Special Focus on Cancer Research News: In the pink with oncology R&D
October 2017
by Jeffrey Bouley  |  Email the author

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Special Focus: Cancer Research News
 
In the pink with oncology R&D
 
A roundup of recent research and clinical work within the realm of breast cancer
 
Every October, the cover of DDNews magazine (and the home page of our website) “goes pink” in terms of the banner color and sports a pink ribbon in honor of Breast Cancer Awareness Month. Given that this October issue was already slated to have a Cancer Research News special focus section, it seemed only fitting to kick off the section with a story related to breast cancer R&D and clinical trial efforts.
 
Or, as it happens, several stories all brought together into one roundup article.
 
We begin with Seattle-based Atossa Genetics—a clinical-stage pharmaceutical company developing novel therapeutics and delivery methods for breast cancer and other breast conditions—which on Oct. 2 announced a new program using chimeric antigen receptor T cell (CAR-T) therapy.
 
More specifically, Atossa plans to use its proprietary intraductal microcatheter technology to deliver CAR-T cells into the ducts of the breast for the potential targeted treatment of breast cancer.
 
Atossa’s novel approach uses its proprietary intraductal microcatheter technology for the potential transpapillary (TRAP) delivery of T cells that have been genetically modified to attack breast cancer cells. Atossa believes this method has several potential advantages, among them the following: reduced toxicity by limiting systemic exposure of the T cells; improved efficacy by placing the T cells in direct contact with the target ductal epithelial cells that are undergoing malignant transformation; and lymphatic migration of the CAR-T cells along the same path taken by migrating cancer cells, potentially extending their cytotoxic actions into the regional lymph system, which could limit tumor cell dissemination.
 
Atossa’s approach is in the research and development phase, with preclinical studies and clinical trials still in the future.
 
“We have been encouraged by the promise that CAR-T has shown in other forms of cancer, which is usually delivered systemically. We believe that our proprietary TRAP technology could provide a potentially safer yet effective method to deliver CAR-T,” said Dr. Steven Quay, CEO of Atossa. “We believe that TRAP CAR-T, as we are calling this novel approach to adaptive T cell therapy in breast cancer, will provide another approach to breast cancer, and that it may be particularly well-suited for the deadlier forms of breast cancer such as triple-negative.
 
“Now that we have developed a foundational intellectual property position with respect to TRAP CAR-T, we intend to continue research and development through partnership with leading investigators, institutions and organizations around the world, bringing Atossa’s technology and expertise in TRAP delivery together with experts in cancer immunology and T cell biology. Multiple studies in both animals and humans have shown that a number of therapeutics can be delivered by the TRAP, intraductal route.”
 
Expanded enrollment for eribulin-pembrolizumab combo trial
TOKYO—Eisai Co. Ltd. in September announced the signing of an agreement with U.S.-based pharma Merck & Co. (known as MSD outside of the United States and Canada) to increase the target number of enrolled patients in a clinical study of its in-house discovered and developed microtubule dynamics inhibitor Halaven (eribulin mesylate) in combination with Merck’s anti-PD-1 therapy Keytruda (pembrolizumab), for the treatment of triple-negative breast cancer (TNBC).
 
The decision to expand the target number of enrolled patients is based on favorable interim analysis results of a Phase 1b/2 study (Study 218) of eribulin in combination with pembrolizumab for metastatic TNBC, which is being jointly conducted by Eisai and Merck. The interim analysis results indicated an objective response rate to the combination therapy of 33.3 percent (one patient experienced a complete response and 12 patients experienced a partial response). Additionally, the combination therapy demonstrated similar antitumor activity regardless of whether PD-L1 was expressed or not.
 
Triple-negative breast cancer is a type of breast cancer where the cancer cells test negative for expression of estrogen receptors and progesterone receptors, which are both targets for hormone therapy, and negative for expression of HER2 receptors, which are targets for HER2 inhibitors—therefore, triple-negative breast cancer is extremely difficult to treat, and the development of new medicines is necessary.
 
Study 218 is a multicenter, single-arm, open-label Phase 1b/2 clinical study examining the activity and safety of eribulin in combination with pembrolizumab in 95 patients (12 patients for the Phase 1b part, 83 patients for the Phase 2 part) with metastatic TNBC previously treated with zero to two lines of chemotherapy in the metastatic setting.
 
Eribulin is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division. In addition, recent nonclinical studies showed that eribulin is associated with increased vascular perfusion and permeability in tumor cores. Eribulin was first approved in November 2010 in the United States as a treatment for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease.
 
Eribulin contributes to maintaining or increasing the activity of cytotoxic T lymphocytes (CTLs), which play a leading role in attacking cancer cells, via reduction of immune suppressive Treg cells and M2 tumor macrophages. The anti-PD-1 therapy pembrolizumab maintains or activates CTLs via its immune-checkpoint blockade. Eribulin in combination with pembrolizumab is expected to work synergistically in cancer immunotherapy.
 
Radius initiates trial for HR+ breast cancer
WALTHAM, Mass.—Late September saw Radius Health Inc. announced that the first patient had been enrolled in the company’s Phase 1 study of RAD140, a nonsteroidal selective androgen receptor modulator (SARM) undergoing clinical evaluation for the treatment of hormone receptor-positive (HR+) breast cancer. The clinical trial is designed to evaluate the safety and maximum tolerated dose of RAD140 in approximately 40 patients.
 
“The RAD140 mechanism of action is differentiated from both selective estrogen receptor modulators and selective estrogen receptor degraders. We expect RAD140 to play a broad role in endocrine resistance, including a genetically defined population, in patients with tumors that are resistant to treatment with the current standard of care,” said Dr. Gary Hattersley, chief scientific officer of Radius Health.
 
The Phase 1 clinical trial is a safety and dose-ranging study in approximately 40 patients with progressive metastatic or locally advanced or metastatic breast cancer. In Part A of the trial, postmenopausal women with metastatic HR+ breast cancer will receive escalating doses of RAD140 by oral administration over a period of 28 days. Primary safety outcomes include rate of dose-limiting toxicities, adverse events related to treatment, and tolerability as measured by dose interruptions or adjustments. In addition, pharmacokinetics, pharmacodynamics and tumor response will also be evaluated.
 
“RAD140 has significant potential to complement future applications of elacestrant (RAD1901) by targeting distinct mechanisms of endocrine resistance,” commented Jesper Høiland, president and CEO of Radius. “We will provide additional details in peer-reviewed publications and plan to report results from the trial at upcoming scientific conferences.”
 
Emerging clinical data suggest that androgen receptor positivity is associated with favorable clinical outcome in breast cancer. RAD140 selectively targets the androgen receptor and has shown significant preclinical activity in endocrine-resistant models as a single agent and in combination with standard of care.
 
Approximately 70 percent of breast cancers are hormone receptor-positive, meaning that they express either estrogen receptors or progesterone receptors. Although some HR+ breast cancers respond to hormone therapies that lower hormone levels or block hormone receptors, these cancers often develop resistance to therapy.
 
Xoft for breast and skin cancer
NASHUA, N.H.—iCAD Inc., a provider of advanced image analysis, workflow solutions and radiation therapy for the early identification and treatment of cancer, announced recently that external researchers would present new clinical data supporting the use of the Xoft Axxent Electronic Brachytherapy (eBx) System for the treatment of nonmelanoma skin cancer (NMSC) and early-stage breast cancer during the 2017 American Society for Radiation Oncology meeting in San Diego.
 
“We look forward to the presentation of these compelling new clinical data by leading external researchers that significantly reinforce the benefits that the Xoft System delivers to patients and physicians in the treatment of both early-stage breast cancer and nonmelanoma skin cancer,” said Ken Ferry, CEO of iCAD, prior to his company’s presentation. “Our technology is proven to be safe and effective in appropriate patients, while offering the opportunity to treat a range of cancers using one versatile, integrated system. iCAD remains committed to providing innovative, leading-edge radiation therapies that empower physicians with full confidence to precisely and effectively treat cancer.”
 
The presented data come from a study published in the Journal of Contemporary Brachytherapy comparing the use of the Xoft System and Mohs micrographic surgery.
 
Biomarker forecast through 2025
 
From research and development of new therapeutics to the creation of new diagnostics, biomarkers are a commonly discussed issue around DDNews, and that holds true for oncology as much as—or perhaps more so than—most therapeutic areas we cover.
 
In recognition of that importance, we now share data from Inkwood Research on the global cancer biomarker forecast from 2017 to 2025.
 
According to Inkwood, this  market is anticipated to grow from what was a mark of just over $10 billion in 2016 to a level of nearly $33.1 billion by 2025, at a compound annual growth rate (CAGR) of almost 14.1 percent between 2016 and 2025. The growth of this market is backed by the increasing prevalence of cancer, rising investment in oncology research, technological advancement, increasing use of cancer biomarkers in drug discovery and development and the support of the U.S. Food and Drug Administration for the development of biomarkers.
 
As Inkwood notes, “Biomarkers act as important molecular signposts of the physiological state of a cell at a specific time. Dynamic genes, their individual protein products and the additional organic elements made by the cell generate these signposts. This is the reason that extensive research is ongoing for cancer biomarkers across the world.”
 
Cancer is a diverse disease that can originate in different organs and tissues, with each type being associated with different risk factors, thus making biomarkers even more valuable in an area like oncology. Biomarkers have various potential applications in oncology, including risk assessment, screening, differential diagnosis, determination of prognosis, prediction of response to treatment and monitoring of progression of the disease—all of which are not just critical to use of approved treatments but also to the conduct of clinical trials to develop new treatments and new indications for existing ones.
 
The biggest factor hindering the cancer biomarker market relates to the high investments and low benefit-cost ratio associated with the development of cancer biomarkers. There is a high cost involved in developing a cancer biomarker for diagnostic purpose, Inkwood maintains, but a low estimated rate of successful clinical trials of biomarkers.
 
Inkwood notes that North America is the market leader, expected to reach revenues of $11.4 billion by the end of 2025 (up from $3.7 billion in 2016). India, however, is the fastest-growing market for cancer biomarkers, with a projected CAGR during the 2017-2025 forecast period of just a hair over 17 percent.

 
Keeping an eye on IO
 
A roundup of recent immuno-oncology news and developments
 
While we may have started this Cancer Research News feature off with breast cancer-specific topics, one of the most active areas in oncology right now generally speaking is immuno-oncology (IO) and, with that in mind, we have a collection of recent IO stories, beginning with the assertion by business information and analytics provider GlobalData that IO seems destined to become the “fifth pillar” of cancer treatment alongside surgery, radiotherapy, chemotherapy, and other targeted treatments.
 
The company’s health team analyzed more than 4,000 clinical trials and more than 800 IO products in Phase 1-3 clinical trials to generate a number of unique actionable insights in their latest report, which is titled “Pharma Focus Visual Analysis of Immuno-Oncology Development and Opportunities” and which predominantly focuses on developments in active immunotherapy products based on their molecular targets and molecule types. The team also assessed immune checkpoint modulators together with a total of 18 solid tumor types and eight blood cancers.
 
A large selection of treatments within immune-oncology focus on using the immune system to induce an antitumor response, leading to tumor stabilization and potential remission from the disease. These treatments achieve their effects through the inhibition, or blockade, of immune checkpoint proteins such as CTLA-4 and PD-1. PD-(L)1 inhibitors are being rapidly adopted in indications receiving approval due to significant survival benefit and relatively good safety profiles in comparison with other standard-of-care (SOC) treatments.
 
“Beyond PD-(L)1 and CTLA-4, 18 other IO targets are currently being explored in Phase 1-3 clinical trials,” noted Maxime Bourgognon, a senior healthcare analyst at GlobalData. “However, agents targeting emerging checkpoint targets will not represent a threat to the uptake of existing PD-(L)1 checkpoint modulators, as most agents will be combined with already marketed immune checkpoint modulators.”
 
As GlobalData points out, excitement around the clinical and market potential of IO has been driven by its ability to harness the natural processes of the body’s immune system to search for, examine and eradicate foreign particles. IO teaches the immune system to recognise and destroy cancer cells and thereby enable the body to regain control.
 
“The future of IO looks brighter than ever, and IO drugs are now in a position to compete as monotherapies against traditional SOC chemotherapy regimens in the first line of the metastatic setting,” according to GlobalData. In addition, these treatments have shown efficacy in a wide variety of indications offering a less toxic treatment alternative.
 
“Despite all the initial setbacks and challenges in IO, researchers and drug developers have now found innovative ways to successfully augment the immune response against cancer,” said Bourgognon. “In the near future, it is hoped that the combination of IO agents with other IO agents, targeted therapies, or chemotherapy regimens will lead to improved long-term survival outcomes for even more cancer patients.”
 
NCI study identifies essential genes for cancer immunotherapy
BETHESDA, Md.—A new study identifies genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy. The study, from the National Cancer Institute (NCI), was led by Dr. Nicholas Restifo, a senior investigator with NCI’s Center for Cancer Research, with coauthors from NCI,  Georgetown University, the Broad Institute of MIT and Harvard University, New York University and the University of Pennsylvania. It was published online in Nature on Aug. 7, 2017.
 
“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said Restifo. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”
 
Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. Restifo and his colleagues have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients. They and others have also shown that T cells can directly recognize and kill tumor cells. However, some tumor cells are resistant to the destruction unleashed by T cells. To investigate the basis for this resistance, the researchers sought to identify the genes in cancer cells that are necessary for them to be killed by T cells.
 
Working with a melanoma tumor cell line, the researchers used the CRISPR gene editing technology. By knocking out every known protein-encoding gene in the human genome and then testing the ability of the gene-modified melanoma cells to respond to T cells, they found more than 100 genes that may play a role in facilitating tumor destruction by T cells.
 
Once the team identified these “candidate” genes, they sought additional evidence that these genes play a role in susceptibility to T cell-mediated killing. To this end, they examined data on “cytolytic activity,” or a genetic profile that shows cancer cells are responding to T cells, in more than 11,000 patient tumors from The Cancer Genome Atlas, a collaboration between NCI and the National Human Genome Research Institute—both of which are part of the U.S. National Institutes of Health. They found that a number of the genes identified in the CRISPR screen as being necessary for tumor cells to respond to T cells were indeed associated with tumor cytolytic activity in patient samples.
 
One such gene is called APLNR. The product of this gene is a protein called the apelin receptor. Although it had been suspected to contribute to the development of some cancers, this was the first indication of a role in the response to T cells. Further investigation of tumors from patients resistant to immunotherapies showed that the apelin receptor protein was nonfunctional in some of them, indicating that the loss of this protein may limit the response to immunotherapy treatment.
 
Dr. Shashank Patel, the first author of the study, said the results show that “many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies.”
 
The researchers wrote that this gene list could serve as a blueprint to study the emergence of tumor resistance to T cell-based cancer therapies. Restifo noted that if this set of genes is validated in clinical trials, then this data could eventually lead to more effective treatments for patients, adding: “If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics,” he said. “In fact, in the future, this knowledge could speed the development of a new category of drugs that can circumvent these escape mechanisms of tumor cells and help patients experience complete responses.”
 
Presage receives first Mark Foundation grant
SEATTLE—Presage Biosciences, an oncology company commercializing CIVO, a novel drug development platform to assess drugs and combinations directly in patient tumors, and The Mark Foundation for Cancer Research, an emerging cancer philanthropic organization, recently announced the foundation’s first-ever award—a grant aimed at advancing Presage’s next-generation intratumoral microdosing platform to assess immuno-oncology drug combinations.
 
“We are deeply honored to be the inaugural grant award for The Mark Foundation,” said Dr. Richard Klinghoffer, chief scientific officer of Presage. “Discovery of effective combinations of immune oncology agents is recognized as key to improving patient outcomes. This project aims to provide a technology to test dozens of potential combinations per patient, with the intent to dramatically accelerate advancement of lifesaving treatments into the cancer clinic.”
 
Resistance to immune checkpoint inhibition by a majority of patients has led oncology researchers to emphasize drug combinations as a means of combating resistance.
 
Traditional means of precision medicine have so far failed to accurately and robustly identify responder patient populations to improve clinical trial outcomes. Unlike static assays such as PD-L1 expression measurement that measure only a patient’s baseline expression of tumor antigens, Presage’s CIVO platform can assess the biology of tumor responses to perturbation by microdoses of multiple different drugs and drug combinations. Importantly, microdoses are administered to the patient’s tumor while the tumor is still in the patient’s body, thus capturing the critical immune microenvironment. This “functional precision oncology” approach may be an important complement to existing efforts to understand the differences in patient responses to cancer treatments.
 
Boosting immune cell memory
SAN DIEGO—Vaccines and cancer immunotherapies do essentially the same thing: They boost a person’s immune system, better enabling it to fight an offender, be it microbe or malignancy. Both approaches focus on CD8+ T cells, a type of immune cell that can either kill immediately or commit the offender to “memory,” providing long-term protection. In mouse experiments, researchers at the University of California San Diego (UC San Diego) School of Medicine have discovered that drugs that activate the cells’ proteasome, or recycling center, tip the balance in favor of memory CD8+ T cells. This approach could be used to improve how well vaccines and immunotherapies work and how long they last.
 
“We already knew that activated CD8+ T cells divide asymmetrically, giving rise to both effector cells and memory cells,” said senior author Dr. John T. Chang, an associate professor at the UC San Diego School of Medicine. “But we didn’t really know how the unequal segregation of cellular components during CD8+ T cell division affects their fate.”
 
Using mice and cellular models, Chang and team determined that the two different types of CD8+ T cells, effector and memory, differ in their proteasome activity rates. A cell’s proteasome is the cellular machinery that degrades and recycles damaged or unneeded proteins. It’s an essential part of all cells, and researchers recently discovered that manipulating proteasome activity can change cellular function.
 
Proteasome activators and inhibitors are commercially available. Bortezomib, an anticancer drug used to treat multiple myeloma, inhibits proteasome activity. Chang and team discovered that cyclosporine, an immunosuppressive drug prescribed to organ transplant recipients, activates the proteasome in CD8+ T cells. Additonally, they found that treating CD8+ T cells with cyclosporine early after microbial infection generated twice as many long-lived memory cells as mock-treated controls.
 
“While so far this work has only been done in mouse cells and experimental models of infection, we envision this approach could one day be used as an adjuvant therapy—a one- or two-dose immune booster given alongside a vaccine or cancer immunotherapy to help the intervention work better and last longer,” Chang said.
 
Gene mutation bodes well for immunotherapy response
HOUSTON—A clinical trial conceived and led by MD Anderson Cancer Center investigators showed that metastatic colorectal cancer patients with a specific genetic defect respond well to a common cancer immunotherapy drug.
 
About 5 percent of patients with metastatic colorectal cancer have a genetic mutation known as DNA mismatch repair deficiency in their tumors. These tumors’ inability to repair a certain type of damage leaves them harboring more DNA mutations, which attract the attention of immune system T cells. This finding suggested that an immunotherapy that frees the immune system to attack by blocking PD1, a protein on T cells that shuts down immune response, could help these patients, according to Dr. Michael Overman, an associate professor of gastrointestinal medical oncology.
 
Overman and Dr. Scott Kopetz,  also an associate professor of gastrointestinal medical oncology, recommended a targeted clinical trial for these patients to Bristol-Myers Squibb, which makes the PD1 checkpoint inhibitor Opdivo (nivolumab). The results of that trial, published online by Lancet Oncology, showed that 31 percent of patients’ tumors shrank and the rest saw disease progression cease for at least 12 weeks.
 
“That level of response and disease control is unheard of in these heavily pretreated patients, outside of frontline therapy,” Overman says. “Because the benefit was so dramatic and the responses durable, this therapy was approved by the FDA based on a single-arm study and is now indicated for microsatellite instability-high metastatic colorectal cancer patients in second- or third-line therapy.”
 
Up to $5 million for pediatric cancer research
 
BETHESDA, Md.—CureSearch for Children’s Cancer announced the application launch for a $2 million to $5 million Catapult Impact Fund Award opportunity. The award will support the advancement of clinical research to improve outcomes for pediatric cancer patients. Letters of intent are due by Nov. 6 of this year and proposals are due by Jan. 22, 2018.
 
Through these awards, CureSearch will provide support for projects that will advance promising therapies for pediatric cancer into or further along in clinical development and that show a strong potential for future approval and commercialization. Highest priority will be given to projects that address areas of highly urgent, unmet needs in pediatric cancer. Catapult Awards will fund support, as requested, up to $5 million for a timeframe of two to three years.
 
Gene fusion links bladder and brain cancer
 
COVENTRY, U.K.—A study by the University of Warwick sheds new light on gene fusion in bladder and brain cancer. Researchers have found that a previously overlooked part of a specific gene fusion has a worsening effect on cancer cells. They have also found that preventing cell signalling from this particular fusion may not be an effective route for future cancer treatment research.
 
Sometimes chromosomes can break and get reattached to a different one in an unusual way which results in a fusion between one gene and another which makes a new gene, called a gene fusion. The scientists at Warwick Medical School examined the gene fusion FGFR3-TACC3 which is associated with bladder and brain cancers. Previously scientists focused on the first part of the fusion, FGFR3, because this was known to be associated with cancer. However the team decided to look at the second half TACC3 or transforming acidic coiled-coil protein 3. They found that this part of the fusion causes mistakes in cell division, making the cancer worse.
 
Cancer Research UK launches trial
 
LONDON—A clinical trial to test a new cancer drug in patients with advanced solid tumors launched in four centers across the United Kingdom in late August through Cancer Research UK’s Centre for Drug Development.
 
This early-phase trial will test the safety and tolerability of the drug, called LY3143921 hydrate, and establish the recommended dose for patients with a variety of cancers including advanced bowel, lung, ovarian, urothelial, pancreatic, breast, head and neck and esophageal cancer.
The drug, discovered by Eli Lilly and Co., was brought to Cancer Research UK through the charity’s Clinical Development Partnership scheme.
 
The drug had not yet been tested in people but has shown preclinical study promise in mice by selectively inhibiting Cdc7, a protein that helps cells to reproduce correctly.
 
Cancer cells are more dependent on Cdc7 than normal cells, causing them to be more sensitive to growth inhibition by this Cdc7 inhibitor. Researchers also believe that cancers that have a particular fault in their p53 gene may be particularly sensitive to inhibition of Cdc7. This study will focus on metastatic bowel cancer, squamous non-small cell lung cancer and high grade serous ovarian cancer, all of which have high levels of p53 mutation and functional loss.
 
Code: E101733

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