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Cancer therapies and insights up top
March 2020
by Jeffrey Bouley  |  Email the author
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Focus Feature: Cancer Research News
 
Cancer therapies and insights up top
A roundup of recent research and development efforts in brain and lung cancers
ByJeffrey Bouley
 
There are several types of cancer that are particularly intractable, from the top of the head to right around the top of the legs, but brain cancer and lung cancer are two that often grab the attention, both among the general populace and in research circles.
 
To that end, we offer here roundups of four research and development efforts—two in glioblastoma (brain cancer) and two in lung cancer—from the University of California, San Diego (UC San Diego), twoXAR, Cancer Research UK, Vaccitech Oncology and the University of Texas MD Anderson Cancer Center.
 
Non-coding DNA may help drive glioblastoma
SAN DIEGO—As noted by UC San Diego, one of the ways a cancer-causing gene is able to turn a normal cell into a cancer cell is by copying itself over and over, and researchers have found that when cancer-causing genes do that, they also “scoop up” extra DNA into their copies. Why this is the case has largely been a mystery, but scientists at the UC San Diego School of Medicine working with colleagues at Case Western Reserve University School of Medicine maintain that the extra DNA that is collected is critical for maintaining a cancer-causing gene’s activation as well as ultimately supporting a cancer cell’s continued survival.
 
Using human glioblastoma brain tumor samples and a public database of patient tumor genetics, the researchers also discovered that even if two different tumor types are driven by the same cancer-causing gene, the extra DNA may differ. The study, published Nov. 21, 2019, in Cell, could explain why drugs will often work for some cancer types but not others.
 
“We’ve been targeting the cancer-causing gene for therapy, but it turns out we should also think about targeting the switches that are carried along with it,” said co-senior author Dr. Peter Scacheri, the Gertrude Donnelly Hess Professor of Oncology at Case Western Reserve University School of Medicine and member of the Case Comprehensive Cancer Center.
 
“In 2004, I was the lead on the first clinical trial to test a small molecule inhibitor of EGFR in glioblastoma,” added co-senior author Dr. Jeremy Rich, a professor of medicine at UC San Diego School of Medicine and director of neuro-oncology and director of the Brain Tumor Institute at UC San Diego Health. “But it didn’t work. And here we are 15 years later, still trying to understand why brain tumors don’t respond to inhibitors of what seems to be one of the most important genes to make this cancer grow.”
 
The team took a closer look at the extra DNA surrounding EGFR circles in nine of 44 different glioblastoma tumor samples donated by patients undergoing surgery. They discovered that the circles contained as many as 20 to 50 enhancers and other regulatory elements. Some of the regulatory elements had been adjacent to EGFR in the genome, but others were pulled in from other regions of the genome.
 
To determine the role each regulatory element plays, the researchers silenced them one at a time. They concluded that nearly every single regulatory element contributed to tumor growth.
 
“It looks like the cancer-causing gene grabs as many switches it can get its hands on ... co-opting their normal activity to maximize its own expression,” Scacheri said.
 
Next, the researchers want to know if the diversity in regulatory elements across cancer types could also be helping tumors evolve and resist chemotherapy. They also hope to find a class of therapeutic drugs that inhibit these regulatory elements, providing another way to put the brakes on cancer-causing genes.
 
1ST Biotherapeutics and twoXAR advance three novel glioblastoma treatment candidates
SEONGNAM, South Korea & MOUNTAIN VIEW, Calif.—1ST Biotherapeutics Inc., a clinical-stage biotechnology company focused on neurodegenerative diseases, immuno-oncology and orphan diseases, and twoXAR Pharmaceuticals, a company that discovers drugs with artificial intelligence (AI), announced recently that they would advance three novel drug leads for the potential treatment of glioblastoma into in-vivo efficacy testing less than one year from launching their drug discovery collaboration.
 
The traditional drug development approach takes four to six years on average to go from target identification to Investigational New Drug (IND)-enabling studies, including years until the first preclinical in-vivo study. The twoXAR process, propelled by the company’s proprietary AI-driven platform to identify promising first-in-class drug discovery hits, initiates preclinical in-vivo screening within months and programs advance to IND-enabling studies in one to three years.
 
“There is an urgent need to identify more efficiently novel targets for challenging diseases like glioblastoma and more rapidly assess the treatment efficacy of those candidates in preclinical studies,” said Jamie Jae Eun Kim, CEO of 1ST Biotherapeutics. “The speed at which we were able to work with twoXAR to identify these three new targets is unprecedented. The combination of twoXAR’s process and AI-driven platform designed specifically for target identification and our deep expertise in neurodegenerative disease and oncology enabled us to rapidly discover and advance these exciting new approaches to potentially treat this devastating disease.”
 
Under a partnership agreement announced in 2019, twoXAR identified a set of drug discovery hits with the potential to slow, stop, or reverse the progression of glioblastoma. twoXAR and 1ST Biotherapeutics then selected leads from this initial set to test in preclinical efficacy models of glioblastoma.
 
“This is a prime example of how AI, together with drug discovery and therapeutic expertise, can bring tremendous efficiency in identifying new targets for traditionally difficult-to-treat diseases,” said Dr. Mark G. Eller, senior vice president of research and development at twoXAR. “We will continue to collaborate with 1ST Biotherapeutics and leverage our combined drug discovery expertise to progress these promising candidates through the remaining preclinical research steps.”
 
First-in-human trial to test immunotherapeutic vaccine against lung cancer
LONDON—Cancer Research UK and Vaccitech Oncology Ltd. (VOLT) late last year announced a new partnership to bring a novel immunotherapeutic vaccine strategy to patients with lung cancer. The vaccine treatment developed by VOLT—a strategic collaboration between Vaccitech Ltd. and the Ludwig Institute for Cancer Research—is designed to stimulate the body’s immune system to attack cancer cells.
 
It will deliver cancer-associated antigens (MAGE A3 and NY-ESO-1) to antigen-presenting cells called dendritic cells, causing the immune system to produce cytotoxic T cells, which target and kill cancerous cells expressing the antigens.
 
This is reportedly the first time a viral vaccine program using this platform will be tested in the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. And separate clinical trials are also ongoing to test similar recombinant virus vaccines to treat people with late-stage prostate cancer.
 
“This partnership with VOLT is an important step to help accelerate this promising immunotherapy and could help more people survive lung cancer, which remains very hard to treat,” said Dr. Nigel Blackburn, Cancer Research UK’s director of drug development. “This novel approach using a modified adenovirus to prime the immune system and alert it to the presence of cancer cells could offer a completely new way to treat the disease.”
 
Added Vaccitech CEO Bill Enright: “We are delighted to enter into a clinical development partnership with two of the world’s most prestigious cancer research institutions. We believe that this partnership is an important validation of our prime boost platform’s utility in oncology as well as infectious disease.”
 
Jonathan Skipper, executive vice president for technology development, Ludwig Institute for Cancer Research, noted that previous clinical trials of experimental cancer vaccines targeting MAGE and NY-ESO antigens demonstrated that the antigens are highly specific to cancer and capable of eliciting strong immune responses, adding, “We believe that Vaccitech’s highly effective T cell induction platform should provide a potent immunotherapeutic that, in combination with checkpoint blockade, is capable of inducing sustained levels of cancer antigen-specific CD8+ T cells and the desired therapeutic effect in patients.”
 
Upon trial completion, VOLT retains the option to undertake further clinical development and commercialization of the immunotherapeutic. If VOLT elects not to exercise its option, Cancer Research UK will have the rights to take the program forward in all cancer indications.
 
Is intratumoral heterogeneity the reason for chemoresistant small cell lung cancer?
HOUSTON―Small cell lung cancer (SCLC) accounts for 14 percent of all lung cancers and is often rapidly resistant to chemotherapy, resulting in poor clinical outcomes. Treatment has changed little for decades, but a study at the MD Anderson Cancer Center found that chemotherapy results in increased heterogeneity within the tumor, leading to the evolution of multiple resistance mechanisms.
 
The research team, led by Dr. Lauren Averett Byers, an associate professor of thoracic/head and neck medical oncology, published their findings February in Nature Cancer.
 
“There have been few therapeutic advances in the past 30 years, and platinum-based chemotherapy remains the backbone of the standard of care. As a result, five-year survival is less than 7 percent across all stages,” Byers said. “Most patients respond well to platinum chemotherapy initially, but relapse within a few months. There are no highly effective second-line therapies when the tumor recurs.”
 
The team found that after treatment, SCLC tumors rapidly evolve. Before treatment, SCLC is largely homogenous, with the same type of cells found throughout the tumor. Within weeks to months of treatment, many new and different types of cells appear; this diversity within the tumor is called intratumoral heterogeneity.
 
“Because you end up with a cancer that has multiple resistance mechanisms turned on at the same time in different cells, the cancer becomes much harder to treat,” Byers said. “Some cells might be resistant through one mechanism or pathway, and other cells might be resistant through a different one. Treatment targeting one type of resistance will only kill a subset of cancer cells.”
 
The investigators performed single-cell RNA sequencing on 14 cell line-derived xenograft (CDX) models to identify gene expression differences between individual cells from chemotherapy-sensitive CDX tumors compared to those that remain resistant. They also performed single-cell sequencing directly on circulating tumor cells retrieved from one patient before treatment, during treatment and after relapse.
 
“To our knowledge, this is the first time in solid tumors that this type of approach has been applied directly to patient blood samples with RNA sequencing analysis of individual circulating tumor cells,” Byers said. “We looked at the tumor model grown from the same patient at the single-cell level before and after treatment, and we saw the same cell diversity in the circulating tumor cells from the patient.”
 
Byers’ lab is beginning to study what causes SCLC to evolve and develop intratumoral heterogeneity to see if the evolution can be stopped or prevented. Clinically, they hope to investigate aggressive early treatment approaches that bring new drugs to patients in the maintenance phase of treatment, before their cancer comes back. Currently, most clinical trials for SCLC enroll patients after their tumor recurs and has become chemoresistant.
 

Two trials aim to study vaccine for ovarian and head and neck cancers
 
STRASBOURG, France & TOKYO—Transgene, a biotech company that designs and develops virus-based immunotherapies for the treatment of cancer, and NEC Corp., a leader in information technology and network technologies, announced in March that the first patients have been enrolled in the first-in-human trials evaluating TG4050, an individualized therapeutic vaccine based on the myvac technology and powered by NEC’s artificial intelligence (AI) capabilities.
 
In these Phase 1 trials, TG4050 is being administered to patients with head and neck cancer who have a high risk of relapse after surgery and patients with ovarian cancer after surgery and adjuvant therapy.
 
Transgene’s myvac technology allows the generation of a virus-based immunotherapy within a very short time frame while encoding patient-specific mutations identified and selected by NEC’s Neoantigen Prediction System. TG4050 has been designed to target up to 30 patient-specific neoantigens (cancer cell mutations). T
 
“As each patient’s cancer is unique, we have developed a therapy that turns their solid tumor’s genetic signature into a powerful highly specific anticancer weapon. TG4050 is based on an MVA viral vector that has proven biological activity and has the ability to elicit an immune response against tumor antigens,” explained Philippe Archinard, chairman and CEO of Transgene. “Our partnership with NEC ensures that TG4050 is benefitting from its world-leading expertise in artificial intelligence and its unique algorithm that is used to select up to 30 patient-specific antigens that allow this novel vaccine to induce a strong immune response. We are convinced that TG4050, which is at the crossroad of immunotherapy and big data sciences, will herald the start of a new era in the fight against cancer.”
 
Added Osamu Fujikawa, a senior vice president at NEC: “We are excited to enroll our first patients in these trials and see TG4050 advance to the clinic. This is another step closer towards the realization of an AI-driven individualized immunotherapy for each patient. Our unique partnership with Transgene enables us to leverage its significant clinical development know-how and proven viral vector delivery platform.”
 

Triple combo study to evaluate COM701 with Opdivo and TIGIT inhibitor
 
HOLON, Israel—Compugen Ltd., a clinical-stage cancer immunotherapy company, in March announced its plan to initiate a Phase 1/2 study evaluating a triple combination of Compugen’s COM701, an investigational anti-PVRIG antibody, in combination with Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor Opdivo (nivolumab) and BMS-986207, which is Bristol-Myers Squibb’s investigational anti-TIGIT antibody.
 
The triple combination study is designed to evaluate the blockade of the three immune checkpoint pathways—PVRIG, TIGIT and PD-1—and will accelerate the clinical evaluation of Compugen’s science-driven DNAM axis hypothesis in various advanced solid tumors. The study is expected to commence in the second half of 2020, following the clearance of a new Investigational New Drug Application by the U.S. Food and Drug Administration.
 
“The triple combination regimen allows us to ultimately test our science-driven hypothesis that the dual inhibition of the DNAM axis with PVRIG and TIGIT blockers, together with the inhibition of the PD-1 pathway, will enable robust activation of T cells leading to anti-tumor immune responses in cancer patients who are non-responsive or refractory to PD-1 blockers,” said Dr. Anat Cohen-Dayag, president and CEO of Compugen.
 
Under the existing collaboration with Bristol-Myers Squibb, COM701 is being investigated as a monotherapy and in combination with Opdivo in an ongoing Phase 1 study. Following the Companies’ joint decision to move forward with a triple combination study, Compugen will complete the dose escalation arm of the dual combination of COM701 with Opdivo under its ongoing Phase 1 study. Future studies evaluating COM701 in combination with a PD-1 inhibitor in specific tumor types will be assessed at a later date.
 

MiNA Therapeutics begins Phase 1 clinical study of MTL CEBPA
 
LONDON—MiNA Therapeutics, which touts itself a pioneer in RNA activation therapeutics, has begun TIMEPOINT, a global Phase 1/1b clinical study of MTL-CEBPA in combination with anti-PD1 checkpoint inhibitor pembrolizumab in patients with advanced solid tumors.
 
The study is designed to assess the safety, tolerability, pharmacology and clinical activity of MTL-CEBPA in combination with pembrolizumab in these patients. MTL-CEBPA is said to be the first therapy to specifically up-regulate CCAAT/enhancer binding protein alpha (C/EBP-α), a transcription factor that acts as a master regulator of myeloid cell lineage determination and differentiation.
 
The drug candidate is also being investigated in an ongoing multicenter Phase 1b clinical trial in patients with advanced liver cancer in combination with sorafenib.
 
“Initiation of the Phase 1 TIMEPOINT clinical trial emphasizes the continued exploration of MTL-CEBPA, the first drug candidate that targets C/EBP-α, a master regulator of immune cells that play a critical role in tumour resistance,” said Robert Habib, CEO of MiNA Therapeutics. “We are excited to take the next step and test MTL CEBPA in additional cancer populations in a potentially synergistic combination with an anti-PD1 checkpoint inhibitor. We look forward to collaborating with our clinical investigators in evaluating this new combination.”
 
The single agent activity of MTL-CEBPA in 39 patients with advanced liver cancer was previously presented by investigators at the European Society for Medical Oncology (ESMO) 2019 Congress. MTL-CEBPA was found to be well tolerated, demonstrating pharmacodynamic target engagement and a reduction of suppressive immune cells in the tumor microenvironment. In addition, MTL-CEBPA demonstrated clear, synergistic activity in patients with liver cancer when also treated with sorafenib standard of care.
 
“MTL-CEBPA has shown real promise as a combination agent in patients with liver cancer and preclinical studies suggest that MTL-CEBPA may also be an attractive agent to enhance the benefits of checkpoint inhibitors,” noted Prof. Ruth Plummer, a clinical professor of experimental medicine at the Clinical and Translational Research Institute of the Newcastle University Centre for Cancer, and chief investigator of the study. “We are looking forward to evaluating this highly innovative combination treatment in the upcoming Phase 1 trial. We hope this combination could become an effective new treatment option for patients with solid tumor cancers.”
 
Code: E032037

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