On April 1, 2019 Apexigen, Inc., a clinical-stage biopharmaceutical company, reported new clinical data on APX005M at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place March 29 – April 3, 2019 in Atlanta, GA (Press release, Apexigen, APR 1, 2019, View Source [SID1234590996]). Apexigen’s lead immuno-oncology (I-O) therapeutic APX005M, a monoclonal antibody targeting CD40, is being evaluated in multiple ongoing clinical trials in different types of solid tumors.

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"We are excited to have new clinical data presented at AACR (Free AACR Whitepaper) on our CD40 antibody APX005M in combination therapy, highlighting the breadth of our clinical development program targeting difficult-to-treat types of cancer," said Ovid Trifan, M.D., Ph.D., Chief Medical Officer and Senior Vice President of Clinical Development of Apexigen. "Yesterday, clinical data in metastatic pancreatic cancer were presented in a plenary session, showing APX005M in combination therapy was well-tolerated and induced promising tumor shrinkage in 20 of 24 evaluable patients. Today, we are presenting clinical data from our ongoing Phase 1b/2 clinical trial in patients with metastatic melanoma demonstrating that APX005M is well tolerated in combination with nivolumab and triggers responses in patients who have progressed on anti-PD-1 therapy. Together, these data speak to the promise of APX005M and we are encouraged by these early results. We look forward to continuing to advance our broad clinical development program for this therapy as a new treatment option for patients living with cancer."

"If a patient with metastatic melanoma does not respond to currently approved immune checkpoint inhibitors, there are no approved treatment options left, unless the tumor has a BRAF mutation," said Harriet Kluger, M.D., Professor of Medicine at Yale Cancer Center. "We are eager to assess whether combining APX005M with nivolumab can reverse the course of this disease for these patients."

About the Phase 1b/2 Clinical Trial
The Phase 1b dose-escalation portion of this clinical trial included patients with metastatic melanoma who had progressed when previously treated with anti-PD-1 therapy. Progression was documented by two consecutive tumor assessments at least four weeks apart. Patients were treated with 3 dose levels of APX005M (0.03, 0.1 and 0.3 mg/kg) combined with a fixed dose of nivolumab (360mg) every 3 weeks. The primary endpoint was to evaluate safety as well as to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of APX005M in combination with nivolumab. Nivolumab was provided by Bristol-Myers Squibb under a clinical supply collaboration agreement.

In the Phase 1b portion of this clinical trial, APX005M was well tolerated and no dose-limiting toxicities (DLTs) were observed. The RP2D for APX005M is 0.3 mg/kg. Of the 5 subjects with metastatic melanoma, 1 had a confirmed partial response (PR), 2 had prolonged stable disease (SD) (>8 months), and 2 had progressive disease (PD) as the best overall response.

The Phase 2 dose-expansion portion of this clinical trial followed a Simon 2-stage design and included two parallel cohorts of patients treated with the RP2D of APX005M with nivolumab. The primary endpoints are safety and overall response rate (ORR) measured by RECIST 1.1 criteria. Secondary endpoints include determining the pharmacokinetic (PK) profile of APX005M, assessing the incidence of APX005M anti-drug antibodies (ADA), and evaluating the duration of response (DOR) and median progression-free survival (PFS) for patients.

In the Phase 2 portion of this clinical trial, the first stage of the cohort enrolled 10 subjects, in addition to the two subjects that carried over from the Phase 1 portion. Of these 12 subjects, 2 had confirmed PR, 3 had SD, and 7 had PD as best overall response.

For additional information on this trial (NCT03123783), please visit www.clinicaltrials.gov.

APX005M Data Presentation at AACR (Free AACR Whitepaper) 2019 Annual Meeting
Late-breaking Abstract Title: Phase Ib/II clinical trial of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC) (Abstract #CT089)
Poster Session Date and Time: Monday, April 1, 2019 1:00 PM – 5:00 PM ET
Poster Session: Phase 1 Clinical Trials
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 16

About APX005M
APX005M is a humanized monoclonal antibody designed to stimulate the anti-tumor immune response. APX005M targets CD40, a co-stimulatory receptor that is essential for activating both innate and adaptive immune systems. Binding of APX005M to CD40 on antigen presenting cells (i.e., dendritic cells, monocytes and B-cells) is believed to initiate a multi-faceted immune response that enables multiple components of the immune system (e.g., T cells, macrophages) to work in concert against cancer. APX005M is currently in Phase 2 clinical development for the treatment of cancers such as pancreatic cancer, melanoma, esophageal and gastroesophageal junction cancers, non-small cell lung cancer, renal cell carcinoma, sarcomas, and pediatric brain cancer in various combinations with immunotherapy, a cancer vaccine, chemotherapy or radiation therapy. Additional information on clinical trials for APX005M can be found at www.clinicaltrials.gov.

On April 1, 2019 Columbia University reported that global team of researchers led by theoretical physicist Raul Rabadan, PhD, professor of systems biology at Columbia’s Vagelos School of Physicians and Surgeons, and Núria Malats, MD, PhD, head of the Genetic and Molecular Epidemiology Group of the Spanish National Cancer Research Centre (CNIO), are working to develop a comprehensive computational framework that will identify high-risk factors for pancreatic cancer (Press release, Columbia University, APR 1, 2019, View Source [SID1234554036]).

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Armed with a new two-year, $1 million grant from the Pancreatic Cancer Collective, the team intends to attack pancreatic cancer research from multiple disciplines—genomics, mathematics and medicine—to provide an integrated, computational approach to studying genomic, environmental and immune factors that could identify populations at high risk of pancreatic cancer. The need for deeper understanding of the contributing factors to this lethal disease is pressing, as pancreatic cancer is projected to become the second leading cause of cancer-related mortality within the next decade.

Rabadan-led Team for Pancreatic Cancer Collective
Drs. Raul Rabadan and Nuria Malats
Pancreatic cancer currently has the lowest overall survival rate across all major cancers. The majority of pancreatic cancer patients overall live 8 to 12 months after diagnosis, and the instances of the disease are on the rise. While some key risk factors have been identified—age, non-genetic factors such as obesity, type-2 diabetes mellitus, and smoking, among others, and a handful of genetic mutations—currently known factors only explain a small fraction of the attributable risk of pancreatic cancer. Early detection remains a major challenge. By the time most patients are diagnosed, their prognosis is bleak.

Drs. Rabadan and Malats will co-lead the project with Ken Olive , PhD, assistant professor and core director at the Herbert Irving Comprehensive Cancer Center (HICCC) at NewYork-Presbyterian / Columbia University Irving Medical Center ; Tal Korem , PhD, assistant professor of systems biology and core member of Columbia’s Program for Mathematical Genomics (PMG) ; Gulam Manji , MD, assistant professor of medicine and faculty member of the HICCC; Ioan Filip , postdoctoral fellow of systems biology; and Esther Molina, Miguel Servet staff scientist in Dr. Malats’ Group.

"Our interdisciplinary team of researchers—from molecular epidemiologists and clinicians to experts in tumor genomics and the microbiome—will work together to tackle this problem," says Dr. Rabadan. "We will explore large-scale datasets from the U.S. and Europe to build this new computational framework, and also study preliminary epidemiological and genetic observations that link pancreatic cancer risk to the immune system. Our goal is to create a reliable, integrated framework for identifying populations high-risk for this detrimental disease."

The researchers will focus on rare gene variants, specific DNA regions and modifications, within large clinical and molecular datasets from multiple published databanks. The datasets include the UK Biobank, European Study on Digestive Illnesses and Genetics (PanGenEU), The Cancer Genome Atlas and the International Cancer Genome Consortium. The team also plans to characterize the tumor microenvironment, specifically the microbiome and expression of proteins important for immune system regulation.

Attempting to understand the cancer biology of pancreatic tumors is arguably a far more difficult undertaking than most cancer tumors, notes Dr. Olive, an expert in pancreatic cancer research and director of the Oncology Precision Therapeutics Imaging Core at the Cancer Center, and this is in large part due to the tumor’s unique structure.

"In pancreatic cancer, some cells within the mass of a tumor that are not mutated—the stroma cells—which are part of your normal body, have been recruited to help drive tumor growth," says Dr. Olive, and this makes studying tissue samples challenging.

"These stroma cells far outnumber mutant tumor cells, and they make it very difficult to study the tumor biology," he adds "We’ve been focusing on how to tease out the biology."

As part of this new project, researchers will also use a unique dataset from the Olive lab derived from manually carving out non-malignant cells from tumor cells in tissue samples, separating the different cell types and analyzing each component. This, and other complex data sets—clinical outcomes data and microbiome data—will help in expanding the team’s integrated computational platform to identify high-risk factors for the disease.

The American Cancer Society estimates for 2019 that about 56,770 people will be diagnosed with pancreatic cancer, and about 45,750 people will die from the disease. Pancreatic cancer is slightly more common in men than in women, and to date, the most common forms of treatment are surgery, chemotherapy and radiation.

"Pancreatic cancer has become one of the most deadly cancers," notes Dr. Rabadan. "Identifying genetic and epidemiological markers can elucidate risk factors that could lead to early detection. Our aim is that this project can greatly improve our ability to screen and identify highly susceptible individuals of this lethal disease."

Drs. Rabadan and Malats’ co-led project was announced March 30 by the Pancreatic Cancer Collective, a partnership of Lustgarten Foundation and Stand Up To Cancer (SU2C) , at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) . Dr. Rabadan’s expertise lies in the cross section of mathematical genomics, tumor evolution and cancer research. In the spring of 2018, SU2C awarded him the Philip A. Sharp Innovation in Collaboration award. At Columbia, Dr. Rabadan also is a professor of biomedical informatics, a faculty member of the HICCC and the founding director of the Program for Mathematical Genomics.

On April 1, 2019 Medigene AG (FSE: MDG1, Prime Standard, SDAX) reported that it has entered into an exclusive license agreement with Helmholtz Zentrum Munich (HMGU), a German public research institution operating in the field of environmental health, for a chimeric co-stimulatory receptor which is a fusion protein of PD-1 and 4-1BB (Press release, MediGene, APR 1, 2019, View Source [SID1234553910]). Medigene intends to explore applying the receptor in combination with Medigene’s T cell receptor-modified T cells (TCR-Ts) for the treatment of solid tumors. The co-stimulator was developed by researchers at the HMGU as a strategy to potentially overcome the blockade of T cells by solid tumors.

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Many solid tumors create a hostile microenvironment to inhibit immune cell attack, employing checkpoint mechanisms to emit signals that impede T cell activity. The PD-1/4-1BB molecule is designed to reverse the "stop" signal to a "go" command to help T cells overcome this checkpoint blockade.

Prof. Dolores Schendel, CEO and CSO of Medigene, comments: "Medigene believes that T cell therapy for solid tumors must include not only an optimal T cell receptor specific for the tumor, but also an additional feature to overcome T cell blockade. Gaining access to this co-stimulator gives us the exciting opportunity to improve functionality of Medigene’s TCR-Ts to achieve an efficacious response against solid tumors. The licensed molecule works by inhibiting negative immune regulation, a principle that was discovered by James P. Allison and Tasuku Honjo, the importance of which was recognized with the Nobel Prize in Medicine in 2018."

Scientists from HMGU and Medigene have previously shown that low-avidity (1) T cells recognizing tumor cells can achieve comparable effector functions to those of high-avidity T cells of identical specificity through the co-expression of a chimeric co-stimulatory receptor (AACR Publication: DOI: 10.1158/0008-5472.CAN-16-1922). By binding to PD-L1/PD-L2 on the surface of tumor cells, a chimeric co-stimulatory receptor converts a normally negative, inhibitory signal into a positive signal in the T cell, thereby activating T cells instead of inactivating them.

Medigene will now evaluate preclinically the use of this chimeric co-stimulatory receptor in combination with tumor-specific TCR-Ts generated by Medigene to potentiate immune responses against solid tumors.

Prof. Dr. Elfriede Nößner, Head of Immunoanalytics at the Helmholtz Zentrum Munich, and inventor of the licensed receptor, comments: "I am excited that Medigene will explore how to implement the use of our chimeric co-stimulatory receptor with their TCR-T platform. We are convinced that Medigene’s TCR technology is perfectly suited for the development of potential clinical applications to improve therapies for a variety of different solid tumor types."

Medigene is acquiring a worldwide, exclusive license for the therapeutic and diagnostic use of this chimeric co-stimulatory receptor in the field of TCR-therapy (TCR-Ts) and DC vaccines (DCs). The chimeric co-stimulatory receptor is covered by a patent application filed by HMGU in 2017 with the application number PCT/EP2017/056931. Medigene will pay HMGU an upfront fee, an annual maintenance fee, milestone payments and royalties on marketed therapeutic and diagnostic products containing the chimeric co-stimulatory receptor. Confidentiality was agreed regarding further financial details. Ascenion GmbH, the technology transfer partner of the HMGU has successfully negotiated the license agreement.

(1) Avidity: Avidity is the totality of the affinities of all receptors on a cell. Affinity is the force of a single antigen-TCR binding

About Medigene’s TCR-Ts: Medigene’s first TCR-T candidate, MDG1011, is in a Phase I/II clinical trial for various blood cancer indications started in 2018. The TCR-T technology aims at arming the patient’s own T cells with tumor-specific T cell receptors. The receptor-modified T cells are then able to detect and efficiently kill tumor cells. This immunotherapy approach attempts to overcome the patient’s tolerance towards cancer cells and tumor-induced immunosuppression by activating and modifying the patient’s T cells outside the body (ex vivo). TCR-T therapy is developed to utilize a higher number of potential tumor antigens than other T cell-based immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy.

Medigene is establishing a pipeline of recombinant T cell receptors and has a collaboration with bluebird bio, Inc. for the development of six TCR-Ts.

On April 1, 2019 MaxCyte presented the corporate presentation (Press release, MaxCyte, APR 1, 2019, View Source [SID1234537621]).

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On April 1, 2019 Candel Therapeutics (a.k.a. Advantagene, Inc.) reported the closing of a $22.5 million Series C Preferred Stock financing led by Northpond Ventures. Participating syndicate members included Sands Capital Ventures, H7 Holdings and Level One Partners. Michael P. Rubin, M.D., Ph.D., founder and CEO of Northpond Ventures, will join the company as a member of its board of directors (Press release, Candel Therapeutics, APR 1, 2019, View Source [SID1234537125]).

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"We are thrilled to join forces with the Candel team and embark on this great journey together. We have the potential to be a force for good in the world, which is what drives us," said Dr. Rubin.

"We are grateful for the financial flexibility resulting from this financing," stated Dr. Estuardo Aguilar-Cordova, Chairman and CEO of Candel Therapeutics. "The addition of Michael to our board of directors is a big win for the company and brings significant relevant expertise."

The completion of the Series C brings the total capital raised by Candel in the last year to $51.2 million. The company plans to use the proceeds to expand its operational capabilities and further accelerate its ongoing clinical development initiatives. Candel’s lead programs are based on the company’s Gene Mediated Cytotoxic Immunotherapy (GMCI) technology and include two randomized studies in prostate cancer, including a Phase 3 under an FDA approved Special Protocol Assessment. The Company also has ongoing clinical programs in glioma, lung and pancreatic cancer.

"We have the most comprehensive and promising clinical data set in the field of developing viral immunotherapies in multiple tumor indications," explained Dr. Aguilar-Cordova. "We are particularly excited about expanding our efforts for brain tumor patients as they are in desperate need of new treatment options."

Candel’s efforts in pursuit of an effective treatment for brain cancer are significant. The company has completed a Phase 2 clinical study in high grade glioma that showed promising results, including an indication of survival benefit. The launch of a combination GMCI-checkpoint inhibitor clinical study, in collaboration with Bristol-Myers Squibb and the Adult Brain Tumor Consortium, was recently announced. The Company also has an ongoing study for recurrent GBM patients with rQNestin34.5, the company’s oncolytic herpes-based platform. Additionally, the Company plans to use proceeds from this financing to launch a GMCI pivotal trial for brain cancer patients.

For more information about its clinical programs, please visit www.clinicaltrials.gov or click the following link: View Source;term=advantagene&cntry=&state=&city=&dist=