Focus Feature: Cancer Research News
At the forefront of cancer research
Researchers look to ‘FLIP’ the script on cancer care, analysts say not to fear so much getting stung by STING—and more
Because cancer has for some time now been one of the most prolific and best-funded areas of life-sciences and pharma/biotech research, we have seen quite a lot of interesting approaches, new breakthroughs and fascinating insight into how tumors work and how they might be stopped.
With researchers balancing on that sharp cutting edge of oncology research, we thought we would share a few bits of news from some of the newer and less-publicized areas of study recently: a first-in-class FLIP inhibitor, insights about whether the STING pathway is a boom or bust, a potential therapeutic target for one of the deadliest cancers, drug-induced xenogenization findings and a previously unknown protein variant with therapeutic implications.
Head over heels for FLIP?
BELFAST & SAFFRON WALDEN, U.K.—In late march, Queen’s University Belfast and Domainex announced that their joint project team had successfully identified novel first-in-class small-molecule inhibitors of the anti-apoptotic protein FLIP and are now seeking a commercial partner for further development of the novel inhibitors. Moreover, the team generated data suggesting multiple therapeutic opportunities for a FLIP inhibitor for both single-agent and combination therapeutic approaches.
This FLIP program has been funded by the Wellcome Trust and has focused on the identification and optimization of novel first-in-class small-molecule FLIP-FADD protein-protein interaction inhibitors. FLIP is a non-redundant inhibitor of the caspase 8 protein, and functional FLIP is believed to allow tumor cells to evade cell death, as well as promoting tumor growth and therapy resistance. The novel FLIP inhibitors activate caspase 8 and are said to have shown efficacy in a number of preclinical models including clinically challenging KRAS and EGFR mutant non-small cell lung cancer.
“Our medicinal chemists have been delighted to work on this exciting target and enable Prof. Dan Longley and his team to identify and optimize the FLIP inhibitors,” said Trevor Perrior, CEO of Domainex. “There were several challenges that we had to solve in order to identify hits and develop a series of potential drug compounds that are potent and selective. We look forward to at least one of these compounds progressing towards the clinic for the benefit of patients. The funding secured from the Wellcome Trust is a clear endorsement of the strength of the integrated drug discovery platform of Domainex to deliver molecules with disease-modifying potential and we remain deeply committed to supporting academic translational research.”
In a poster presentation at the American Association for Cancer Research (AACR) annual meeting this year, the researchers highlighted the on-target effects of the inhibitors and their drug-like properties; their potency against B cell lymphomas, triple-negative breast cancer and KRAS and EGFR mutant non-small cell lung cancer; and their potential for combination with chemotherapy, immune oncology agents and EGFR-targeted therapeutics.
The next phase of the program will involve selection of a preclinical development candidate and completion of preclinical activities.
“Resistance to cancer therapeutics such as chemotherapy is a major clinical problem that limits the effectiveness of many current cancer treatments. Very often, this is caused by the failure of anticancer therapies to kill the cancer cells. FLIP is a cellular protein that cancer cells frequently express at high levels, and this increases their resistance to chemotherapy and other types of therapy used to treat cancer, such as radiotherapy,” explained Longley, who is at the Centre for Cancer Research and Cell Biology at Queen’s University Belfast. “The agents that we are developing target FLIP and prevent it from causing therapy resistance. In addition, some tumor-promoting immune cells also need FLIP, so our FLIP inhibitors may also have beneficial effects in the tumor microenvironment by reactivating immune cells to attack cancer cells.”
Some feel hurt by STING, but pathway has potential
BOSTON—News out of 2018 put a damper on the enthusiasm that some had for investigational immuno-oncology therapeutics targeting STING (stimulator of interferon genes), but analysts at SVB Leerink LLC urge pharma and life-sciences market-watchers not to give up on the pathway just yet.
Many investors are down on STING following reports of zero percent to 5 percent objective responses with single-agent agonists in 2018 from candidates being explored by Merck & Co. (known as MSD outside the United States and Canada) and Aduro Biotech.
“We remain enthusiastic about STING for several reasons,” wrote Dr. Daina M. Graybosch of Leerink, though, adding that “...we know from murine experiments that establishing durable immunity with STING requires combination with checkpoints ... Multiple clinical trials of TLR9 plus checkpoints had promising results, building evidence for the type I interferon approach, a target shared by STING ... Without more extensive preclinical data, we are hesitant to assume [Merck’s] STING agonist is representative of the class, given wide variation in molecule selectivity and potency.”
In addition to those three points, Graybosch noted that “STING agonism is fully complementary to checkpoint inhibition, positively impacting four steps in the adaptive immunity cycle as well as stimulating innate immunity [natural killer cells]” and that the “scientific community remains optimistic,” pointing out that half of the MEDACorp key opinions leaders that Leerink surveyed in 2018 picked STING as “top 10” potential mechanism.
In other STING news, Kirkland, Wash.-based Mavupharma early this year announced that it had selected its first immuno-oncology clinical development candidate, MAVU-104, a small-molecule inhibitor of ENPP1 (a phosphodiesterase that negatively regulates the STING pathway). Inhibiting ENPP1 activity with MAVU-104 reportedly allows for highly-controlled enhancement of STING signaling in all tumors and lymph nodes without any injections.
“With our approach, which focuses on blocking a key negative regulator of the STING pathway, as opposed to directly stimulating STING itself, the degree and duration of innate immune activation are tunable, which avoids both overstimulation of the pathway and high levels of cytokine release,” said Dr. Mike Gallatin, Mavupharma’s president and co-founder. “Having selected our first immuno-oncology drug candidate, we are now focused on the path to IND for MAVU-104, which we expect to file in the second half of 2019.”
The company’s approach may have significant advantages over other developmental therapies that stimulate the STING pathway. Published studies on the direct STING agonists in clinical development show that these therapies are administered via direct injection into the tumors and may induce release of pro-inflammatory cytokines into systemic circulation, which has been associated with side effects.
Possible Achilles’ heel for pancreatic cancer
LA JOLLA, Calif.—Aside from its frequent lack of symptoms—leading to late diagnosis and often metastasis—there is another challenge when it comes to treating pancreatic cancer: the tumor cells are encased in a “protective shield,” a microenvironment conferring resistance to many cancer treatment drugs. But recently researchers at the Salk Institute for Biological Studies, along with an international team of collaborators, uncovered the role of a signaling protein that may be a fatal vulnerable point for pancreatic cancer.
The findings, published in the paper “Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring” in Nature on April 17, show that pancreatic stellate cells—resident cells typically dormant in normal tissue—become activated and secrete proteins to form a shell around the tumor in an attempt to wall off and contain it. The activated stellate cells also secrete a signaling protein called LIF, which conveys stimulatory signals to tumor cells to drive pancreatic cancer development and progression. Results also suggest LIF may be a useful biomarker to help diagnose pancreatic cancer more quickly and efficiently.
"There haven’t been very many advances in pancreatic cancer therapy because it’s a difficult cancer to diagnose and treat,” said Dr. Tony Hunter, American Cancer Society Professor at Salk. “Understanding this communication network between the cancer cells and stellate cells may enable us to develop more effective therapies, along with tools for earlier diagnosis.”
Yu Shi, a postdoctoral fellow at Salk and first author of the paper, noted that most solid cancers are not caused by abnormality in a single cell type; rather, the tumor cells function cooperatively with surrounding normal cells in the tissue
“They can also ‘go bad’ together as an unholy alliance, which can lead to cancer,” said Shi. “If we can understand how the different types of cells interact with each other within the tumor microenvironment, then we may uncover a good target to eventually cure the disease.”
To understand the method of communication between the pancreatic stellate cells and the cancer cells, the researchers first developed cell cultures to analyze the proteins that were being exported from the stellate cells. They suspected that stellate cells were communicating with tumor cells using specific signaling proteins, but until now, they did not know which ones.
“We wanted to see what kind of signaling was activated in the tumor cells in pancreatic cancer,” explained Shi. “LIF is an important factor that normally helps stem cells maintain their developmental potential during the embryonic period, but usually vanishes in adulthood. We found that activated stellate cells are secreting LIF, which acts on neighboring cancer cells.”
After pinpointing LIF as the critical communicator, the researchers wanted to better understand the function of LIF during pancreatic cancer progression to evaluate the protein as a potential therapeutic target. By observing the effects on tumor growth of blocking or destroying LIF—both of which render the protein nonfunctional—in a mouse model of pancreatic cancer, the researchers examined how LIF affects tumor progression and response to treatment. Both techniques independently showed that without functional LIF signaling, tumor progression slowed down and responses to chemotherapeutic drugs used in treating human cancer (such as gemcitabine) were improved.
Basically, it came down to this: Destroying pancreatic stellate cells can actually worsen the tumors, so the goal is not to destroy the pancreatic stellate cells that secrete signaling factors, but instead to stop them from delivering the stimulatory signals to the tumor cells.
In addition to checking the consequences of LIF blockade in mice, the researchers also examined the levels of LIF in tumor tissue and blood from human pancreatic cancer patients. They found high levels of LIF in both the patients’ tumors and blood and also found a significant correlation between LIF levels, tumor progression and patient response to chemotherapy. These early findings suggest that LIF holds promise as a biomarker for pancreatic cancer stage and treatment response.
Based in part on the Hunter lab’s discovery of a role for LIF in pancreatic cancer, a Phase 1 clinical trial has been initiated by Canadian company Northern Biologics to test the effect of treatment with a monoclonal antibody that binds to and blocks LIF from signaling in advanced pancreatic and other types of cancer.
Can DIX nix glioblastoma and pancreatic cancer?
AGOURA HILLS, Calif.—Early March saw Oncotelic, a clinical-stage biopharmaceutical company, announce clinical data supporting the use of chemotherapy-induced xenogenization for in-situ immunization against glioblastoma and pancreatic cancer. According to the company, drug-induced xenogenization (DIX) was found to be the result of pharmacologically-driven mutational events generating tumor neoantigens able to induce T cell-mediated immune responses. Alkylating agents such as TMZ possess high DIX properties, the company noted, more potent than a number of other antitumor mutagenic compounds, and it says that “repeated mutational damage should eventually break through the innate immune resistance of the tumor, resulting in improved overall survival.”
“These results validated our concept leveraging xenogenization potential of approved chemotherapeutic agents with known safety and efficacy profiles for rapid in-situ immunization protocol,” said Dr. Vuong Trieu, CEO of Oncotelic. “Countering drug resistance by new chemical entities is a long, expensive, and highly unsuccessful endeavor; therefore it is desirable to explore new properties of the approved drug against drug resistance. Indeed, TMZ xenogenization is most active in TMZ resistance.”
Tübingen team discovers previously unknown protein variant
TÜBINGEN, Germany—Oncologists associated with the University of Tübingen said in April that they had discovered a new protein variant that plays an important role in the development and therapy response of cancer, opening up the opportunity for new options in the diagnosis and therapy of cancer. The results of the study were published on April 2 in the journal EBioMedicine, an open-access journal published by The Lancet.
The research team, led by Dr. Kerstin Kampa-Schittenhelm, discovered the protein variant ASPP2kappa in the cells of leukemia patients. They were able to show that as soon as this particular form of protein occurs, the cancer grows faster and is more difficult to treat with drugs. In the meantime, the researchers have also been able to detect this protein variant in other hematologic and solid tumors. The scientists were mainly funded by the Wilhelm Sander Foundation for Cancer Research.
According the researchers, the special feature of the newly discovered protein variant, which concerns a central gene in the signaling pathway of programmed cell death, is “the dynamic character of its development.” Specifically, ASPP2kappa is not detectable in healthy cells or is only detectable to a limited extent, and it occurs as a reaction to cell damage, such as that caused by radioactive or ultraviolet radiation, harmful environmental influences or contact with toxins. The Tübingen researchers assume that the previously unknown protein variant is produced because the DNA in the affected cells is read incorrectly. This is followed by the formation of a protein that lacks important components.
Under normal circumstances, the cell would induce controlled cell death in the event of external damage. However, the defective protein variant apparently slows down this process and protects the cell from destruction. This protective mechanism is only advantageous at first sight as the damaged cells become a long-term problem for the organism—cell damage accumulates and can eventually lead to degeneration of the cell, forming a tumor.
These findings are of far-reaching importance for understanding the development of tumors but also offer starting points for improving the diagnosis and treatment of cancer, the university maintains. The Tübingen researchers are now working on ways of turning these new findings into improved therapeutic options.
“Our results suggest that it may be useful in the future to check whether cancer patients have ASPP2kappa in their cells or not before starting therapy,” says Kampa-Schittenhelm. In addition, an increase in the protein concentration during the treatment may indicate whether the treatment is successful: “If the protein multiplies, our findings suggest that the patient is less responsive to the respective therapy.” Accordingly, there is the opportunity to better adapt therapies to individual needs in the future.
Further clinical studies are now needed with defined tumor entities and patient cohorts to validate the results of the study. In addition, the Tübingen researchers hope to develop drugs that will prevent the formation of the newly discovered protein. “It will certainly take several more years before the findings of the current study can be used in clinical everyday life,” noted Kampa-Schittenhelm.
Mount Sinai and IBM explore efficacy in cancer treatment
NEW YORK—Researchers from Mount Sinai and IBM say that they have discovered a novel clue in explaining how cancer cells with identical genomes can respond differently to the same therapy. In a Nature Communications paper published in March, they revealed for the first time that the number of mitochondria in a cell is, in great part, associated with how the cancer responds to drug therapy.
While treatments for cancer continue to improve as technology advances, researchers and clinicians have been unsuccessful in explaining the diversity of responses in cancer cells to treatments of oncological disease. In many cases, cancer cells with matching genetic makeup will respond differently to the same treatment. Mount Sinai and IBM researchers combined computational and biological methods to uncover a clue to this behavior.
Cells die when met with bacteria, malnourishment or viruses. But also, to promote normal function, our bodies eliminate billions of cells each day—a process known as “programmed cell death” or apoptosis. Mitochondria, often referred to as the powerhouse of the cell because of their ability to produce cellular energy, can also act as a catalyst in the activation of programmed cell death, and certain anticancer drugs work by activating this process. This function encouraged researchers to explore the hypothesis that cancer cells with identical genetic makeup, but different quantities of mitochondria, may have varying susceptibility to death if exposed to the same drugs that promote apoptosis.
In exposing various types of cells to six concentrations of a pro-apoptotic drug and measuring the abundance of mitochondria within the surviving cells, Mount Sinai and IBM researchers discovered that surviving cells had a greater amount of mitochondria than untreated cells. This strongly suggests that cells with fewer mitochondria are more likely to respond to certain drug treatments.
To analyze this data, researchers used a mathematical framework called DEPICTIVE (an acronym for Determining Parameter Influence on Cell-to-cell variability Through the Inference of Variance Explained) to quantify variability in the survival or death of cells due to mitochondrial abundance. Overall, the framework determined that the variability of mitochondria explained up to 30 percent of the varying responses to the pro-apoptotic drug.
“Enhancing our understanding of the relationship between mitochondria variability and drug response may lead to more effective targeted cancer treatments, allowing us to find new ways to tackle the problem of drug resistance,” said Dr. Pablo Meyer, adjunct assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, team leader of translational systems biology at IBM Research and co-corresponding author of the publication. “The outcomes of this study were truly multidisciplinary, and only made possible by the strong scientific collaboration established between Mount Sinai and IBM.”
Drug discovered in fruit fly used in cancer patients
MOUNTAIN VIEW, Calif.—Tosk Inc. announced at the end of April that its patented drug, TK-90, which is designed to prevent the adverse side effects of frontline cancer therapies, is succeeding so far in human clinical studies involving 25 head-and-neck cancer patients. The company says that TK-90 is the first drug discovered through screening using the common fruit fly (Drosophila melanogaster) to be tested in patients. The drug is aimed at preventing mucositis, a painful, dose-limiting side effect suffered by many cancer patients undergoing chemotherapy and radiation therapy.
“Fruit flies have played an important role in scientific research for generations,” said Brian Frenzel, Tosk’s CEO. “However, Drosophila have not been widely used for drug discovery and development by the pharmaceutical industry. Tosk is an exception. Our scientists have developed two proprietary drug discovery platforms that use fruit flies to identify new drugs to combat cancer and other diseases.”
Ad he noted, adult fruit flies have body parts that mimic mammalian hearts, kidneys, digestive tracts and lungs, and nearly 70 percent of human disease-related genes have analogs in the fruit fly.
“Because the life cycle of a fruit fly is short, only 50 days from birth to death and only two weeks from birth to adulthood, drug discovery in flies can be done quickly and cost effectively,” Frenzel says. “Using non-mammals as a discovery tool may yield new drugs that could not have been found using other, more traditional methods.”
Tosk selected TK-90 out of tens of thousands of compounds using what the company calls the Side Effect Fly. Tosk incubates test compounds with a toxic chemotherapeutic that would otherwise prevent eggs from hatching and developing. Compounds that increase survival and result in larvae or mature fruit flies are considered “hits.” Hits are tested in cell culture models using human cancer cells to select leads that do not affect the cancer killing efficacy of the chemotherapy.
“Instead of picking a target and fitting compounds to match, as most pharmaceutical companies do, our scientists let the fruit fly tell us which compounds are safe and effective. We then work backward to identify the molecular target or targets through which the drug works, opening what we believe is an exciting new vista on the process of drug discovery.”
Tosk has innovated a second, and what it thinks is perhaps even more important, drug discovery platform, which it calls the Genetically Modified Fly. In this platform, Tosk integrates a human disease gene into Drosophila and then tests compounds for their ability to block the activity of the disease gene. This model is designed to discover drugs for disease targets that have previously been considered undruggable.
Merck KGaA and Pfizer join pancreatic cancer collaboration
NEW HAVEN, Conn.—BioXcel Therapeutics Inc. recently announced the addition of Merck KGaA, Darmstadt, Germany (which operates its biopharmaceutical business as EMD Serono in the United States and Canada) and Pfizer Inc. to its Nektar Therapeutics clinical collaboration to evaluate a novel triple combination therapy in pancreatic cancer.
The collaboration now includes avelumab, BXCL701 and NKTR-214 as a potential combination therapy for pancreatic cancer. Avelumab is a human anti-programmed death ligand (PD-L1) co-developed and co-commercialized by Merck KGaA and Pfizer. BXCL701 is an orally-available systemic innate-immune activator that inhibits dipeptidyl peptidase (DPP) 8/9 and FAP developed by BTI, a clinical-stage biopharmaceutical development company using artificial intelligence approaches to identify the “next wave of medicines” across neuroscience and immuno-oncology. NKTR-214 is a CD122-biased agonist developed by Nektar.
Under the collaboration, BTI will be responsible for initiating and managing the clinical program, with Merck KGaA and Pfizer supplying avelumab and Nektar supplying NKTR-214. BTI and Nektar will equally share all development costs. The primary objectives of the study are to evaluate safety and efficacy of the triple combination of BXCL701, NKTR-214 and avelumab for the treatment of patients with pancreatic cancer. Additionally, correlative immune activation markers will be evaluated in blood and tumor tissue.
“We are excited to welcome Merck KGaA, Darmstadt, Germany and Pfizer as partners for the development of this novel triple combination regimen with Nektar,” said Vimal Mehta, CEO of BTI. “We believe that the expansion of this clinical collaboration provides clear evidence of industry enthusiasm toward BXCL701.”
“We believe it is essential to target multiple dimensions of the immune system in parallel to address the multi-faceted etiologies underlying cancer cell growth in difficult-to-treat tumors such as pancreatic cancer,” added Jonathan Zalevsky, chief scientific officer of Nektar Therapeutics. “This experimental triple combination regimen of BXCL701, NKTR-214 and avelumab is designed to leverage multiple mechanisms of action to better fight pancreatic cancer while potentially generating long-term cancer immunity.”
OSE announces new cancer research collaboration using AI
NANTES, France—OSE Immunotherapeutics recently announced a new research collaboration with cancer research hospital Léon Bérard Cancer Center in Lyon, France, to use artificial intelligence (AI)-based bioanalysis and bioinformatics to identify novel targets in immuno-oncology.
This new collaborative immuno-oncology research program will use different patient cohorts and tumor biopsies to identify novel molecular targets associated with the primary and secondary resistance to PD-1/PD-L1 immune checkpoint inhibitors and to validate a strategy of combining drugs based on target expression profile.
The research is based on a jointly developed AI approach that will be applied to analyze gene expression in the human tumor microenvironment and the composition of tumor infiltrates. The findings from this collaboration will be used for the selection and validation of targets for early development of new drug candidates from the platform of bispecific fusion proteins targeting PD-1 and innovative targets known as BiCKI.
“The goal of this partnership is to identify and validate new targets that will help streamline the development of new treatment approaches for cancer, especially in difficult to treat tumors,” said Alexis Peyroles, CEO of OSE Immunotherapeutics.
Added Dr. Jean-Yves Blay, director of the Léon Bérard Cancer Center: “Our AI approach combined with our translational and immunological research platforms will enable us to analyze tumor immune parameters and to identify potential new pathways to address unmet needs for cancer patients. This partnership brings together top experts in oncology research and translational science with the hopes of rapidly advancing the discovery of first-class treatment options for cancer patients.”
Phio and Glycostem collaborate on NK cell-based immunotherapy for cancer treatment
MARLBOROUGH, Mass.—Phio Pharmaceuticals Corp. has entered into a research collaboration with Glycostem Therapeutics BV to explore the potential synergies of using Phio’s self-delivering RNAi technology (sd-rxRNA) in combination with Glycostem’s proprietary natural killer (NK) cell generation technology (oNKord) to develop cellular immunotherapies for cancer treatment with enhanced efficacy and/or safety.
The companies’ research teams will collaborate and examine the applicability of Phio’s sd-rxRNA technology to be integrated into Glycostem’s processes to produce NK cells with the ultimate goal to further improve Glycostem’s cellular immunotherapies for the treatment of cancer patients.
Dr. Jan Spanholtz, CSO of Glycostem commented, “One of the research focuses of Glycostem is novel oNKord products with improved functions. Towards that goal we have already established several collaborations, and we are glad to expand our efforts in this field in collaboration with Phio Pharmaceuticals. We believe their proprietary self-delivering RNAi technology can provide new and more effective ways for expanding and differentiating NK-cells. In addition, their technology can help overcome immune checkpoints or other immunosuppressive roadblocks that NK-cells may encounter, which may further enhance the efficacy and safety of our cellular therapies.”
TYME advance studies of SM-88 in metastatic pancreatic cancer
NEW YORK—Tyme Technologies Inc., an emerging biotechnology company developing cancer metabolism-based therapies (CMBTs), announced the closing of its underwritten registered offering with a group of three existing and one new investors resulting in gross proceeds of $12 million. The company intends to primarily use the net proceeds from the offering to continue development of its clinical and preclinical programs, including two upcoming pivotal trials in pancreatic cancer, as well as for general corporate purposes.
TYME is in the process of finalizing a randomized pivotal trial protocol amendment for use of SM-88 in third-line pancreatic cancer. TYME also will be studying SM-88 in a pivotal trial for second-line pancreatic cancer in partnership with the Pancreatic Cancer Action Network as part of its innovative Precision Promise adaptive design study. Both trials are expected to initiate in mid-2019.
“We believe this funding demonstrates that the investors who reached out to TYME saw the promise of advancing SM-88 in late stage pancreatic cancer,” said Steve Hoffman, Chairman and CEO of TYME. “Our goal is to give these patients a new treatment option that can help them live longer while also maintaining better quality of life. There is no standard of care for the 10,000 patients actively seeking treatment for third-line pancreatic cancer and the expected prognosis for these patients is only a few months survival.”
BioAtla and BeiGene form worldwide collaboration to develop CTLA-4 therapy
SAN DIEGO, BEIJING & CAMBRIDGE, Mass.—BioAtla LLC, a global clinical-stage biotech focused on the development of Conditionally Active Biologic (CAB) protein therapeutics, and BeiGene Ltd., a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs, recently announced that they had entered into a global co-development and collaboration agreement for the development, manufacturing and commercialization of BioAtla’s investigational CAB CTLA-4 antibody (BA3071).
BA3071 is a novel, CTLA-4 inhibitor that is designed to be conditionally activated in the tumor microenvironment in order to reduce systemic toxicity and potentially enable safer combinations with checkpoint inhibitors such as BeiGene’s investigational anti-PD-1 antibody, tislelizumab, a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages.
Under the terms of the collaboration, BioAtla will co-develop the CAB-CTLA-4 antibody to defined early clinical objectives and BeiGene will then lead the parties’ joint efforts to develop the product candidate and be responsible for global regulatory filings and commercialization. Subject to the terms of the agreement, BeiGene will hold a co-exclusive license with BioAtla to develop and manufacture the product candidate globally and an exclusive license to commercialize the product candidate globally. BeiGene will be responsible for all costs of development, manufacturing and commercialization in Asia (ex-Japan), Australia and New Zealand, and the parties will share development and manufacturing costs and commercial profits and losses upon specified terms in the rest of the world.
Bacteria promote lung tumor development, study suggests
CAMBRIDGE, Mass.—Massachusetts Institute of Technology (MIT) cancer biologists have discovered a new mechanism that lung tumors exploit to promote their own survival: These tumors alter bacterial populations within the lung, provoking the immune system to create an inflammatory environment that in turn helps the tumor cells to thrive.
In mice that were genetically programmed to develop lung cancer, those raised in a bacteria-free environment developed much smaller tumors than mice raised under normal conditions, the researchers found. Furthermore, the researchers were able to greatly reduce the number and size of the lung tumors by treating the mice with antibiotics or blocking the immune cells stimulated by the bacteria.
The findings suggest several possible strategies for developing new lung cancer treatments, the researchers say.
“This research directly links bacterial burden in the lung to lung cancer development and opens up multiple potential avenues toward lung cancer interception and treatment,” says Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the paper. Chengcheng Jin, a Koch Institute postdoc, is the lead author of the study, which appeared in the Jan. 31 online edition of Cell.
Mice (and humans) typically have many harmless bacteria growing in their lungs. However, the MIT team found that in the mice engineered to develop lung tumors, the bacterial populations in their lungs changed dramatically. The overall population grew significantly, but the number of different bacterial species went down. The researchers are not sure exactly how the lung cancers bring about these changes, but they suspect one possibility is that tumors may obstruct the airway and prevent bacteria from being cleared from the lungs.
This bacterial population expansion induced immune cells called gamma delta T cells to proliferate and begin secreting inflammatory molecules called cytokines. These molecules, especially IL-17 and IL-22, create a progrowth, prosurvival environment for the tumor cells. They also stimulate activation of neutrophils, another kind of immune cell that releases proinflammatory chemicals, further enhancing the favorable environment for the tumors.
“You can think of it as a feed-forward loop that forms a vicious cycle to further promote tumor growth,” Jin says. “The developing tumors hijack existing immune cells in the lungs, using them to their own advantage through a mechanism that’s dependent on local bacteria.”
However, in mice that were born and raised in a germ-free environment, this immune reaction did not occur and the tumors the mice developed were much smaller.
The researchers found that when they treated the mice with antibiotics either two or seven weeks after the tumors began to grow, the tumors shrank by about 50 percent. The tumors also shrank if the researchers gave the mice drugs that block gamma delta T cells or that block IL-17.
The researchers believe that such drugs may be worth testing in humans, because when they analyzed human lung tumors, they found altered bacterial signals similar to those seen in the mice that developed cancer. The human lung tumor samples also had unusually high numbers of gamma delta T cells.
“If we can come up with ways to selectively block the bacteria that are causing all of these effects, or if we can block the cytokines that activate the gamma delta T cells or neutralize their downstream pathogenic factors, these could all be potential new ways to treat lung cancer,” Jin says.
Adapted from an article written by Anne Trafton of the MIT News Office