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Focus Feature on Cancer Research News: Hitting the target
July 2019
by Jeffrey Bouley  |  Email the author
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Precision matters. Sure, you could bake those cookies for twice as much time as called for to make sure they’re done, but then you’ll have ash-flavored, tooth-cracking little bricks. You could take out a single person with a missile, but that doesn’t bode well for the rest of the people all around. You could literally bathe in sunscreen before heading out to the beach, but your hair will be greasy and your eyes surely will sting.
 
And so it has been with so many cancer treatments that have either not gotten to all of the cancerous cells, leaving room for recurrence, or damaged healthy cells in the process, leading to all kinds of nasty side effects.
 
Researchers and others in healthcare, life sciences and elsewhere understand this, and fortunately many of them are trying to change the landscape of treatment to be more friendly to humans and less so to tumors.
 
Confining cell-killing treatments to tumors
Late June saw news from the Massachusetts Institute of Technology (MIT) that researchers at the Koch Institute for Integrative Cancer Research at MIT have developed a technique to prevent cytokines from escaping once they have been injected into the tumor, by adding a Velcro-like protein that attaches itself to the tissue.
 
You see, cytokines, small proteins released by immune cells to communicate with each other, have for some time been investigated as a potential cancer treatment. But while they have known potency and potential for use alongside other immunotherapies, these proteins are highly toxic to both healthy tissue and tumors.
 
And that is where the MIT research comes in, because while injecting the cytokine treatment directly into the tumor itself could better target the tumor and spare healthy tissue, previous attempts to do this have resulted in the proteins leaking out of the cancerous tissue.
 
And so it was that the researchers, led by Dane Wittrup, MIT’s Carbon P. Dubbs Professor in Chemical Engineering and Biological Engineering and a member of the Koch Institute, discovered a collagen-binding protein called lumican, which they then attached to the cytokines.
 
“When we inject (a collagen-anchoring cytokine treatment) intratumorally, we don’t have to worry about collagen found elsewhere in the body; we just have to make sure we have a protein that binds to collagen very tightly,” said lead author Noor Momin, a graduate student in the Wittrup Lab at MIT.
 
To test the treatment, the researchers used two cytokines known to stimulate and expand immune cell responses. The cytokines, interleukin-2 (IL-2) and interleukin-12 (IL-12), are also known to combine well with other immunotherapies.
 
“In addition, all of the cytokine therapies were given alongside a form of systemic therapy, such as a tumor-targeting antibody, a vaccine, a checkpoint blockade or chimeric antigen receptor T cell therapy, as we wanted to show the potential of combining cytokines with many different immunotherapy modalities,” Momin says.
 
The researchers now plan to carry out further work to improve the technique, and to explore other treatments that could benefit from being combined with collagen-binding lumican. Ultimately, they hope the work will encourage other researchers to consider the use of collagen binding for cancer treatments, Momin remarks.
 
Nodding to neoantigens
Tumor-specific neoantigens, which arise via mutations that alter amino acid coding sequences, can be expressed on the surface of tumor cells and subsequently recognized by T cells. Normal tissues don’t express these particular mutations, and thus immuno-oncology therapies based on neoantigen-specific T cells should pose no harm to normal tissues.
 
Ziopharm Oncology Inc., a clinical-stage immuno-oncology company developing next-generation cell and gene therapies, recently announced an exclusive licensing agreement with the National Cancer Institute of the National Institutes of Health for neoantigen-related intellectual property related to the development and commercialization of cell therapies for cancer.
 
Under the terms of the agreement, Ziopharm is granted rights to two groups of technologies for use with the company’s Sleeping Beauty platform. The first group of technologies covers intellectual property related to T cell receptors (TCRs) reactive to mutations, or neoantigens, within KRAS, p53 and EGFR gene families. Alterations within these genes are referred to as “hotspots,” as the genetic changes can be driver mutations found in multiple types of solid tumors and between individuals with the same cancer type.
 
The second group includes manufacturing methods and processes to generate large numbers of Sleeping Beauty-modified T cells expressing high levels of the introduced neoantigen-specific TCRs.
 
“This license significantly expands our library of neoantigen-specific TCRs against hotspots and provides additional enhancements to our manufacturing capabilities for clinical-grade T cells through our Sleeping Beauty platform,” said Dr. Laurence Cooper, CEO of Ziopharm. “We are pleased to finalize this licensing agreement with the NCI, which is a result of our ongoing collaboration with Dr. Rosenberg and his team and enhances our shared efforts to pursue a nonviral approach to treating patients with solid tumors with TCR-expressing T cells.”
 
Also related to neoantigens, Genocea Biosciences Inc., a biopharmaceutical company developing personalized cancer immunotherapies, announced in May a research collaboration with Iovance Biotherapeutics Inc. to assess the potential of applying Genocea’s neoantigen identification platform, ATLAS, to next-generation TIL (tumor-infiltrating lymphocyte) product development.
 
“We are pleased to collaborate with Iovance, as they are recognized leaders in TIL therapies,” said Chip Clark, Genocea’s president and CEO, “and are excited to explore the utility of ATLAS, with its ability to identify and characterize neoantigens, in developing neoantigen-targeted TIL therapies, which would naturally complement our ongoing personalized cancer vaccine and cell therapy programs.”
 
Also from Genocea came news in June of best-in-class clinical results from its ongoing Phase 1/2a trial for GEN-009, the company’s lead neoantigen vaccine candidate. The company noted that in the five patients for whom immune response results are available to date, GEN-009 monotherapy elicited T cell responses to 91 percent of the vaccine neoantigens administered. Also, GEN-009 reportedly has proven to be unique among neoantigen vaccines in its ability to elicit ex-vivo CD8+ T cell responses, which were observed for 47 percent of vaccine neoantigens.
 
The company believes that these data could represent a breakthrough in the development of neoantigen vaccines—using patients’ own T cells and antigen-presenting cells to select vaccine neoantigens results in higher immunogenicity, and Genocea is keen explore whether this higher immunogenicity translates into greater clinical greater efficacy than seen with other neoantigen vaccines.
 
Imaging tumors more precisely
Taking a spin away from pharmacologic treatments toward surgery, but also with a nod toward cancer diagnostics, we have news from spring out of MIT that researchers there, working with surgeons and oncologists at Massachusetts General Hospital, have now developed a way to improve the accuracy of this debulking surgery for ovarian cancer.
 
Using a novel fluorescence imaging system, they were able to find and remove tumors as small as 0.3 millimeters—smaller than a poppy seed—during surgery in mice. Mice that underwent this type of image-guided surgery survived 40 percent longer than those who had tumors removed without the guided system.
 
“What’s nice about this system is that it allows for real-time information about the size, depth and distribution of tumors,” says Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science at MIT, a member of the Koch Institute for Integrative Cancer Research and the recently appointed head of MIT’s Department of Biological Engineering.
 
The researchers are now seeking FDA approval for a Phase 1 clinical trial to test the imaging system in human patients. In the future, they hope to adapt the system for monitoring patients at risk for tumor recurrence and, eventually, for early diagnosis of ovarian cancer since the disease is often caught late when it is very hard to treat.
 
“A major focus for us right now is developing the technology to be able to diagnose ovarian cancer early, in stage 1 or stage 2, before the disease becomes disseminated,” Belcher comments. “That could have a huge impact on survival rates, because survival is related to the stage of detection.”
 

Serving up a trio of combos
 
Combination therapies are nothing new, particularly when it comes to cancer treatment. Still, it is worth checking in on some of the more recent news on this front to see some of the new twists on an old approach, and to that end Roswell Park Comprehensive Cancer Center, MD Anderson Cancer Center and Synlogic Inc. all have some work to highlight.
 
Immunotherapy-chemo combination gets FDA approval
BUFFALO, N.Y.—A new cancer therapy based on the work of Dr. Ben Seon at Roswell Park has been approved by the U.S. Food and Drug Administration (FDA) for patients with an aggressive form of non-Hodgkin lymphoma. On June 10, the FDA granted accelerated approval to polatuzumab vedotin as part of  a new chemotherapy/immunotherapy treatment combination for patients with relapsed or refractory diffuse large B-cell lymphoma.
 
Polatuzumab vedotin incorporates a monoclonal antibody—a manufactured protein that can bind to and kill tumor cells. While Roswell Park has played a role in many other FDA-approved innovations in cancer treatment and diagnostics, the approval of polatuzumab vedotin marks the first time an immunotherapy from Roswell Park has been part of an FDA-approved treatment.
 
Manufactured by Genentech Inc., polatuzumab vedotin is an antibody-drug conjugate that specifically targets CD79b, a protein expressed in the majority of B cells.
 
“What Ben has done is really remarkable,” said Dr. Kelvin Lee, the Jacobs Family Chair in Immunology and Senior Vice President for Basic Science at Roswell Park. “Through his systematic, diligent approach, he came up with ideas decades ago in his lab that larger teams have only begun to hit upon in the last few years.”
 
“I didn’t take the conventional approach. I decided to develop a new system for isolating antigens,” observed Seon, and he says he is especially proud that a therapy he developed has helped many patients at Roswell Park, one of the participating sites in the clinical trials incorporating polatuzumab vedotin. “My father died from stomach cancer when I was a high school student, and my brother died of cancer many years ago in his 50s. So it’s always been in my mind that hopefully someday I could find a new cancer drug, a better cancer drug.”
 
Triple combo shows promise against advanced melanoma
HOUSTON—Combining two types of drugs that, separately, have extended the lives of people with metastatic melanoma has yielded higher response rates in three early-phase clinical trials reported in Nature Medicine, one led by MD Anderson Cancer Center investigators.
 
“These are the first clinical trials that combine targeted therapy and immunotherapy that are maturing, with promising durable results for patients so far,” said Dr. Patrick Hwu, head of the Division of Cancer Medicine, professor of Melanoma Medical Oncology and senior author of one of the papers.
 
Patients received the immune checkpoint inhibitor atezolizumab, which blocks the PD-L1 ligand that activates the PD-1 off-switch on T cells, as well as the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.
 
About half of advanced-stage melanoma patients have the BRAF mutation in their tumors. The 71.8-percent response rate to the triple combination is similar to that of patients who receive vemurafenib and cobimetinib in the frontline setting. The durability of the triple combination is comparable to the greater durability seen with anti PD-L1/PD-1 checkpoint blockade compared to that of the targeted therapy combination.
 
Research by MD Anderson and an Australian group of investigators found that treatment with BRAF inhibitors increased the penetration of immune T cells in tumors, providing a scientific basis for testing the combination.
 
Nature Medicine also published two other studies that used a different combination of drugs against the same targets (PD-1 inhibitor pembrolizumab plus BRAF inhibitor dabrafenib and MEK inhibitor trametinib) that reported similar results.
 
A synthetic biotic IO program
CAMBRIDGE, Mass.—This spring, clinical-stage drug discovery and development company Synlogic Inc. announced that preclinical data from its immuno-oncology (IO) program were featured in two presentations at the annual meeting of the American Association for Cancer Research (AACR). The data demonstrate that, in mouse models, Synlogic’s Synthetic Biotic medicines were shown to stimulate an antitumor response and robustly reprogram the tumor microenvironment, potentially enabling the treatment of a variety of cancers.
 
“Our IO program highlights the potential of our Synthetic Biotic platform for the design and engineering of novel living medicines with multiple mechanisms of action to treat a broad range of diseases, including cancer,” said Dr. J.C. Gutiérrez-Ramos, Synlogic’s president and CEO. “Our approach enables us, in a single treatment, to locally deliver multiple, regulatable activities that stimulate an immune response and modulate the tumor environment in order to mobilize the immune system against the tumor and its metastases. We intend to advance our first IO program into IND-enabling studies this year.”
 
Synlogic is focused initially on developing Synthetic Biotic medicines to treat so-called “cold tumors,” which lack infiltrating antitumor T cells, by first stimulating an innate antitumor response to make the tumor “hot” and then modifying the tumor microenvironment (TME) to enable T cell expansion and the development of memory, using a single agent to both prime T cells to mount an immune response and sustain the response.
 
In a presentation in the late-breaking research immunology session, “Activation of Innate and Adaptive Immunity via Combinatorial Immunotherapy using Synthetic Biotic Medicines,” Synlogic described two new genetic circuits engineered into E. coli Nissle, an immune “initiator” STING activating circuit (SYN-STING) and an immune “sustainer” kynurenine consuming circuit (SYN-Kyn).
 
Among the findings were that combining SYN-Kyn with a checkpoint inhibitor led to profound antitumor activity in the CT26 immunocompetent tumor model and that a strain engineered to combine both genetic circuits (SYN-STING:Kyn) demonstrates equivalent production of ci-di-AMP and consumption of kynurenine in vitro compared to the individual strains SYN-STING and SYN-Kyn, respectively.
 
The second presentation, “Metabolic Modulation of the Tumor Microenvironment using Synthetic Biotic Medicines,” demonstrated that engineered bacterial strains designed to consume either kynurenine (SYN-Kyn) or adenosine (SYN-Ade) effectively relieved TME immunosuppression and promoted antitumor activity. One of the findings was that a combination of either SYN-Kyn or SYN-Ade with checkpoint inhibition led to superior antitumor activity in the MC38 immunocompetent tumor model compared with checkpoint inhibitors alone.
 
Innocent passengers?
A news analysis of cancer genomes by researchers at Massachusetts General Hospital and the University of California, Irvine—as well as colleagues elsewhere—indicates that some alterations found at so-called mutation “hotspots” might not be driving the disease but may simply be “passenger” mutations.
 
As noted in the abstract for the paper “Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features” that appeared in the June 28 issue of Science, “Our results indicate that there are multiple possible routes to mutational hotspots in cancer. Functional mutations in oncogenes or tumor suppressors can rise to prominence through positive selection. These driver hotspots are not restricted to the “favorite” sites of any particular mutagen. In contrast, DNA sites that happen to be perfect substrates for a mutagen can give rise to “passenger hotspot mutations” that owe their prevalence to substrate optimality, not to any effects on tumor fitness. In light of these findings, we recommend caution in interpreting the long lists of putative novel cancer driver hotspots being produced by high-throughput sequencing projects.”
 
Or, put more simply, cancer drivers require statistical modeling to distinguish them from passenger events, which accumulate during tumorigenesis but provide no fitness advantage to cancer cells.
 
Novel oncology dual inhibitor moves closer to clinical trials
TEL AVIV, Israe—Kitov Pharma Ltd., a pharmaceutical company focused on advancing first-in-class oncology therapies to overcome tumor drug resistance, increase treatment response rate and slow tumor progression, has successfully completed the laboratory phase of the IND-enabling studies for NT219, a first-in-class, dual-inhibitor small molecule designed to prevent and overcome cancer drug resistance.
 
The preclinical GLP toxicology studies have demonstrated good tolerability at the highest dose levels expected to be tested in Kitov’s planned Phase 1/2 study treating patients with squamous cell carcinoma of the head and neck (SCCHN).
 
Kitov is preparing for completion of the GMP manufacturing of the drug product and submission of an Investigational New Drug  application with the U.S. Food and Drug Administration (FDA) to initiate a dose-escalation Phase 1/2 study to treat SCCHN cancer patients with the combination of NT219 and cetuximab.
 
 “We are excited with the completion of the IND-enabling studies for NT219 which advances our growing oncology pipeline to the clinic,” stated Isaac Israel, CEO of Kitov. “Our planned development of NT219 is based on strong preclinical evidence demonstrating that the combination of NT219 with the EGFR antibody cetuximab has potential clinical benefits for patients with recurrent or metastatic SCCHN whose cancer has not responded or has become resistant to early-line immuno-oncology or chemotherapy treatments. Pending a smooth regulatory review process, we look forward to initiating a Phase 1/2 trial with NT219 and cetuximab in the U.S. by the end of 2019.”
 
NT-219 is an inhibitor of two signaling proteins involved in drug resistance, insulin receptor substrate 1 and 2 (IRS1/2) and signal transducer and activator of transcription 3 (STAT3).
 
Teams awarded £18M in Cancer Research UK brain tumour awards
LONDON—Three teams have been awarded a combined total of £18 million in funding as part of the Cancer Research UK Brain Tumour Awards. Cancer Research UK, in partnership with The Brain Tumour Charity, established these Awards to advance understanding of the biology of brain tumours and tackle the challenge of translating discoveries into treatments for patients.
 
Two of the internationally funded teams are based at the University of Edinburgh, and one is led from the University of Cambridge. Teams will focus on the most aggressive type of brain tumour, called glioblastoma, as well as children’s brain tumours.
 
Prof. Neil Carragher’s team, from the University of Edinburgh, aims to identify and target the best drug combinations against aggressive brain tumours. Working with a team from the Massachusetts Institute of Technology in the United States, they will develop prototype nanoparticles, 1,000 times smaller than a human hair, which are able to cross the blood-brain barrier. The nanoparticles can carry multiple drugs at once by holding them inside layers, similarly to the way Russian dolls fit inside one another.
 
They will test whether this way of configuring multiple drugs in particles will be more effective and safe at carrying combinations to cancer cells without being taken up by healthy cells, in the hope of minimising side-effects for future patients.
 
Meanwhile, Prof. Steven Pollard’s team, also from the University of Edinburgh, aims to control the sleep/wake cycle of cancer cells to stop tumors from growing back. Glioblastoma, the most aggressive type of brain tumour, can grow by hijacking tools we use during embryonic development, reactivating them in the wrong place and time. Professor Pollard will lead a team of researchers from the United Kingdom, United States and Canada to find new strategies to target this process. For example, the researchers plan to degrade key tools that are used by cancer cells to turn on these embryonic gene programs.
 
The team will also study the mechanisms that control this switch from dormancy to wakefulness, and how tumours respond to cues from their environment such as mechanical forces or signals from immune cells.
 
Finally, Prof. Richard Gilbertson, from the University of Cambridge, and his collaborators in the United States and Canada seek to build maps of developing human and mice brains to identify which parts of the embryonic brain turn into which type of brain tumor. They are hoping to use what we already know about embryonic brain development to discover new drug targets for the corresponding tumours.
 
The team will also explore the way children’s brain tumours behave, so that they may target some of their unique features. For example, a group of U.S.-based collaborators will investigate how we could stop brain tumor cells from “reaching out” to healthy cells and taking nutrients from them.
 

Jounce initiates Phase 2 EMERGE study
CAMBRIDGE, Mass.—Jounce Therapeutics Inc., a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, recently initiated dosing in the Phase 2 EMERGE clinical trial of its lead product candidate, vopratelimab, in combination with ipilimumab in patients with non-small cell lung cancer (NSCLC) or urothelial cancer who have progressed on or after PD-1/PD-L1 inhibitor therapies.
 
These patient populations represent a rapidly growing area of unmet need as PD-1 inhibitors move into earlier lines of therapy, with few options and no established standard of care for patients who progress after a PD-1/PD-L1 inhibitor.
 
“The Phase 2 EMERGE clinical trial of vopratelimab and ipilimumab builds upon the original science from our founders as well as the reverse translational subset analysis from patients who benefitted in our ICONIC trial versus those who did not. Vopratelimab treatment resulted in the emergence of ICOS hi CD4 T effector cells in the peripheral blood and emergence of these cells was associated with response and improvements in progression free survival and overall survival,” said Dr. Beth Trehu, chief medical officer of Jounce Therapeutics. “Ipilimumab is known to induce a population of ICOS hi CD4 T cells, making it a scientifically logical combination partner for vopratelimab in the EMERGE study, as we have shown vopratelimab stimulates, expands and sustains ICOS hi CD4 T cells.”
 
In the initial stage, Jounce expects to enroll approximately 40 patients with NSCLC and approximately 40 patients with urothelial cancer. The primary endpoint is overall response rate  and secondary endpoints include safety, duration of response, progression free survival and overall survival. Jounce expects to report preliminary efficacy and biomarker relationships to clinical outcomes on up to 80 patients in 2020.
 
Code: E071936

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