of rare diseases/disorders that affect fewer than 200,000 people in the U.S. Under the Orphan Drug Act, the FDA may provide grant funding toward clinical trial costs, tax advantages, FDA user-fee benefits, and seven years of market exclusivity in the United States following marketing approval by the FDA. For more information about orphan designation, please visit the FDA website at www.fda.gov.

About AUTO1
AUTO1 is a CD19 CAR T cell investigational therapy designed to overcome the limitations in safety – while maintaining similar levels of efficacy – compared to current CD19 CAR T cell therapies. Designed to have a fast target binding off-rate to minimize excessive activation of the programmed T cells, AUTO1 may reduce toxicity and be less prone to T cell exhaustion, which could enhance persistence and improve the T cells’ abilities to engage in serial killing of target cancer cells. In 2018, Autolus signed a license agreement under which Autolus acquired global rights from UCL Business plc (UCLB), the technology-transfer company of UCL, to develop and commercialize AUTO1 for the treatment of B cell malignancies. AUTO1 is currently being evaluated in two Phase 1 studies, one in pediatric ALL and one in adult ALL.

On November 5, 2019 BioLineRx Ltd. (NASDAQ/TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology, reported positive preclinical results further elucidating the mechanism of action of BL-8040 in combination with an anti PD-1 and chemotherapy (Press release, BioLineRx, NOV 5, 2019, View Source [SID1234550288]). The results, summarized in a poster entitled, "Combination of BL-8040, anti PD-1 and chemotherapy significantly reduced pancreatic tumor growth and changed the balance between CD4+/FOXP3+ cells and CD8+ cells in the tumor," will be presented on November 8, 2019 at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting in National Harbor, Maryland.

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"The results seen in this preclinical pancreatic cancer study support our hypothesis that the triple combination of BL-8040, anti-PD-1 and chemotherapy helps combat this difficult to treat cancer," said Philip Serlin, Chief Executive Officer of BioLineRx. "These preclinical data from the triple combination study support the mechanism of action of BL-8040 demonstrated in earlier clinical data from the dual combination of BL-8040 and pembrolizumab, showing a reduction in immuno-suppressive cells, accompanied by an increase in activated effector CD8+ T cells. We believe the ability of BL-8040 to modulate the tumor microenvironment allows for better activation of immune effector cells when combined with chemotherapy and immunotherapy. We are very hopeful that this anti-tumor activity will be confirmed in humans as we eagerly await results from the triple combination arm of our COMBAT/KEYNOTE-202 Phase 2 study of BL-8040, KEYTRUDA and chemotherapy in metastatic pancreatic cancer, which we expect to report by year end."

About the Pre-Clinical Study
The pre-clinical study assessed the effects of BL-8040, anti-PD-1 and chemotherapy (Irinotecan, Fluorouracil and Leucovorin), both alone and in various combinations, on tumor growth and immune cell constitution in a mouse model for pancreatic cancer.

Key findings include:

•The triple combination of BL-8040+anti-PD-1+chemotherapy had a significantly better effect on tumor growth compared to chemotherapy alone or any dual combination with chemotherapy.

The triple combination of BL-8040+anti-PD-1+chemotherapy showed the best effect in modulation of the tumor microenvironment, resulting in reduction in immunosuppressive cells, and accompanied by increase of activated T effector cells.

About BL-8040
BL-8040 is a short synthetic peptide that functions as a high-affinity best-in-class antagonist for CXCR4, a chemokine receptor over-expressed in many human cancers. CXCR4 has been shown to be correlated with poor prognosis, and plays a key role in tumor growth, invasion, angiogenesis, metastasis and therapeutic resistance. CXCR4 is also directly involved in the homing and retention of hematopoietic stem cells (HSCs) and various hematological malignant cells in the bone marrow.

In a number of clinical and preclinical studies, BL-8040 has shown a critical role in immune cell trafficking, tumor infiltration by immune effector T cells and reduction in immunosuppressive cells within the tumor niche, turning "cold" tumors, such as pancreatic cancer, into "hot" tumors (i.e., sensitizing them to immune check point inhibitors). BL-8040-mediated inhibition of the CXCR4-CXCL12 (SDF-1) axis has also shown robust mobilization of HSCs for transplantation in hematological malignancies.

BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.