BriaCell Provides Clinical Update on its Lead Immunotherapy Drug in Advanced Breast Cancer

BriaCell, an immuno-oncology focused biotechnology company with a proprietary targeted immunotherapy technology, has provided a clinical update regarding its ongoing clinical trials of Bria-IMT™ (formerly referred to as SV-BR-1-GM).

BriaCell currently is enrolling patients in two separate but related clinical trials. Trial WRI-GEV-007 (listed in ClinicalTrials.gov as NCT03066947) is a Phase I/IIa clinical study designed to evaluate the safety and efficacy of Bria-IMT™ in metastatic or locally recurrent breast cancer patients.  In this study, Bria-IMT™ is given in a regimen including low-dose pre-dose cyclophosphamide (to reduce suppression of the immune response) and post-dose interferon-alpha (to boost the immune response).  The second clinical trial, BRI-ROL-001 (listed in ClinicalTrials.gov as NCT03328026), is a rollover study of Bria-IMT™ in combination with Keytruda® [pembrolizumab] or Yervoy® [ipilimumab].

Patient recruitment is on schedule despite interruption due to temporary shutdown of some clinical sites, affected by wildfires and hurricanes. Seven patients have enrolled in the WRI-GEV-007 clinical trial with 6 treated to date (1 patient dropped out after cyclophosphamide pre-treatment and did not receive Bria-IMT™). Based on results to-date, Bria-IMT™ has been very well tolerated and the majority of adverse events were limited to expected minor local irritation at the injection sites.  No serious adverse events related to Bria-IMT™ have been reported and no new or unexpected safety issues related to Bria-IMT™ have been observed.  The Phase I portion of the study has been successfully completed, and the Phase IIa portion is currently enrolling.

One patient is worth discussing in detail. This 73-year-old woman had breast cancer diagnosed in 1995.  She developed liver metastases in 2010, and then lung metastases in 2017. Prior treatments included surgery, radiation therapy, hormonal therapy and seven rounds of chemotherapy with 8 different chemotherapy agents. She received 5 cycles of Bria-IMT™ over the first 3 months of treatment, then 3 additional cycles over the following 3 months (6 months total).  Evaluation was performed after 3 months and 6 months. After 3 months, despite the extensive prior therapy, her scans noted that, “there has been a clear response in the multiple bilateral pulmonary nodules” indicating that several lung tumors had disappeared or decreased in size.  This response was maintained after 6 months of treatment with Bria-IMT™.  The liver tumors were stable to slightly increased at 3 months, and then progressed after 6 months.

Like the patient reported previously by Dr. Wiseman, BriaCell’s Scientific Founder, in a proof-of-concept clinical study, this patient is a double match with Bria-IMT™ at two specific biomarkers (HLA-A and HLA-DRB3).  This is highly significant, as it supports our BriaDX™ hypothesis that these biomarkers can be used to select the patients most likely to respond to Bria-IMT™ therapy.  We also noted in this patient that, while circulating tumor-associated cells decreased following the initial treatment, the expression of PD-L1, a molecule that suppresses the immune response, increased during treatment. This suggests that treating this patient (and other similar patients) with Bria-IMT™ in combination with a potent PD-1 inhibitor such as Keytruda® [pembrolizumab] may be a highly effective method to improve the efficacy of the treatment and patient outcomes.

A third clinical site was recently added to the study and several patients are being evaluated for the WRI-GEV-007 study. Discussions are ongoing with two additional clinical sites which are expected to be added in the near future. The combination rollover study, BRI-ROL-001, is available to enroll patients.

Other activities remain on track.  The companion diagnostic, BriaDX™, has been bolstered by the important supporting data for the HLA biomarker matching hypothesis noted above.  BriaCell is also developing an off-the-shelf, personalized immunotherapy (Bria-OTS™) to treat a much wider patient population (with ~90% of the population being a double-match with Bria-OTS™).  In collaboration with University of Zurich, Switzerland, BriaCell is testing other drugs/product candidates that are expected to boost the effectiveness of Bria-IMT™ and Bria-OTS™.

Ongoing work in the small molecule program to select protein kinase C delta inhibitors for cancer and fibrotic diseases is also progressing according to our timelines. The medicinal chemistry work is being performed at Colorado State University where the current library of compounds available is being augmented.

BriaCell is an immuno-oncology focused biotechnology company developing a targeted and safe approach to the management of cancer. Immunotherapy has come to the forefront of the fight against cancer, harnessing the body’s own immune system in recognizing and selectively destroying cancer cells while sparing normal ones. Immunotherapy, in addition to generally being more targeted and less toxic than commonly used types of chemotherapy, is also thought to be a potent approach with the potential to prevent cancer recurrence.

Bria-IMT™ (SV-BR-1-GM), the Company’s lead product candidate, is derived from a breast cancer cell line genetically engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), a substance that activates the immune system by allowing the body to recognize and eliminate cancerous cells by inducing tumor-directed T cell and potentially antibody responses.

The results of two previous proof-of-concept clinical trials (one with the precursor cell line not genetically engineered to produce GM-CSF and one with Bria-IMT™) produced encouraging results in patients with advanced breast cancer. Most notably, one patient with metastatic breast cancer responded to Bria-IMT™ with substantial reduction in tumor burden including breast, lung, soft tissue and brain metastases. The company is currently conducting a Phase I/IIa clinical trial for Bria-IMT™ in patients with advanced breast cancer.  This trial is listed in ClinicalTrials.gov as NCT03066947.  The trial is being conducted along with the co-development of BriaDX™, the Company’s companion diagnostic test. The interim data for the first 10 patients is expected by the first quarter of 2018. Additionally, the FDA recently approved the roll-over combination study of Bria-IMT™ with pembrolizumab [Keytruda; manufactured by Merck & Co., Inc.] or ipilimumab [Yervoy; manufactured by Bristol-Myers Squibb Company] for patients previously treated with Bria-IMT™ in the Company’s ongoing Phase I/IIa clinical trial in advanced breast cancer. The roll-over trial is listed in ClinicalTrials.gov as NCT03328026.

BriaCell is also developing Bria-OTS™, an off-the-shelf personalized Immunotherapy.  Bria-OTS™ consists of 14 individually pre-manufactured genetic alleles. BriaCell’s BriaDX™ companion diagnostic reveals a patient’s specific HLA-types and the 2 best matching alleles are administered to the patient. BriaCell’s 14 alleles (8 Class I and 6 Class II) cover approximately 90% of the Breast Cancer population while eliminating the complex manufacturing logistics required for other personalized immunotherapies. Bria-OTS™ is a personalized therapy without the need for personalized manufacturing.

BriaCell is also developing novel, selective protein kinase C delta (PKCδ) inhibitors. PKCδ inhibitors have shown activity in a number of pre-clinical models of RAS genes’ transformed cancers including breast, pancreatic, non-small cell lung cancer and neuroendocrine tumors (such as carcinoid tumors).

For additional information on BriaCell, please visit our website: http://briacell.com.

How Defeating THOR Could Bring a Hammer Down on Cancer

It turns out Thor, the Norse god of thunder and the Marvel superhero, has special powers when it comes to cancer too.

Researchers at the University of Michigan Comprehensive Cancer Center uncovered a novel gene they named THOR while investigating previously unexplored regions of the human genome – the dark matter of the human genome.

They characterized a long non-coding RNA (lncRNA) that is expressed in humans, mice and zebrafish. It’s unusual for this type of RNA to be conserved throughout species like this. The team’s thinking was that if the RNA plays a role in other animals and species besides humans, it must be important.

“Genes that are evolutionarily conserved are likely important for biological processes. The fact that we found THOR to be a highly conserved lncRNA was exciting. We chose to focus on it with the thought that it has been selected by evolution for having important functions,” says Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at Michigan Medicine.

In fact, the researchers found this particular lncRNA plays a role in cancer development. And that knocking it out can halt the growth of tumors.

This is the first group to identify and characterize THOR, which stands for Testis-associated Highly-conserved Oncogenic long non-coding RNA. They published their results in Cell.

It’s an early example of how this previously unexplored portion of the genome could lead to a potential new way of attacking cancer.

In 2015, Chinnaiyan’s team published a paper analyzing the global landscape of lncRNAs, which had been considered dark matter because so little was known about it. They identified thousands of potential lncRNAs that might warrant future study.

THOR rose to the top of the list because it was evolutionarily highly conserved. It was also highly expressed, specifically in testes cells. It had little to no expression in other types of adult normal tissue.

Because THOR is highly conserved, researchers were able to study it in mice and zebrafish, as well as in human cells.

“That is one of the challenges of studying lncRNAs that are not conserved. If they’re not conserved in model systems, they are difficult to characterize. Here, because THOR is so highly conserved, we were able to look at its expression and function in zebrafish models,” Chinnaiyan says.

In addition to finding THOR expression in normal testis tissue, the researchers found it was highly expressed in some subsets of cancers, particularly lung cancer and melanoma. As they investigated THOR, they found its expression had a direct impact on cancer development. If they knocked down THOR in cell lines expressing it, tumor growth slowed. If they overexpressed THOR, cells grew faster. And when they eliminated THOR from normal cells, the cells continued to develop normally, suggesting it only impacts cancer cells.

“We’ve gone through a lot of lncRNAs to get to that. Most of the ones we test don’t have a clear function like this,” Chinnaiyan says.

Researchers also found that THOR impacted proteins called IGFBPs, which are thought to be involved in stabilizing RNAs. Knocking down THOR inhibited IGFBP activity.

“If we perturb THOR function, we disturb the ability to stabilize RNA. This inhibits cell proliferation,” Chinnaiyan says. Conversely, when researchers overexpressed THOR, cells grew faster.

Chinnaiyan suggests THOR could be a good target for drug development because blocking it does not impact normal cells. That would likely mean fewer toxic side effects. In future studies, the researchers will look at how to create a compound that binds with THOR in a complimentary sequence designed to knock it down. This approach, known as antisense oligonucleotides, has been used successfully in other contexts.

UK Study Finds Biomarker Targets to Make Drugs More Effective in Fighting Cancer

A new study published in Nature Communications and led by University of Kentucky Markey Cancer Center researcher Qing-Bai She identifies biomarker targets that may make existing drugs more effective in fighting certain cancers.

The mTOR protein is a central regulator of cell growth and division. Abnormal activation of mTOR protein results in limitless cell division in many human cancers. Though mTOR-targeted drugs exist, their effectiveness has so far been limited, possibly due to the loss of the mTOR downstream effector 4E-BP1, a key repressor of protein production.

The study identifies Snail, a nuclear transcription regulator known to promote cancer progression, as a strong repressor of 4E-BP1 expression. She’s team found an inverse correlation between Snail and 4E-BP1 levels in colorectal cancer, the second leading cause of cancer-related mortality in the United States. This study shows promise that the Snail level may serve as a predictive marker to tailor personalized treatments using mTOR-targeted drugs. Physicians may be able to prescribe treatment for cancers that have high Snail/low 4E-BP1 activities, using cancer drugs that are already in clinical development.

“This finding has significant clinical ramification, because incorporating the analysis of Snail and 4E-BP1 expression in cancers may help to prospectively identify resistance to mTOR-targeted drugs in the clinic,” said She, associate professor in the UK Department of Pharmacology & Nutritional Sciences.

Deadly Lung Cancers Are Driven by Multiple Genetic Changes

Blood-Based Cancer Tests Reveal Complex Genomic Landscape of Non-Small Cell Lung Cancers

A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant “driver” mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world’s most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.

These findings — published online on November 6, 2017 in Nature Genetics — strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient’s cancer and prevent drug resistance from arising.

“Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment,” said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.

Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best — sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.

The new UCSF-led study — which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health — is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.

“The field has been so focused on treating the ‘driver’ mutation controlling a tumor’s growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment,” said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. “This could also explain why many tumors are already drug-resistant when treatment is first applied.”

FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma

This week, the U.S. Food and Drug Administration approved Yescarta (axicabtagene ciloleucel), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta, a chimeric antigen receptor (CAR) T cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).

“Today marks another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases. In just several decades, gene therapy has gone from being a promising concept to a practical solution to deadly and largely untreatable forms of cancer,” said FDA Commissioner Scott Gottlieb, M.D. “This approval demonstrates the continued momentum of this promising new area of medicine and we’re committed to supporting and helping expedite the development of these products. We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine. That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.”

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in adults. NHLs are cancers that begin in certain cells of the immune system and can be either fast-growing (aggressive) or slow-growing. Approximately 72,000 new cases of NHL are diagnosed in the U.S. each year, and DLBCL represents approximately one in three newly diagnosed cases. Yescarta is approved for use in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed, including DLBCL, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Each dose of Yescarta is a customized treatment created using a patient’s own immune system to help fight the lymphoma. The patient’s T-cells, a type of white blood cell, are collected and genetically modified to include a new gene that targets and kills the lymphoma cells. Once the cells are modified, they are infused back into the patient.

“The approval of Yescarta brings this innovative class of CAR-T cell therapies to an additional group of cancer patients with few other options – those adults with certain types of lymphoma that have not responded to previous treatments,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER).

The safety and efficacy of Yescarta were established in a multicenter clinical trial of more than 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment with Yescarta was 51 percent.

Treatment with Yescarta has the potential to cause severe side effects. It carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR-T cells causing high fever and flu-like symptoms, and for neurologic toxicities. Both CRS and neurologic toxicities can be fatal or life-threatening. Other side effects include serious infections, low blood cell counts and a weakened immune system. Side effects from treatment with Yescarta usually appear within the first one to two weeks, but some side effects may occur later.

Because of the risk of CRS and neurologic toxicities, Yescarta is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring that hospitals and their associated clinics that dispense Yescarta be specially certified. As part of that certification, staff involved in the prescribing, dispensing or administering of Yescarta are required to be trained to recognize and manage CRS and nervous system toxicities. Also, patients must be informed of the potential serious side effects and of the importance of promptly returning to the treatment site if side effects develop.

To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving patients treated with Yescarta.

The FDA granted Yescarta Priority Review and Breakthrough Therapy designations. Yescarta also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The Yescarta application was reviewed using a coordinated, cross-agency approach. The clinical review was conducted by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Yescarta to Kite Pharma, Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Accelerating the Development of Next-Generation Cancer Therapies

To accelerate the development of next-generation cancer therapies, the Gene Editing Institute of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System has agreed to provide genetically modified cell lines to Analytical Biological Services, Inc. (ABS) of Wilmington, Delaware.

Under a three-year agreement, the Gene Editing Institute will act as sole provider of gene editing services and genetically modified cell lines to ABS for replication, marketing and distribution to leading pharmaceutical and biomedical research companies worldwide.

“This agreement with ABS will speed the progress in the discovery of effective cancer therapies and accelerate the path to prevention, diagnosis and treatment of many forms of cancer,” said Nicholas J. Petrelli, M.D., the Bank of America endowed medical director of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System.

“This partnership greatly enhances our capability to provide the highest quality genetically engineered cells for drug discovery,” said ABS President and CEO Charles Saller, Ph.D. “Our partners at the Gene Editing Institute are advancing molecular medicine, and their expertise adds a new dimension to our efforts to speed up drug discovery.”

“One goal of The Gene Editing Institute is to develop community partnerships that can advance translational cancer research,” said Eric Kmiec, Ph.D., founder and director of the Gene Editing Institute. “The Gene Editing Institute is driving innovation in gene engineering, and ABS has the know-how to grow and expand the cells in sufficient quantities, as well as to market them to pharmaceutical and biotechnology clients for drug screening and research.”

The Gene Editing Institute is a worldwide leader in the design of the tools that scientists need to manipulate and alter human genetic material easier and more efficiently than ever before. Scientists at the Gene Editing Institute have designed and customized an expanding tool-kit for gene editing, including the renowned CRISPR-Cas9 system, to permanently disrupt or knock out genes, add or knock in DNA fragments and create point mutations in genomic DNA. Last year, scientists at the Gene Editing Institute described in the journal Scientific Reports how they combined CRISPR and short strands of synthetic DNA to greatly enhance the precision and reliability of the CRISPR gene editing technique. Called Excision and Corrective Therapy, or EXACT, this new tool acts as both a Band-Aid and a template during gene mutation repairs.

Genetically modified cells can help advance cancer research. By inactivating a single gene, scientists can test if it affects tumor formation or somehow alters the response to cancer therapies. Similarly, inserting a gene into a cell can produce a gene product that is a target for potential new drugs.

“Gene editing and the CRISPR technology is having a major impact on anticancer drug development because it allows us to validate the target of the candidate drug,” said Dr. Kmiec. “Pharmaceutical companies want to use gene editing tools to identify new targets for anti-cancer drugs and to validate the targets they already have identified.”

The Delaware BioScience Association helped connect the Gene Editing Institute with ABS. “The collaborative agreement between the Gene Editing Institute and ABS exemplifies the power of building a strong biotech community, flourishing further innovation, and keeping businesses engaged and thriving in the state of Delaware,” said Helen Stimson, president and CEO of The Delaware BioScience Association. “The Delaware BioScience Association is committed to fostering meaningful relationships, such as this one, among its members, and establishing strategic partnerships that bolster the state’s innovation economy,” she said.

“This is one of those times when the forces of nature align to bring two perfectly matched skill sets together,” said Dr. Kmiec. “There is no question that our collaboration with ABS will accelerate the pace of drug discovery around the world.”

About The Gene Editing Institute

The Gene Editing Institute of Christiana Care Health System’s Helen F. Graham Cancer Center & Research Institute is unlocking the genetic mechanisms that drive cancer that can lead to new therapies and pharmaceuticals to revolutionize cancer treatment. Gene editing in lung cancer research has already begun setting the stage for clinical trials.

The Gene Editing Institute is integrated into the Molecular Screening Facility at The Wistar Institute in Philadelphia, PA, where its innovative gene-editing technologies are available to research projects at Wistar and to external users. Working with Wistar scientists, the Gene Editing Institute has begun research to conduct a clinical trial in melanoma. With funding from the National Institutes of Health, the Gene Editing Institute is partnering with A.I. duPont/Nemours to develop a gene editing strategy for the treatment of sickle cell anemia and leukemia. Under a grant from the U.S.–Israel Binational Industrial Research & Development Foundation, the Gene Editing Institute is working with Jerusalem-based NovellusDx to improve the efficiency and speed of cancer diagnostic screening tools. This work could lead to earlier identification of genetic mechanisms responsible for both the onset and progression of many types of cancers and the development of individualized therapeutics.

Gene Editing Institute scientists also provide instruction in the design and implementation of genetic tools. Partnerships with Bio-Rad Inc. and the Delaware Technical and Community College are producing gene editing curricula and teacher training workshops for both community colleges and secondary schools.

Cancer Immunotherapy May Get a Boost by Disabling Specific T Cells

Cancer immunotherapy drugs only work for a minority of patients, but a generic drug now used to increase blood flow may be able to improve those odds, a study by Columbia University Medical Center (CUMC) researchers suggests.

In mice with melanoma, the researchers found that the drug – called pentoxifylline – boosts the effectiveness of immune-checkpoint inhibitors, a type of immunotherapy now commonly used in the treatment of melanoma and other cancers.

The study was published today in the online edition of Cell.

Checkpoint-blockade immunotherapy drugs – the first drugs were approved in 2011 – target proteins on tumor cells or cells of the immune system that prevent “killer” T cells from attacking cancer. These drugs have revolutionized cancer care, but do not work for all patients. “In advanced melanoma, for example, the cure rate is only about 20 percent. That’s a remarkable improvement over previous therapies,” says study leader Sankar Ghosh, PhD, Chair and Silverstein and Hutt Family Professor of Microbiology & Immunology. “But why doesn’t it work for the other 80 percent? There must be another mechanism that contributes to the suppression of the immune response.”

Dr. Ghosh and other cancer biologists suspected that a different type of T cell, known as regulatory T cells, or Tregs, may also suppress the immune system’s attack on cancer. Large numbers of these cells are found within several types of tumors. “One possible therapy would be to get rid of Tregs,” he said. “But Tregs are also needed to keep the immune system in check, and shutting down Tregs completely would unleash an attack against the body’s healthy cells and organs.”

This point is underscored by a related study, published today in Immunity, in which Dr. Ghosh and colleagues found that removing NF-kB from Tregs caused widespread and lethal autoimmunity in mice. However, a partial inhibition of NF-kB, achieved by removing only one, specific, NF-kB protein, called c-Rel, changed Treg function without causing widespread autoimmunity.  In the Cell study Ghosh and colleagues showed that these c-Rel deficient Tregs were specifically crippled in their ability to protect cancer cells. As a result, when c-Rel is blocked, killer T cells mounted a more robust attack on cancer cells without causing autoimmunity.

Pentoxifylline is a drug that is used in patients to increase blood flow in the hands and feet of people with poor circulation, but it’s also known to inhibit the c-Rel protein. In the Cell study, the researchers demonstrated that pentoxifylline blocked Treg function and boosted the effectiveness of standard checkpoint-blockade immunotherapies.  As a result, mice treated with both drugs showed significantly reduced melanoma tumor burden, compared to animals that received the standard therapy alone.

“The next step is to test this drug combination in human clinical trials,” Dr. Ghosh says. “If trials are successful, the use of c-Rel inhibitors could become a standard addition to immune checkpoint therapy for many types of cancer.”

Experimental CAR-T Treatment Halted as Two More Patients Die During Clinical Trials

Juno Therapeutics said Wednesday it has suspended a Phase II clinical trial of a cancer drug after two patients suffered cerebral edema earlier this week, leaving one dead and the other not expected to recover. The company’s ‘Rocket’ trial for B cell acute lymphoblastic leukemia is testing a drug it calls JCAR015.

These drugs work by extracting T cells from patients and then equipping them with chimeric antigen receptors, which then zero in on cancer cells. This first generation of CAR-Ts, which is likely to be eclipsed by early-stage efforts, has been known to trigger harsh side effects.

The cause of death in these patients was cerebral edema, or swelling in the brain. Cerebral edema was the same condition that killed three patients earlier this year and forced the company to stop the trial in this summer. Juno, at that time, had blamed the deadly reaction on one of the chemotherapy drugs that it was using to “precondition,” or prepare the patients for JCAR015. The FDA allowed Juno to restart the trial in short order, however, without the chemo drug, called fludarabine.

Juno said it has notified the Food and Drug Administration of the voluntary hold and is working with the agency and the Data and Safety Monitoring Board to determine next steps. Juno’s trials and plans for its other product candidates are not affected, the company said in a prepared statement.

 

Researchers Restore Drug Sensitivity in Breast Cancer Tumors

A team of Case Western Reserve University School of Medicine cancer researchers has uncovered one way certain tumors resist vital medication.

In the study published in Oncotarget, the researchers studied tumor biopsies collected from breast cancer patients before and after treatment with the go-to breast cancer drug trastuzumab (also known as Herceptin). Some of the tumors were treatable with trastuzumab, and others were not. By comparing genes activated in the responsive tumors to those in non-responsive tumors, the researchers uncovered several genes that may help tumors evade the drug. Tumors previously resistant to trastuzumab were resensitized when the researchers blocked one of the genes, called S100P.

The study zeroed in on small pieces of genetic material called mRNAs and lincRNAs. These tiny fragments are created from DNA inside normal cells but become dysregulated in tumors. The research team initially identified 1,542 mRNAs and 371 lincRNAs that were different between tumors cells responsive to trastuzumab and non-responsive tumors. These differences indicated to the researchers that separate networks of cell signals were being activated in each group of tumor cells. The researchers narrowed down the list of RNAs using cells grown in their laboratory. They were interested in finding an RNA molecule that could be therapeutically manipulated to disrupt signals in the tumor cells related to trastuzumab resistance.

Ahmad Khalil, PhD, Assistant Professor of Genetics at Case Western Reserve University School of Medicine led the study and explained, “Our hypothesis was that there are gene expression differences of both mRNAs and lincRNAs between tumors from patients that respond to trastuzumab and tumors from patients that do not.”

Trastuzumab works by sticking to a protein called HER2 found on the surfaces of 25-30% of early-stage breast cancer tumor cells. The drug prevents HER2 from activating and controlling genes inside breast cancer cells. The research team grew breast cancer tumor cells with HER2 on their surfaces in their laboratory so they could validate findings from tumor biopsies. They exposed the cells to trastuzumab, mimicking cancer treatment regimens. Some breast cancer cells became resistant to trastuzumab after long-term exposure, just like the tumors collected from patients.

The researchers could identify mRNAs and lincRNAs that varied between trastuzumab-resistant and -sensitive HER2 cancer cells grown in the laboratory. They looked for overlap between the list of different RNAs in tumor biopsies and laboratory-grown cancer cells. The team identified 18 mRNAs and 7 lincRNAs that were associated with trastuzumab resistance in both models. The team zeroed in on a single gene that may be central to trastuzumab resistance after performing additional experiments in the laboratory.

The gene, S100P, is highly activated in breast cancer cells resistant to trastuzumab, as compared to normal breast tissue. Other studies have associated S100P with prostate and pancreatic cancers. It belongs to a family of genes that work together to support tumor growth and has been found in multiple compartments inside cancer cells.

“S100P was one of the key genes that showed significant expression differences,” said Khalil. “It further stood out because it was part of a pathway that emerged from a separate set of computational analyses of large datasets.”

The researchers designed small pieces of genetic material to block S100P in breast cancer cells. Cells grown in the laboratory that were previously resistant to trastuzumab became sensitive to the drug after exposure to S100P blockers. Further analyses indicated that S100P activates critical proteins inside breast cancer cells to compensate for those turned off when trastuzumab blocks HER2. The activated proteins may help tumor cells adjust their gene expression in response to drugs in their environment.

“Our data demonstrated that high expression levels of S100P are required for cancer cells to become resistant to trastuzumab,” concluded Khalil.

This exciting discovery indicates that depleting S100P in breast cancer may be one way to resensitize tumors to trastuzumab. The next step will be to further investigate the resistance mechanism, and screen for drugs that could be used to block S100P in human tumors. The researchers also plan to investigate the role of other mRNAs and lincRNAs from their list in regulating trastuzumab resistance.

Approximately one-third of early-stage breast cancer patients relapse after trastuzumab treatment, even if the drug is successful at first. Tumors in relapsed patients become resistant to trastuzumab which limits further treatment options. The mechanism behind trastuzumab resistance has not been easy to identify. Some studies have proposed mechanisms of trastuzumab resistance using cell culture models, but this study is the first to find mechanisms present in both cells growing in a laboratory dish and tumors growing in breast cancer patients.

According to Khalil, “Trastuzumab is a first line treatment for breast cancer patients with HER2 gene amplification. Thus, finding the mechanism of resistance to this major drug now opens the door to reverse the resistance, potentially curing many more patients.”

Four NCI Cancer Centers Announce Landmark Research Consortium and Collaborations with Celgene

The Abramson Cancer Center at the University of Pennsylvania, The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai announced the establishment of a research consortium focused on accelerating the discovery and development of novel cancer therapeutics and diagnostics for the benefit of patients.

The consortium aligns four major academic institutions in a unified partnership with the shared goal of creating high-impact research programs to discover new treatments for cancer. The magnitude of the multi-institutional consortium and agreements between Celgene Corporation (NASDAQ: CELG) and each institution will support the rapid delivery of disease-altering programs to the clinic that may ultimately benefit cancer patients, global healthcare systems and society.
Subsequent to establishing the consortium, Celgene entered into four public-private collaboration agreements in which it paid a total of $50 million, $12.5 million to each institution, for the option to enter into future agreements to develop and commercialize novel cancer therapeutics arising from the consortium’s efforts. Over the next ten years the institutions intend to present multiple high-impact research programs to Celgene with the goal of developing new life-saving therapeutics. Subject to Celgene’s decision to opt-in and license the resulting technologies, each program has the potential to be valued at hundreds of millions of dollars.
The four cancer center directors, Steven Burakoff, M.D., of the Icahn School of Medicine at Mount Sinai, Stephen G. Emerson, M.D., Ph.D., of Columbia University, William Nelson, M.D., Ph.D., of Johns Hopkins University and Chi Van Dang, M.D., Ph.D., of the University of Pennsylvania, said in a shared statement, “The active and coordinated engagement, creative thinking and unique perspectives and expertise of each institution have made this collaboration a reality. Our shared vision and unified approach to biomedical research, discovery and development, combined with Celgene’s vast research, development and global commercial expertise, will enable us to accelerate the development and delivery of next-generation cancer therapies to patients worldwide.”

In addition to the benefits of long-standing professional relationships among the four cancer center directors, the depth and breadth of the institutions’ combined research and clinical infrastructures provide an exceptional foundation upon which to build this transformative collaboration. The four institutions collectively care for more than 30,000 new cancer patients each year, and have nearly 800 faculty members who are active in basic and clinical research, and clinical care.

“This is a paradigm-shifting collaboration that further strengthens our innovative ecosystem,” said Bob Hugin, Executive Chairman of Celgene Corporation. “We remain firmly committed to driving critical advances in cancer and believe the tremendous expertise of our collaboration partner institutions will be invaluable in identifying new therapies for cancer patients.”
The four consortium members are among the 69 institutions designated as Cancer Centers by the National Cancer Institute (NCI). These 69 institutions serve as the backbone of NCI’s research in the war against cancer.
The Cancer Trust, a non-profit organization, brought together the four institutions, thereby establishing the multi-institutional research consortium. T.R. Winston & Company, LLC served as the strategic advisor to The Cancer Trust and facilitated negotiations among The Cancer Trust, the institutions and Celgene. The commercialization offices of the four institutions, Columbia Technology Ventures, Johns Hopkins Technology Ventures, Mount Sinai Innovation Partners and the Penn Center for Innovation, subsequently collaborated with Celgene to accelerate this effort to discover and develop new therapies for the treatment of cancer.

“We are extremely proud of what we’ve collectively accomplished through establishing this collaboration and aligning all participants,” said Erik Lium, Ph.D., Senior Vice President of Mount Sinai Innovation Partners. “We look forward to continuing to work closely with one another, our colleagues in research and clinical care, and now with Celgene to advance the discovery of new therapies that will dramatically improve the lives of patients worldwide.”