On June 25, 2020 Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs to modulate powerful cytokine pathways, reported that this week shared data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting highlighting the potent effects on natural killer cells and stem-like CD8+ cells of its lead asset, a customized variant of IL-18 purpose-built to reverse the immunosuppressive tumor microenvironment (Press release, Simcha Therapeutics, JUN 25, 2020, View Source [SID1234561474]).

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An oral presentation given by Yale researcher Ting Zhou, Ph.D., detailed findings that the IL-18 variant, which was engineered to avoid the "decoy" receptors that abound in the tumor microenvironment, promotes a strong response by natural killer cells against "cold" tumors – those that are no longer expressing significant MHC Class 1 antigens. NK cells quickly become exhausted and lose efficacy when confronted with tumor cells deficient in MHC Class 1. Those tumors are thus refractory to traditional checkpoint inhibition immunotherapy. The decoy-resistant IL-18 (DR-18) engineered in the lab of Simcha’s founder, Aaron Ring, M.D., Ph.D., showed an ability to rescue those exhausted NK cells and thereby stimulate strong anti-tumor activity in multiple animal models.

Single cell RNA sequencing and flow cytometry revealed that DR-18 promoted functional maturation of highly proliferative NK cells. These newly matured cells retained polyfunctional capacity to produce effector molecules that play a critical role in orchestrating both innate and adaptive immune responses, including IFN-γ, Gzmb, and TRAIL. Ablation of NK cells or neutralization of IFN-γ reversed these effects.

"These results highlight the potential of our tailored cytokine to overcome the immunosuppressive tumor microenvironment and elicit a strong therapeutic response by NK cells, even in cold tumors," said Dr. Ring. "The single-agent activity of this decoy-resistant IL-18 is compelling, and we are optimistic that it could bring new hope to patients who no longer respond to checkpoint inhibitors. We look forward to bringing this investigational therapy to the clinic in the first half of 2021."

Dr. Zhou also presented a poster at AACR (Free AACR Whitepaper) demonstrating that DR-18 acts on a crucial population of "stem-like" T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. These results highlight DR-18’s ability to remodel the intratumoral ecosystem to encourage the proliferation of potent anti-tumor effector cells.

"These results make clear that the IL-18 pathway is a powerful target for immunotherapeutic intervention — as long as that intervention avoids the decoy receptors in the tumor microenvironment," Dr. Ring said. "We’re delighted to be able to share these data with the scientific community at AACR (Free AACR Whitepaper)."

The human variant of the DR-18 is designated ST-067 in Simcha’s pipeline. Simcha is moving through IND-enabling studies and expects to initiate a Phase 1 trial in people with cancer refractory to checkpoint inhibitors in the first half of 2021.

On June 25, 2020 Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs that modulate powerful cytokine pathways, launched today with $25 million in Series A financing and a mission to harness the precision and power of the immune system through the use of directed evolution (Press release, Simcha Therapeutics, JUN 25, 2020, View Source [SID1234561473]).

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Simcha’s lead program involves a customized variant of interleukin-18 (IL-18), a cytokine with potent antitumor effects, developed in the lab of Scientific Founder Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The biology and preclinical profile of this molecule, which Simcha expects to advance to the clinic in the first half of 2021, is described in detail in a scientific paper published today in the journal Nature.

Cytokine therapies heralded the immuno-oncology revolution more than 30 years ago with the discovery that interleukin-2 (IL-2) could promote rare, but dramatic, responses in melanoma and kidney cancer patients. However, they have not lived up to their promise as a class due to substantial toxicities and limited efficacy. Simcha was founded to overcome those obstacles by using directed evolution to engineer a new generation of cytokines with improved properties relative to those of their native variants. Simcha’s molecules are purpose-built to control immune cell activation, differentiation and proliferation — and to reverse the immunosuppressive tumor microenvironment that is a barrier to effective eradication of the cancer.

"Cytokines represent a compelling therapeutic class because they tap into pathways that are hard-wired into immune cells. The challenge is that nature didn’t design them to be anti-cancer therapies; they’re signaling molecules, so their activity can be hard to specifically direct," Dr. Ring said. "At Simcha, we set out to improve on nature’s design by engineering custom-built proteins that can precisely activate and expand populations of crucial immune responders, such as natural killer (NK) cells and T cells. Too many cancer patients do not respond to the immunotherapies available today. We’re hopeful that our approach will provide new options and potential benefits to these patients."

Evading a "Decoy" Receptor

Simcha’s lead asset, ST-067, activates the IL-18 receptor, triggering potent inflammatory signaling in antitumor immune cells of both the adaptive and innate branches of the immune system.

Early efforts by leading pharmaceutical companies to develop IL-18 into a drug failed. Dr. Ring’s lab broke new ground by identifying the reason for that failure: The tumor microenvironment is teeming with a "decoy" called IL-18BP, which binds IL-18 and blocks it from activating its receptor. When infused as a drug, IL-18 is drawn to the decoy and fails to reach its true target. As described in the Nature paper, the decoy receptor is a "major barrier to IL-18 immunotherapy."

To overcome that barrier, Dr. Ring’s lab used directed evolution to create a version of the cytokine that would evade the decoy and bind only to the true IL-18 receptor. This was a difficult task, since IL-18 normally binds its decoy 10,000 times tighter than it does to the IL-18 receptor. The designer version of IL-18 made in Ring’s lab has dramatic alterations in its receptor binding properties, biasing binding towards the IL-18 receptor and away from the decoy by more than one million-fold. This "decoy-resistant" property enables the custom-built cytokine to work effectively in the immunosuppressive tumor microenvironment.

Potent Single-agent Antitumor Effects

When Ring’s lab tested the decoy-resistant IL-18 and compared it to natural IL-18 in mice, they found that — just as in human patients — natural IL-18 had little to no antitumor activity. By contrast, the decoy-resistant IL-18 had potent single-agent activity that inhibited tumor growth and even produced complete tumor regression in many animals, including in tumor types that are refractory to checkpoint inhibitors.

Ring’s lab also examined the effect of decoy-resistant IL-18 on the tumor microenvironment. A key finding: The engineered IL-18 acted on a crucial population of "stem-like" T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. In checkpoint-resistant tumors, the engineered IL-18 also acted on innate NK cells, increasing their numbers and maturation to promote antitumor activity.

"The mechanism of action of decoy-resistant IL-18 is unique and distinct from immunotherapeutic agents that are being developed for other pathways. For this reason, we are hopeful it could be effective in tumors that have not otherwise responded to immune-based treatments, as well as enhance the activity of standard cancer immunotherapies," said Dr. Ring.

Founder’s Strong Record in IO Drug Discovery

Dr. Ring has a strong track record in immuno-oncology drug discovery. He co-invented the first described CD122-biased IL-2 variant, originally detailed in Nature in 2012, which is now advancing through preclinical studies at Medicenna Therapeutics. He also developed a high-affinity SIRPα antagonist, featured in Science in 2013, that is now in clinical development at ALX Oncology as ALX-148. For these and other discoveries, Ring was named to Forbes ‘30 under 30’ list of rising stars in health care in 2016 and has been honored with an NIH Director’s Early Independence Award and recognition as a Pew-Stewart Scholar in Cancer Research.

Simcha plans to build out a full executive team as the company prepares to move ST-067 into the clinic next year.

The company’s investors include WuXi AppTec’s Corporate Venture Fund, Sequoia Capital China and Connecticut Innovations.

On June 25, 2020 The board of directors of Pfizer Inc. (NYSE:PFE) reported a 38-cent third-quarter 2020 dividend on the company’s common stock, payable September 1, 2020, to holders of the Common Stock of record at the close of business on July 31, 2020 (Press release, Pfizer, JUN 25, 2020, View Source [SID1234561472]). The third-quarter 2020 cash dividend will be the 327th consecutive quarterly dividend paid by Pfizer.

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On June 25, 2020 Genprex, Inc. ("Genprex" or the "Company") (Nasdaq: GNPX), a clinical-stage gene therapy company developing potentially life-changing technologies for patients with cancer and diabetes, reported that the United States Adopted Names (USAN) Council has approved the non-proprietary name quaratusugene ozeplasmid for GPX-001, formerly called Oncoprex immunogene therapy, the Company’s lead drug candidate for non-small cell lung cancer (NSCLC) (Press release, Genprex, JUN 25, 2020, View Source [SID1234561470]).

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The USAN Council is responsible for selecting simple, informative, and unique non-proprietary (generic) drug names. As a part of Genprex’s corporate communication strategy and drug nomenclature branding, the Company is also pursuing formal proprietary brand name approval for its lead drug candidate, GPX-001 (quaratusugene ozeplasmid). Obtaining regulatory approval of these adopted drug names is a necessary step in securing marketing approval.

In conjunction with the adoption of quaratusugene ozeplasmid as the Company’s non-proprietary name for GPX-001, Genprex has rebranded the naming of its unique, proprietary, non-viral nanoparticle delivery system, now referred to as its Oncoprex Nanoparticle Delivery Platform, which is the vehicle used to deliver its oncology platform technologies.

"The USAN’s adoption of our non-proprietary name is another step toward advancing our lead drug candidate, GPX-001 for non-small cell lung cancer, toward commercialization," said Rodney Varner, Chairman and Chief Executive Officer of Genprex. "We look forward to the adoption and rollout of a brand name for this drug as we continue to move along the development pathway. In the meantime, we’ve focused our branding efforts on our proprietary, non-viral nanoparticle delivery system with our recognized Oncoprex name. We believe this delivery system is a significant differentiator for GPX-001, as well as an important platform delivery system that could be used for additional drug candidates."

As a part of the rollout of its newly adopted nomenclature and to also include its gene therapy drug candidate for diabetes, referred to as GPX-002, the Company has completed an overhaul of its website, fact sheet and pipeline. For more information, please visit www.genprex.com.

On June 25, 2020 Varian Medical Systems reported that Long-term results of the Stereotactic Ablative Radiotherapy for Comprehensive Treatment of Oligometastatic Cancers (SABR-COMET) study published June 2, 2020 in the Journal of Clinical Oncology showed positive increases in overall survival for patients with multiple sites of metastasis when treated with stereotactic ablative radiotherapy (SABR) versus standard-of-care (Press release, Varian Medical Systems, JUN 25, 2020, View Source [SID1234561469]).1 Through the extended follow-up, the impact of SABR on overall survival was larger in magnitude than in the study’s initial analysis published last year in The Lancet.2

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"The durability of the randomized data indicates a paradigm shift in our approach to the treatment of patients with low burden metastatic disease," commented senior study author Suresh Senan, MRCP, FRCR, PhD, Professor of Radiation Oncology at the Amsterdam University Medical Centres in Amsterdam, the Netherlands. "These data add to a growing body of evidence that supports the use of SABR as an ablative therapy for oligometastatic cancers."

As outlined in the latest study results, patients in the international randomized phase II trial who received SABR demonstrated a 22-month improvement in 5-year median overall survival compared with patients who received a standard-of-care approach alone, corresponding to an absolute survival benefit of 24.6%.3 This is a marked improvement from the results of the initial analysis2 in which the patients receiving SABR demonstrated a 13-month improvement in median overall survival over the control group.

"The size of the effect on long-term survival in this seminal study marks a step-change in the way clinicians should treat metastases from the highest incidence cancers," said Ricky Sharma, MD, PhD, vice president of Clinical Affairs at Varian (NYSE: VAR). "With over one million stereotactic body radiotherapy cases treated on TrueBeam alone, Varian continues to invest heavily to incorporate artificial intelligence, extraordinary precision, and unrivalled patient workflow into our industry leading delivery platforms for radiosurgery. We believe our continued pursuit of innovation and investment will ultimately help change the trajectory of cancer outcomes for all patients."

While systemic therapy, including chemotherapy, has been offered to patients with multiple metastases, the SABR-COMET data add to the growing body of evidence that suggests the addition of non-invasive treatments such as SABR can improve long-term outcomes for patients. Phase III randomized trials are ongoing to confirm the magnitude of the survival benefit for patients with a variety of metastatic cancers, including the international, multi-center SABR-COMET-3 clinical trial funded by Varian.

Mirroring the most common cancers treated across the world, primary tumor types in the study were breast, lung, colorectal and prostate. All patients enrolled had one to five new metastatic lesions. Although patients treated with radiotherapy were 20% more likely to suffer adverse events, there was no long-term impairment of quality of life. The study further showed that even with SABR, patients may progress with new metastases, likely due to the presence of micrometastatic disease, but that some can receive salvage therapy with repeat SABR.