On December 1, 2020 A cancer-killing virus that City of Hope scientists developed could one day improve the immune system’s ability to eradicate tumors in colon cancer patients, reported a new study in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, City of Hope, DEC 1, 2020, View Source [SID1234572051]).

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The preclinical research is a first step to showing that City of Hope’s oncolytic virus CF33 can target hard-to-treat tumors that "handcuff" the immune system and keep T cells from activating the immune system to kill cancer cells. More specifically, the researchers demonstrated in mouse models that CF33 appears to increase PD-L1 expression in tumor cells and causes them to die in a way that stimulates an influx of activated immune cells.

"CF33 is a safe, innovative virus City of Hope developed that can become a game changer because of how potent it is and because of its ability to recruit and activate immune cells," said Susanne Warner, M.D., a surgical oncologist at City of Hope and senior author of the study. "Our oncolytic virus trains the immune system to target a specific cancer cell. Preclinical models show that a combination treatment of oncolytic virus CF33 with anti-PD-L1 checkpoint inhibition leads to lasting anti-tumor immunity, meaning if a similar cancer cell ever tries to regrow, the immune system will be ready and waiting to shut it down."

Colorectal cancer is the third leading cause of cancer-related deaths in the United States and is expected to cause 53,200 deaths in 2020, according to the American Cancer Society. City of Hope researchers are excited about the potential of CF33 to enhance colon cancer treatment and point out that CF33 has been effective preclinically against a wide variety of cancers.

Yuman Fong, M.D., the Sangiacomo Family Chair in Surgical Oncology at City of Hope, and his team created oncolytic virus CF33 and expect to open a clinical trial to test the safety of this treatment in human patients in 2021. This treatment addresses a problem in cancer: Most solid tumors do not respond to checkpoint inhibitors because the "uncloaked tumor cell" still isn’t recognized by the immune system, Fong said.

"CF33 selectively infects, replicates in and kills cancer cells. This study demonstrates that a designer virus we created to infect a wide variety of cancers can make tumor cells very recognizable to the immune system," Fong said. He, Warner and other City of Hope physician-scientists are working on turning "cold tumors" resistant to treatment into "hot tumors" that can be killed by a well-trained immune system.

The U.S. Food and Drug Administration has approved only one oncolytic virus thus far: T-VEC, which is a local immunotherapy treatment that kills melanoma cells.

To confirm their hypothesis, City of Hope scientists tested four groups: control with no treatment, anti-PD-L1 alone, CF33 alone, and a combination of CF33 and anti-PD-L1. Results indicated that a combined treatment of City of Hope’s oncolytic virus and anti-PD-L1 appeared to be most effective. It also increased CD8+ T cells, which are immune cells that remember previous diseases and are trained to kill them if they are reintroduced later. In other words, the models developed anti-tumor immunity. This means that animals cured of their cancer were effectively immune to future tumor growth.

Fong and colleagues have demonstrated CF33’s anti-tumor immune efficacy against triple-negative breast cancer cell lines, in brain tumor cells, in liver cancer models, and in pancreatic, prostate, ovarian, lung and head and neck cancer. Moreover, a recent City of Hope-led study found that CF33 could be combined with chimeric antigen receptor (CAR) T cell therapy to target and eliminate solid tumors that are otherwise difficult to treat with CAR T therapy alone. City of Hope has licensed CF33 to Imugene Limited, a company developing novel therapies that activate the immune system against cancer.

Notably, the CF33 virus may be tracked by non-invasive PET scanning. "If we can perfect the technique, we can give someone a viral injection and watch it work – see where it goes and identify cancer cells that we didn’t even know existed," Warner said. "Doctors would have real-time data and know if we should give a patient a higher dose or where to direct the treatment based on tumors that have not yet been killed."

What Warner describes is a developing field called theranostic precision medicine, meaning doctors are able to give patients therapies and concurrently diagnose them to provide the most appropriate treatment for that patient. It is one of many precision medicine approaches City of Hope is developing and offering to patients.

The next step for the current study is to test the innovative CF33 virus platform in different solid tumor models.

This research was supported by the American Cancer Society Mentored Research Scholar Grant (MRSG-16-047-01-MPC) and through the generosity of the Natalie and David Roberts Family.

On December 1, 2020 Cellaria Inc (Wakefield, MA, USA) and the Spring Lab, Northeastern University, reported the successful receipt of a National Institutes of Health (NIH) R01 grant to extend and advance the application of innovative new photomedicine-based therapies for hard-to-treat cancers (Press release, Cellaria, DEC 1, 2020, View Source [SID1234572050]). The grant highlights the close working relationship of the two organizations and will provide $3.2M funding to develop precision therapeutics closely tailored to the requirements of specific patient populations. Cellaria’s contribution to the partnership is next generation, patient-derived, customized cell models that boost the effectiveness of in vitro studies, helping researchers to identify where the technology can have the most impact. Dr Bryan Spring, Assistant Professor of Biomedical Physics credits Cellaria with a vital role in accelerating his research.

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"We’ve demonstrated proof of concept and seen significant interest from clinicians," said Dr Spring. "However, we initially targeted just a single ovarian cancer biomarker. To capture the heterogeneity of the disease and efficiently study multiple biomarkers we needed to upgrade our cell models. Developing new models in-house would have taken years and instead we chose to work with Cellaria. This has really accelerated progress by providing rapid access to rigorously characterized cell models for specific molecular subtypes and patient populations."

Dr Spring’s research focuses on the use of antibody-photosensitizer conjugates to make cancer cells susceptible to light-induced destruction, targeting microscopic cancer cell deposits left behind by conventional therapies. Primary areas of application are pancreatic and ovarian cancer. With these cancers, cells left behind by surgery and other conventional therapies can metastasize in the peritoneal cavity and abdomen, attacking other organs and increasing the severity of the disease. The new NIH research grant is entitled "Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers."

Cellaria provides cell models, complete with comprehensive omics data, that help the researchers to determine which biomarkers are most actionable when it comes to targeting drug resistant cells and applying the photomedicine. These cell models robustly represent the full heterogeneity of the cancers, which is essential for the development of precision therapies. Dr Spring has been using Powder, a high grade serous ovarian cancer cell model developed from the carcinoma of a 65 – 69 Caucasian, stage IV patient. New models for pancreatic cancer have recently been added to the Cellaria portfolio. All have a robustly authenticated lineage and are provided with protocols to maintain specific biomarker expression. Cellaria’s unrivalled expertise in cell line growth, stabilization and characterization underpin the company’s ability to supply customised models that enable researchers to identify the specific biomarkers of most relevance to their work.

"Cellaria have all the -omics in place and are highly responsive in terms of refining models to our requirements," said Dr Spring. "The Cellaria team are experts in their field and great to work with. The bottom line is that via this collaboration we get to concentrate on our science, rather than the tools we need to support it, which is just as we prefer it."

On December 1, 2020 Calidi Biotherapeutics, Inc., a clinical-stage biotechnology company at the forefront of oncolytic virus-based immunotherapies for cancer, reported that it has been granted a new patent from the European Patent Office (EPO) (Press release, Calidi Biotherapeutics, DEC 1, 2020, View Source [SID1234572049]). European Patent Number 3209382, "Combination Immunotherapy Approach for Treatment of Cancer," secures Calidi’s proprietary technology platform, Supernova 1 (SNV1), composed of the oncolytic agent, CAL1 vaccinia virus, loaded into allogeneic, adipose-derived mesenchymal stem cells (AD-MSC).

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"We’re very excited to be granted this European Patent to protect our innovative immunotherapy product and combination approach abroad," said Allan J. Camaisa, CEO and Chairman of Calidi Biotherapeutics. "This new patent provides considerable opportunity for the expansion of Calidi’s years of research into the profound oncolytic potential of SNV1."

Pre-clinical data has shown Calidi’s SVN1 product to shield the viral payload of CAL1 vaccinia virus from the patient’s immune system, supporting efficient delivery to tumor sites and effectively potentiating oncolytic viruses.

"Our talented, seasoned team of doctors and scientists have exerted years of intensive research and groundbreaking work to produce Calidi’s SVN1 technology," said Boris Minev, MD, President, Medical and Scientific Affairs at Calidi Biotherapeutics. "This patent represents the culmination of their impressive expertise, dedication, and passion."

As of the EP Grant Date, November 25, 2020, the European Patent covers Calidi’s combination immunotherapy approach and SNV1 product in 37 contracting European countries. Earlier in the year, the patent was also granted in Canada, Russia, Singapore, Australia, and New Zealand.

On December 1, 2020 BostonGene Corporation, a biomedical software company committed to defining optimal precision medicine-based therapies for cancer patients, reported that two abstracts were selected for poster presentations at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, BostonGene, DEC 1, 2020, View Source [SID1234572048]). The all-virtual event will be held from December 5 – 8, 2020.

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Details of the presentations are below:

Title: Integration and Iteration: Using Advanced, High-Content Imaging and Single-Cell Gene Expression Analysis to Uncover Unique Aspects of Follicular Lymphoma Biology
Session: 621: Lymphoma—Genetic/Epigenetic Biology: Poster I
Abstract Number: 1106
Date and Time: Saturday, December 5, 2020: 10:00 AM – 6:30 PM ET
Presenter: Andrea J. Radtke, PhD, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Follicular lymphoma is an indolent B-cell lymphoma with remarkable heterogeneity in disease progression and trajectory; therefore, determining the cell intrinsic and extrinsic factors underlying this clinical heterogeneity is necessary to impact patient clinical outcomes. Using a multi-omics approach, including whole exome sequencing (WES) and bulk RNA-seq integrated with single-cell analyses such as scRNA-seq and multiparameter imaging, notable patient-specific cellular interactions and expression patterns were identified that may drive cancer patient survival. This integrated approach provides insights into both tumor biology and disease trajectory, which can ultimately benefit therapeutic strategies in follicular lymphoma.

Research conducted with the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health (NIH).

Title: High Dimensional Tissue-based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles
Session: 622
Abstract Number: 1117
Date and Time: Saturday, December 5, 2020: 10:00 AM – 6:30 PM ET
Presenter: Jose C. Villasboas, MD, Mayo Clinic

Cells of the immune system play an important role in modulating the trajectory of lymphomas; therefore, understanding the composition and spatial distribution of immune cells within the tumor microenvironment (TME) is critical to improve clinical outcomes for patients. Analysis of a follicular lymphoma tumor section that used Co-Detection by Indexing (CODEX) multiplex immunofluorescence image processing identified unique cell subsets and specific spatial distribution of immune cells. These insights into the complex immune cell composition and architecture of the TME add to the prognostic value of the TME as a therapeutic target in follicular lymphoma.

Research conducted with Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Mayo Clinic, Memorial Sloan Kettering Cancer Center, Université Claude Bernard Lyon and the University of Iowa.

In addition to the poster presentations, the abstracts have been published online in the November supplemental issue of "Blood".

On December 1, 2020 Zymeworks Inc. (NYSE:ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported that its partner, BeiGene, Ltd., has dosed the first patient in South Korea in a pivotal, single-arm clinical trial of zanidatamab (formerly ZW25) monotherapy in patients with advanced or metastatic HER2-amplified biliary tract cancer (BTC) (Press release, Zymeworks, DEC 1, 2020, View Source [SID1234572047]). Zymeworks will receive a US$10 million payment under its collaboration with BeiGene as a result of the achievement of this development milestone.

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"Patients with biliary tract cancer generally have a poor prognosis and few treatment options," said Diana Hausman, M.D., Chief Medical Officer at Zymeworks. "While BTC occurs in patients throughout the world, the incidence is particularly high in Asia. Our collaboration with BeiGene expands the potential of zanidatamab to help address this global unmet need."

Zymeworks and BeiGene are progressing the opening of multiple clinical trial sites in support of the global registration-enabling Phase 2b clinical trial of zanidatamab in patients with HER2-amplified BTC. In the Asia region, multiple sites are open for enrollment in South Korea, and in China all sites have been selected with enrollment anticipated to begin in the first quarter of 2021.

This global zanidatamab study may enable the submission of a Biologics License Application by Zymeworks in the United States as early as 2022. Multiple clinical sites are now open to enrollment in the U.S., Europe, and Asia, with additional sites planned, including in Canada and South America.

"We are pleased to have been able to initiate this important clinical trial and hope that it may help contribute to improving the lives of patients with advanced or metastatic BTC and HER2 amplification," said Lai Wang, Ph.D., Senior Vice President, Head of Global Research and APAC Clinical Development at BeiGene. "As our collaboration with Zymeworks continues, this trial may help lead to expedited global regulatory approvals, including in China and South Korea."

This pivotal Phase 2b clinical trial is a global, multicenter, open-label, single-arm study designed to evaluate the antitumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTC, including gallbladder cancer and cholangiocarcinoma (Phase 2:NCT04466891). Patients must have received at least one prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and have experienced disease progression after (or developed intolerance to) their most recent prior therapy. The primary endpoint of the study is the confirmed objective response rate (ORR) by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

Ongoing clinical trials are evaluating zanidatamab in first-line HER2-positive gastroesophageal adenocarcinoma (GEA) in combination with standard of care chemotherapy (Phase 2: NCT03929666) as well as in combination with the oral CDK4/6 inhibitor palbociclib (Ibrance, Pfizer) and fulvestrant in advanced HER2-positive, HR-positive breast cancer (Phase 2: NCT04224272). Zymeworks, in collaboration with BeiGene, plans to develop zanidatamab as a potential first-line treatment for patients with HER2-positive GEA. BeiGene is also conducting a two-arm Phase 1b/2 trial evaluating zanidatamab in combination with chemotherapy as a first-line treatment for patients with metastatic HER2-positive breast cancer and in combination with chemotherapy and BeiGene’s PD-1-targeted antibody tislelizumab as a first-line treatment for patients with metastatic HER2-positive GEA (NCT04276493). In addition, an ongoing Phase 1 trial is evaluating the safety and antitumor activity of zanidatamab as a single agent and in combination with chemotherapy in HER2-expressing cancers that have progressed after prior standard of care treatments, including HER2-targeted agents (Phase 1: NCT02892123).

About Zanidatamab

Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2, and registration-enabling clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. The FDA has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified BTC, and two Fast Track designations to zanidatamab, one as a single agent for refractory BTC and one in combination with standard of care chemotherapy, for first-line gastroesophageal adenocarcinoma (GEA). These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations for the treatment of biliary tract, gastric and ovarian cancers, as well as Orphan Drug designation for the treatment of gastric cancer from the European Medicines Agency.

About Biliary Tract Cancer

Biliary tract cancer (BTC), including gallbladder cancer and cholangiocarcinoma (bile duct cancer), accounts for approximately 3% of all adult cancers and is associated with a poor prognosis. Globally, more than 210,000 people are diagnosed with BTC every year. Most patients (> 65%) with BTC are diagnosed with tumors that cannot be removed surgically, and even those patients who undergo potentially curative surgery have a high recurrence rate. Treatment options are limited for patients with advanced BTC who experience disease progression after front-line chemotherapy.

The human epidermal growth factor receptor 2 (HER2) is a well-described target for anti-cancer therapy. Tumor cells that produce a higher than normal level of HER2 tend to grow more quickly and spread to other parts of the body. About 5% to 19% of patients with BTC have tumors that express HER2, suggesting that these patients may potentially benefit from HER2-targeted therapy. Currently no HER2-targeted therapy has been approved for the treatment of BTC.

About the Zymeworks-BeiGene Collaboration

In November 2018, Zymeworks and BeiGene entered into license and collaboration agreements in which BeiGene was granted an exclusive license for the research, development, and commercialization of zanidatamab and ZW49 in Asia (excluding Japan), Australia, and New Zealand. The companies are collaborating on joint global development for selected indications, with the goal of developing zanidatamab and ZW49 worldwide across multiple HER2-expressing cancers and lines of therapy.