publication date: Apr. 17, 2020

Clinical Roundup

Elicio Therapeutics and NCI study ELI-002 mutant KRAS targeting mechanism

Elicio Therapeutics and NCI are working together to characterize T cell responses to ELI-002 in animals.

The collaboration will be led by James Yang, senior investigator in the Surgery Branch of the Center for Cancer Research at NCI.

Elicio has demonstrated in multiple tumor models that improving the targeting of immunogens and cell-therapy activators to lymph nodes, where resident immune cells potently orchestrate immunity, can substantially amplify their ability to induce effective tumor-killing immune responses. ELI-002 is an “AMP KRAS-vaccine” containing seven amphiphile mKRAS peptides and a proprietary amphiphile adjuvant, administered subcutaneously.

KRAS mutations are present in 90% of pancreatic cancers, 40% of colorectal cancers, 30% of non-small cell lung, 30% of bile duct, 14% of endometrial, and 14% of ovarian cancers. ELI-002 has completed preclinical validation, IND-enabling GLP toxicology studies, and a pre-IND meeting with the FDA. P1/2 trials will be multi-site, starting with an open label dose escalation, progression to expansion cohorts in KRAS mutated solid tumors, and seamlessly progressing into a randomized, controlled cohort.

“This research investigates the mechanism of action of ELI-002 in mice that have key human HLA genes important for immune response,” Christopher Haqq, Elicio’s executive vice president, head of Research and Development, and chief medical officer, said in a statement. “Dr. Yang is a pioneer of T cell therapy for solid tumors, and we are excited to collaborate in the study, which may help monitor patient responses in the planned clinical study of ELI-002, and would set the stage for clinical trials combining ELI-002 with KRAS targeting T cells.”

The Elicio Amphiphile platform enables precise targeting and delivery of immunogens and cell-therapy activators directly to the lymphatic system, the “brain center” of the immune response, to significantly amplify and enhance the body’s own system of defenses, defeat solid and hematologic cancers, and prevent their recurrence. Elicio’s ELI-002 targets seven position 12 and 13 KRAS mutations, present in approximately 25% of all human solid tumors. ELI-002 has the potential to become a multi-targeted mKRAS therapy with the ability to treat and prevent disease recurrence for hundreds of thousands of patients with mKRAS-driven cancers, including pancreatic, colorectal, lung, bile duct, endometrial, and ovarian.

 

ACS study: JUUL sales bounced back within weeks of self-imposed flavor ban

Juul sales recovered within weeks following a dip after the company withdrew some flavored products from stores, eventually surpassing sales from before the change, according to a study by American Cancer Society researchers in the American Journal of Public Health.

In November 2018, under pressure from FDA to curb rising youth vaping rates, Juul removed most of their flavored products, excluding tobacco, menthol, and mint flavors, from retail stores. Using Scantrack data on e-cigarette sales in the United States from January 2015 to October 2019 provided by The Nielsen Company, investigators led by Alex Liber, senior scientist, with the Economic & Health Policy Research program at the American Cancer Society, looked at sales trends to characterize the effects of Juul removing mango, crème brûlée, fruit medley, and cucumber flavors from store shelves.

From 2017 through 2018, Juul sales grew, with a concurrent increase in the share of fruit-flavored e-cigarettes sold in Nielsen-tracked retail channels. Fruit-flavors rose from 12.9% of sales ($10,161,000 per month) in January 2017 to 33.3% of sales ($96,486,000) in October 2018. Fruit briefly exceeded menthol/mint as the flavor category with the largest proportion of sales in October 2018. At the same time, tobacco-flavored e-cigarettes’ share dropped from 39.7% of sales to 16.6% of sales.

Juul’s voluntary decision to remove fruit flavors in November 2018 led to a decline in sales of fruit-flavored products across Nielsen-tracked retailers to 9.1% ($30,494,000) by April 2019. During this period, the share of menthol/mint flavor spiked from 33.0% to 62.5% ($95,592,000 to $209,567,000), and the share of tobacco flavor rose from 16.6% to 22.3% ($48,038,000 to $74,789,000).

Fully 91% of the growth in tobacco and all of the growth in menthol/mint was captured by Juul. Juul sales surpassed their previous maximum within 12 weeks, as Juul consumption shifted marginally toward the tobacco and heavily toward the menthol/mint flavors that remained on shelves. Fruit-flavor sales began to increase again to 15.8% ($60,594,000) by September 2019, driven by sales of the NJOY brand.

Notably, e-cigarette sales in the Nielsen data peaked in August 2019 at $441 million per month (including hardware). The authors say while it is too soon to determine why sales slowed after that peak, plausible explanations include consumers’ reactions to media reports detailing the outbreak of vaping-related illnesses and announced government actions including forthcoming bans on the sales of all or some e-cigarettes by the governors of several states and the president of the United States.

“Companies’ attempts to self-impose their own restrictions are unlikely to improve public health. Juul’s withdrawal of fruit-flavored products was quickly offset by a combination of increased fruit-flavored sales by Juul’s competitors and increased sales of other flavors—notably, mint/menthol—by Juul,” Liber said in a statement. “It is highly unlikely that overall youth use declined given the short-lived impact on sales trends for Juul cartridges and the rapid recovery of flavored cartridge sales within the very retail channels that should have seen the largest declines from Juul’s actions.”

“Our study shows when exceptions to regulatory policies are made, the market will fill the void. The growth of fruit-flavored sales experienced by NJOY once Juul stopped selling mango-flavored e-cigarettes is a striking indication of that happening. If governments exempt some e-cigarettes from a flavor regulation and not others –for example if governments exempt disposable or “open system” e-cigarettes from prohibitions on selling flavored products—we might expect consumer demand for flavored products to migrate to those types of products.”

 

Chronic stress can impact response to radiation therapy

New preclinical research from a team at Roswell Park Comprehensive Cancer Center suggests a strategy for significantly increasing both the local and distant, or “abscopal,” effects of radiation, according to a study.

Results of the study, led by Elizabeth Repasky of Roswell Park Comprehensive Cancer Center,     were published in Nature Communications.

“Our work suggests that the benefits of radiation therapy, both on the target site and in tumors located elsewhere in the body, are directly related to the degree of stress an individual may be experiencing,” Repasky, Cell Stress Program co-leader and William Huebsch Professor of Immunology at Roswell Park, said in a statement.

“In our laboratory studies, irradiated tumors went away faster when stress was reduced, and even distant tumors that did not receive radiation also shrunk or disappeared. Repasky said. “We have demonstrated that even mild stress that occurs over a longer period of time — not just singular moments, but chronic stress—can significantly influence  the efficacy of radiation therapy.”

“People often say, ‘Stress is a part of life.’ And while that’s true, because there is frequently more stress that occurs in cancer patients because of their cancer diagnosis, we need to work to mitigate those enduring, longer-term stressors, because our work shows that it can inhibit  the ongoing immune responses to cancer and an individual’s response to therapy,” first author Minhui Chen,, a senior postdoctoral researcher in Repasky’s lab, said in a statement.

The effects the team observed in their preclinical study hinge upon the body’s fight or flight response to stresses through the network of nerves and organs known as the adrenergic nervous system.

The team reports that when adrenergic stress was lessened, triggering lower levels of the neurotransmitters adrenaline and norepinephrine, tumor control in both irradiated and non-irradiated sites improved. This enhancement of the effects of radiation therapy also occurred when signaling through the β2-adrenergic receptor was reduced, suggesting that blockade of β2 adrenergic signaling could be  a safe and feasible option for patients receiving radiation. Based on earlier preclinical research, Repasky and colleagues are investigating in clinical studies whether the efficacy of chemotherapy and immunotherapy can be improved by giving patients beta blockers, such propranolol — a common blood pressure medication.

“Researchers have suspected a relationship between stress and cancer treatment outcomes for some time, but many questions remain,” co-author Anurag Singh, director of radiation research and professor of oncology in the Department of Radiation Medicine at Roswell Park, said in a statement. “This research has uncovered a major molecular and immunological pathway that appears to underlie the association between how much stress an individual is experiencing and how they respond to cancer therapy. Our results suggest that by blocking the β2 adrenergic receptor, you may not only make radiation and chemotherapy work better, you give a boost to the immune system — and may even be able to reduce metastasis, or spread of a tumor to a different part of the body.”

Copyright (c) 2020 The Cancer Letter Inc.