β1-adrenergic receptor

Cash, cash equivalents, marketable securities and restricted cash totaled approximately $440 million on June 30, 2024 Biohaven's Molecular Degrader of Extracellular Proteins (MoDE™) platform advancing multiple new targets and reported positive interim data from its lead investigational drug in an ongoing Phase 1 study of BHV-1300: The Company reported dose-dependent and rapid IgG reductions in its ongoing Phase 1 trial with its lead investigational degrader BHV-1300 No serious adverse events (SAEs) reported with BHV-1300 to date; most adverse events (AEs) were mild, deemed unrelated to study drug and resolved spontaneously Phase 1 study also completed an assessment of an optimized subcutaneous (SC) formulation of BHV-1300 that demonstrated approximately a 44% higher than expected exposure compared to the dose-equivalent intravenous formulation previously studied; this new human data further confirms feasibility of convenient self-administered SC auto-injector and the SC formulation was not associated with injection site reactions Degrader platform expected to deliver 3 INDs for new MoDE programs before year-end in addition to continued data from SAD/MAD with BHV-1300 Biohaven's beta-1 adrenergic receptor (β1AR) autoantibody targeting MoDE, BHV-1600, granted INTERACT meeting with FDA in 2H 2024 regarding development program for dilated cardiomyopathy Advancing novel ion channel program targeting Kv7 activation and TRPM3 antagonism across multiple neurological, pain and neuropsychiatric disease indications: 5 Phase 2/3 trials with BHV-7000 underway in epilepsy and mood disorders Released positive Phase 1 data with TRPM3 antagonist BHV-2100 showing drug concentrations above EC90 target and well-tolerated profile across all doses in SAD/MAD study; advancing Phase 2 study in acute migraine and proof-of-concept (POC) study in pain in 2H 2024 Taldefgrobep alfa, a myostatin-inhibitor, progressing on track with Phase 3 topline data in spinal muscular atrophy (SMA) and Phase 2 trial initiation in obesity expected in 2H 2024 Taldefgrobep alfa has demonstrated direct effects on reducing adipose tissue (including lipid storage and mitochondrial content) independent of increases in muscle mass In a MAD study, conducted in healthy adults, taldefgrobep alfa (45 mg SC QW) produced significant reductions in total body fat while increasing total body lean mass Preclinical data released at the 2024 American Diabetes Association conference demonstrated that taldefgrobep alfa, as a monotherapy or in combination with a GLP-1 agonist, demonstrated significant reductions in fat and total body weight. Taldefgrobep alfa-treated animals showed significant increases in lean muscle, despite co-administration with a GLP-1 receptor agonist Tyrosine Kinase 2/Janus Kinase 1 (TYK2/JAK1) selective inhibitor, BHV-8000, completed Phase 1 and confirmed biomarker target engagement with reductions in inflammatory markers and demonstrated central nervous system penetration with confirmed cerebrospinal fluid (CSF) target exposures in healthy subjects Advancing registrational programs for Parkinson's disease and prevention of Amyloid-Related Imaging Abnormalities (ARIA) following interactions with the FDA Expect interim data analysis from second ongoing Phase 3 OCD trial with troriluzole in 2H 2024; topline data from first Phase 3 OCD trial expected in 1H 2025 SCA interactions with troriluzole filing in Europe ongoing and constructive interactions in the US with the FDA New real-world evidence (RWE) protocol, incorporating feedback from the FDA, assessing 3-years of treatment with troriluzole expected to deliver topline results in 2H 2024 Biohaven antibody drug conjugate (ADC) portfolio positioned to deliver differentiated profiles and address unmet needs in oncology: BHV-1510 currently dosing cancer patients in Phase1/2 study and now advancing towards combination with Libtayo® by 4Q 2024 Portfolio of multiple advanced nonclinical BHVN ADCs demonstrate improved plasma stability and in vitro/in vivo differentiation NEW HAVEN, Conn., Aug. 8, 2024 /PRNewswire/ -- Biohaven Ltd. (NYSE: BHVN) (Biohaven or the Company), a global clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of life-changing therapies to treat a broad range of rare and common diseases, today reported financial results for the second quarter ended June 30, 2024, and provided a review of recent accomplishments and anticipated upcoming developments. Vlad Coric, M.D., Chairman and Chief Executive Officer of Biohaven, commented, "Last quarter, we showcased an array of exciting updates across our pipeline spanning immunology, neuroscience, obesity, and oncology at our annual R&D Day. First, it has been incredible working with Yale Professor David Spiegel and my colleagues at Biohaven to drive the advancement of groundbreaking degrader science represented by BHV-1300 using our Molecular Degrader of Extracellular Protein (MoDE™) technology — we consider our initial Phase 1 data to be paradigm-shifting and we are accelerating our entire platform based upon these early results. BHV-1300 has been well-tolerated with no significant adverse effects and no clinically significant lab abnormalities or ECG changes observed to date and emerging subcutaneous data from our Phase 1 study highlights the ease of use of this technology. The platform represents a brand-new technology that has potential to treat diseases like Type 1 diabetes, autoimmune dilated cardiomyopathy, IgA nephropathy, and many others. Our differentiation continues to focus on convenient SC patient self-administration, rapid onset of action, potential for deeper IgG reduction and concurrent use with Fc containing standard of care biologics. We are excited that we remain on timelines with multiple INDs from our MoDE platform for later this year, including drug candidates that target autoantibodies against β-1AR for the potential treatment of dilated cardiomyopathy, galactose deficient IgA for IgA nephropathy and a further optimized IgG degrader for use in rare diseases." Dr. Coric continued, "While our degrader program continues to garner significant focus, our broader pipeline is increasingly derisked with several potentially paradigm-shifting treatments for conditions including epilepsy, mood disorders, pain, immunology, rare diseases, obesity and neurodegenerative disorders. Starting with our ion channel platform; five studies with Kv7 activator BHV-7000 (three in epilepsy and two in major depressive disorder and bipolar) are underway with brisk patient enrollment. In addition, our TRPM3 antagonist BHV-2100 has completed its initial Phase 1 SAD/MAD study, attaining an exceptional PK/PD profile for the treatment of migraine and other pain disorders. All doses being advanced have reached the targeted EC90 for this molecule with excellent preliminary safety. We are excited about being back in the migraine space with this novel target and will initiate a Phase 2 study in migraine before year end, as well as initiate a POC study as a non-opiate pain treatment. With BHV-8000, our oral and brain penetrant TYK2/JAK1 inhibitor, we have aligned with the FDA on two novel study designs: one for the prevention of ARIA associated with amyloid lowering agents in Alzheimer's disease and another with the goal of slowing disease progression in early Parkinson's disease. The Phase 1 profile of BHV-8000 is invigorating our translational team as we have data confirming both CNS penetration and biomarker engagement of inflammatory targets in humans. Regarding our anti-myostatin taldefgrobep alfa, we shared new preclinical data demonstrating improved, durable weight reduction and lean mass preservation in combo with GLP-1 semaglutide, which was particularly noteworthy, given the muscle wasting limitations that have plagued the GLP-1 class. We also showed that taldefgrobep has direct effects on modulating fat in addition to increasing muscle mass. Our oncology platform has also emerged into the clinic with our lead Trop-2 ADC, BHV-1510, enrolling cancer patients and our efforts advancing a portfolio of several Biohaven ADCs. We are excited to get preliminary safety and efficacy data from cancer patients suffering with select advanced or metastatic epithelial tumors in the Phase 1/2 study of BHV-1510 and will be evaluating the combination of BHV-1510 with Regeneron's anti-PD1 Libtayo — combination dosing with BHV-1510 and Libtayo is anticipated to begin in 2H 2024. Finally, with our glutamate platform represented by troriluzole, topline data from an interim analysis of the second OCD trial is expected in 2H 2024 and our first OCD trial is expected to read out in 1H 2025. Separately, we continue to have constructive dialogue with the FDA regarding our SCA development program and our European Medicines Agency application for SCA3 remains under review. We now expect topline data from a new RWE protocol assessing the efficacy of troriluzole in SCA patients treated for up to 3 years— this includes new patient data that has not previously been available. I never cease to be amazed by the power of our small but mighty Biohaven R&D team that has innovated across each of these important medical areas. We are driven to fulfill a promise to patients and our investors that we will diligently evaluate and advance potentially transformative therapies to those suffering from disease." Second Quarter 2024 and Recent Business Highlights Additional data supports the paradigm-shifting potential of the MoDE Platform for the treatment of immunological and inflammatory disorders – In May 2024, the Company disclosed positive new data from its ongoing Phase 1 SAD study in healthy subjects with BHV-1300, a first-in-human IgG degrader from its innovative MoDE platform. Results from the initial dose cohorts in the SAD study confirmed that BHV-1300 rapidly and selectively lowers IgG in a dose-dependent manner. Emerging Phase 1 data also showed that our novel SC formulation of BHV-1300 delivered exposures higher than the intravenous formulation, enabling the profile of a convenient patient administered auto-injector to attain targeted reduction of IgG. The Company expects to provide an update from our SAD and MAD studies of BHV-1300 in the second half of 2024 and is on schedule to file multiple new MoDE INDs this year. FDA granted INTERACT meeting request for BHV-1600, β1AR autoantibody MoDE, development program. Ion Channel Platform: Kv7 activator and TRPM3 antagonist candidates represent transformational targets in neurology and neuropsychiatry – The Company is enrolling participants in five ongoing pivotal clinical trials with Kv7 activator, BHV-7000, targeting focal epilepsy, generalized epilepsy, bipolar disorder and major depressive disorder; separately, Phase 2 and POC studies are planned in migraine and pain, respectively, with the TRPM3 antagonist, BHV-2100, in 2H 2024. Committed to improving muscle health with Myostatin Platform – In May 2024, the Company presented new preclinical data showing that administration of taldefgrobep alfa directly reduced the increased adipose fat storage caused by myostatin; the Company also presented new preclinical data from a diet-induced obesity mouse model showing treatment with taldefgrobep alfa together with a GLP-1 agonist produced greater reductions in body weight and fat mass, and a larger increase in lean muscle mass, compared to treatment with GLP-1 alone. The Company plans to initiate a Phase 2 study in obesity in 2H2024. Separately, the Company continues to expect Phase 3 study topline results in SMA in 2H 2024. Selectively targeting the immune system to treat neurodegenerative diseases with neuroinflammation platform – In May 2024, the Company reported positive results from the Phase 1 SAD and MAD study with our brain-penetrant TYK2/JAK1 inhibitor, BHV-8000 in healthy subjects, including demonstration of CSF target exposures and biomarker engagement along with a well-tolerated safety profile. The Company also announced key regulatory updates, including the successful completion of two FDA meetings with favorable feedback enabling registrational programs for Parkinson's disease and for the prevention of ARIA, a novel indication. Oncology Platform: Antibody Drug Conjugate portfolio: positioned to achieve enhanced stability and improved efficacy – In May 2024, the Company announced that its novel Trop-2 ADC, BHV-1510, entered into the clinic for patients with advanced or metastatic epithelial tumors; the first patient was dosed in a Phase 1/2 clinical trial as monotherapy. Biohaven also entered into a clinical supply agreement with Regeneron to study the combination of BHV-1510 with Regeneron's anti-PD1 Libtayo (cemiplimab-rwlc) in the clinical study. Expected Upcoming Milestones: We believe Biohaven is well positioned to achieve significant milestones in 2024 and 2025 across numerous programs: Selective Kv7 Activator: Continue 5 ongoing Phase 2/3 trials with BHV-7000 in focal epilepsy, idiopathic generalized epilepsy, MDD, and bipolar disorder Troriluzole: Topline results from a new RWE protocol of 3-year data from troriluzole treated patients in SCA in 2H 2024 Two Phase 3 trials with troriluzole in OCD: conduct interim analysis of the second Phase 3 OCD trial in 2H 2024 and report topline data from first Phase 3 OCD trial in 1H 2025 Taldefgrobep alfa: Initiate Phase 2 trial with taldefgrobep in obesity in 2H 2024 Report topline data from Phase 3 trial with taldefgrobep in SMA in 2H 2024 First-in-class TRPM3 Antagonist: Initiate Phase 2 trial with BHV-2100 in acute migraine in 2H 2024 Initiate POC study with BHV-2100 for pain in 2H 2024 TYK2/JAK1 Inhibitor: Complete SAD/MAD studies with BHV-8000 and advance to Phase 2 in the coming months MoDE™ Platform Submit a total of 4 INDs in 2024 Continue to advance Phase 1 SAD and MAD studies with BHV-1300, with a further study update in 2H 2024 INTERACT meeting with FDA regarding BHV-1600, β1AR autoantibody degrader, in 2H 2024 Next Generation ADC Platform: Advance Phase 1 Trop-2 directed program BHV-1510 into a Phase 1 study in multiple tumor types Capital Position: Cash, cash equivalents, marketable securities and restricted cash totaled approximately $440 million on June 30, 2024. Second Quarter 2024 Financial Highlights: Research and Development (R&D) Expenses: R&D expenses, including non-cash share-based compensation costs, were $314.8 million for the three months ended June 30, 2024, compared to $79.5 million for the three months ended June 30, 2023. The increase was primarily due to a one-time, non-cash expense of $171.9 million paid to Knopp Biosciences, LLC (Knopp) for a milestone and royalty buyback related to our BHV-7000 and broader Kv7 platform that was recognized during the three months ended June 30, 2024 (the buyback reduced our potential future milestone payments by $867.5 million, and replaced the scaled high single digit to low teens royalty payment obligations with a flat royalty payment in the mid-single digits for the Kv7 programs). The increase in R&D expenses was also due to advancing our 6 clinical platforms including 5 Phase 3 starts for BHV-7000, follow-on Kv7 assets, preclinical research programs, and increases in direct program spend for additional and advancing multiple clinical development programs. Non-cash share-based compensation expense was $7.1 million for the three months ended June 30, 2024, an increase of $4.6 million as compared to the same period in 2023. Non-cash share-based compensation expense was higher in the second quarter of 2024, primarily due to our annual equity incentive awards granted in the fourth quarter of 2023 and the first quarter of 2024. General and Administrative (G&A) Expenses: General and administrative expenses were $19.0 million for the three months ended June 30, 2024, compared to $14.5 million for the three months ended June 30, 2023. The increase of $4.4 million was primarily due to increased non-cash share-based compensation expense, which was $5.2 million for the three months ended June 30, 2024, an increase of $2.9 million as compared to the same period in 2023. Non-cash share-based compensation expense was higher in the second quarter of 2024 primarily due to our annual equity incentive awards granted in the fourth quarter of 2023 and the first quarter of 2024. Other Income, Net: Other income, net was a net other income of $14.2 million for the three months ended June 30, 2024, compared to a net other income of $5.8 million for the three months ended June 30, 2023. The increase of $8.3 million was primarily due to a $9.2 million gain recorded upon the settlement of our forward contract liability for share consideration issued under the amendment entered into with Knopp in May 2024, and increased investment income, partially offset by a decrease in other income recognized during the three months ended June 30, 2024, as compared to the same period in 2023 related to the Transition Services Agreement entered into with Biohaven Pharmaceutical Holding Company Ltd. (the Former Parent). Net Loss: Biohaven reported a net loss for the three months ended June 30, 2024 of $319.8 million, or $3.64 per share, compared to $90.3 million, or $1.32 per share, for the same period in 2023. Non-GAAP adjusted net loss for the three months ended June 30, 2024 was $307.4 million, or $3.50 per share, compared to $85.7 million, or $1.25 per share for the same period in 2023. These non-GAAP adjusted net loss and non-GAAP adjusted net loss per share measures, more fully described below under "Non-GAAP Financial Measures," exclude non-cash share-based compensation charges and losses from the change in fair value of derivatives. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the tables below. Non-GAAP Financial Measures This press release includes financial results prepared in accordance with accounting principles generally accepted in the United States (GAAP), and certain non-GAAP financial measures. In particular, Biohaven has provided non-GAAP adjusted net loss and adjusted net loss per share, which are adjusted to exclude non-cash share-based compensation, which is substantially dependent on changes in the market price of common shares, and changes in the fair value of derivative liabilities, which do not correlate to actual cash payment obligations in the relevant periods. Non-GAAP financial measures are not an alternative for financial measures prepared in accordance with GAAP. However, Biohaven believes the presentation of non-GAAP adjusted net loss and adjusted net loss per share, when viewed in conjunction with GAAP results, provides investors with a more meaningful understanding of ongoing operating performance and can assist investors in comparing Biohaven's performance between periods. In addition, these non-GAAP financial measures are among those indicators Biohaven uses as a basis for evaluating performance, and planning and forecasting future periods. These non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between these non-GAAP measures and the most directly comparable GAAP measures is provided later in this news release. About Biohaven Biohaven is a biopharmaceutical company focused on the discovery, development, and commercialization of life-changing treatments in key therapeutic areas, including immunology, neuroscience, and oncology. The company is advancing its innovative portfolio of therapeutics, leveraging its proven drug development experience and multiple proprietary drug development platforms. Biohaven's extensive clinical and preclinical programs include Kv7 ion channel modulation for epilepsy and mood disorders; extracellular protein degradation for immunological diseases; TRPM3 antagonism for migraine and neuropathic pain; TYK2/JAK1 inhibition for neuroinflammatory disorders; glutamate modulation for OCD and SCA (spinocerebellar ataxia); myostatin inhibition for neuromuscular and metabolic diseases, including SMA and obesity; antibody recruiting bispecific molecules and antibody drug conjugates for cancer. Forward-looking Statements This news release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The use of certain words, including "continue", "plan", "will", "believe", "may", "expect", "anticipate" and similar expressions, is intended to identify forward-looking statements. Investors are cautioned that any forward-looking statements, including statements regarding the future development, timing and potential marketing approval and commercialization of development candidates, are not guarantees of future performance or results and involve substantial risks and uncertainties. Actual results, developments and events may differ materially from those in the forward-looking statements as a result of various factors including: the expected timing, commencement and outcomes of Biohaven's planned and ongoing clinical trials; the timing of planned interactions and filings with the FDA; the timing and outcome of expected regulatory filings; complying with applicable U.S. regulatory requirements; the potential commercialization of Biohaven's product candidates; the potential for Biohaven's product candidates to be first in class therapies; and the effectiveness and safety of Biohaven's product candidates. Additional important factors to be considered in connection with forward-looking statements are described in Biohaven's filings with the Securities and Exchange Commission, including within the sections titled "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations". The forward-looking statements are made as of the date of this news release, and Biohaven does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. MoDEs is a trademark of Biohaven Therapeutics Ltd. Libtayo is a registered trademark of Regeneron Pharmaceuticals, Inc. Investor Contact: Jennifer Porcelli Vice President, Investor Relations [email protected] +1 (201) 248-0741 Media Contact: Mike Beyer Sam Brown Inc. [email protected] +1 (312) 961-2502 SOURCE Biohaven Ltd.

Researchers have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature. New UCSF study shows that suppressing a protein turns ordinary fat into a calorie burner and may explain why drug trials attempting the feat haven't been successful. Researchers at UC San Francisco have figured out how to turn ordinary white fat cells, which store calories, into beige fat cells that burn calories to maintain body temperature. The discovery could open the door to developing a new class of weight-loss drugs and may explain why clinical trials of related therapies have not been successful. Until now, researchers believed creating beige fat might require starting from stem cells. The new study published July 1 in the Journal of Clinical Investigation, showed that ordinary white fat cells can be converted into beige fat simply by limiting production of a protein. "A lot of people thought this wasn't feasible," said Brian Feldman, MD, PhD, the Walter L. Miller, MD Distinguished Professor in Pediatric Endocrinology and senior author of the study. "We showed not only that this approach works to turn these white fat cells into beige ones, but also that the bar to doing so isn't as high as we'd thought." A fat transformation Many mammals have three "shades" of fat cells: white, brown and beige. White fat serves as energy reserves for the body, while brown fat cells burn energy to release heat, which helps maintain body temperature. Beige fat cells combine these characteristics. They burn energy, and unlike brown fat cells, which grow in clusters, beige fat cells are embedded throughout white fat deposits. Humans and many other mammals are born with brown fat deposits that help them maintain body temperature after birth. But, while a human baby's brown fat disappears in the first year of life, beige fat persists. Humans can naturally turn white fat cells into beige ones in response to diet or a cold environment. Scientists tried to mimic this by coaxing stem cells into becoming mature beige fat cells. But stem cells are rare, and Feldman wanted to find a switch he could flip to turn white fat cells directly into beige ones. "For most of us, white fat cells are not rare and we're happy to part with some of them," he said. Of mice and humans Feldman knew from his earlier experiments that a protein called KLF-15 plays a role in metabolism and the function of fat cells. With postdoctoral scholar Liang Li, PhD, Feldman decided to investigate how the protein functioned in mice, which retain brown fat throughout their lives. They found that KLF-15 was much less abundant in white fat cells than in brown or beige fat cells. When they then bred mice with white fat cells that lacked KLF-15, the mice converted them from white to beige. Not only could the fat cells switch from one form into another, but without the protein, the default setting appeared to be beige. The researchers then looked at how KLF-15 exerts this influence. They cultured human fat cells and found that the protein controls the abundance of a receptor called Adrb1, which helps maintain energy balance. Scientists knew that stimulating a related receptor, Adrb3, caused mice to lose weight. But human trials of drugs that act on this receptor have had disappointing results. A different drug targeting the Adrb1 receptor in humans is more likely to work, according to Feldman, and it could have significant advantages over the new, injectable weight-loss drugs that are aimed at suppressing appetite and blood sugar. Feldman's approach might avoid side effects like nausea because its activity would be limited to fat deposits, rather than affecting the brain. And the effects would be long lasting, because fat cells are relatively long-lived. "We're certainly not at the finish line, but we're close enough that you can clearly see how these discoveries could have a big impact on treating obesity," he said. Liang Li is also an author of this study. This work was funded by NIH grant R01DK132404.

Scientists discovered a relationship between the immune system's killer T cells and the body's sympathetic stress response ('fight-or-flight') in varying cancer types in mouse and human tissue samples, finding that killer T cells and sympathetic stress response hormones interact to 'exhaust' killer T cells -- but that exhaustion can be inhibited with beta-blockers. The findings demonstrate the benefit of pairing beta-blockers with existing immunotherapies to improve cancer treatment. Even for killer T cells -- specialized immune cells -- seeking and destroying cancer cells around the clock can be exhausting. If scientists can understand why killer T cells become exhausted, then they can create more resilient cancer-killing cells. In a new study, Salk Institute scientists discovered a relationship between killer T cell exhaustion and the body's sympathetic stress response ("fight-or-flight") in varying cancer types in mouse and human tissue samples. What's more, the team found that the interaction between killer T cells and sympathetic stress response hormones can be inhibited with beta-blockers -- a class of drugs already used in humans for controlling blood pressure and heart rate -- to create killer T cells that fight the tumor more efficiently. The findings, published in Nature on September 20, 2023, establish a new link between the sympathetic stress response and how the immune system responds to cancer. Additionally, they demonstrate the benefit of pairing beta-blockers with existing immunotherapies to improve cancer treatment by bolstering killer T cell function. "There is no question immunotherapy has revolutionized cancer patient treatment -- but there are many patients for whom it's ineffective," says Professor Susan Kaech, senior author and director of Salk's NOMIS Center for Immunobiology and Microbial Pathogenesis. "Finding that our nervous system can suppress the function of cancer-destroying immune cells opens up entirely new ways to think about how to rejuvenate T cells in tumors." The sympathetic nervous system is responsible for mediating the body's stress response, also known as the fight-or-flight response. However, little was known about how the nerves regulate the immune response to infections or cancer. The researchers focused on sympathetic nerves that innervate our organs and produce the messenger hormone noradrenaline, which is also a stress hormone. The scientists used a variety of cancer and chronic illness models in mice and human tissue samples to study when and how killer T cells are influenced by the sympathetic nerves. They found that the sympathetic nerves were producing noradrenaline, which was binding to killer T cells using a receptor called ADRB1. Exhausted killer T cells expressed more ADRB1 receptors than their functional counterparts, allowing the T cells to "listen" to the noradrenaline released by the nerves. To test whether killer T cell exhaustion could be prevented, the researchers tested two approaches to intercepting noradrenaline and ADRB1 interaction: either removing ADRB1 altogether or impairing ADRB1 function with beta-blockers, which resulted in more-functional killer T cells that were better at destroying cancer cells. The authors also found that the exhausted T cells do not just listen to nerves from afar, but cluster right around them in tissues. Surprisingly, the ADRB1 receptor provided the T cells with critical instructions to migrate near the nerves, which in turn suppressed their functions -- making them worse at fighting cancer. "The innervation of tumors is an understudied area of tumor immunology. Our study has now uncovered that nerves contribute to the process of T cell exhaustion in tumors, where T cells become worn out and less powerful in their fight against the tumor over time," says first author Anna-Maria Globig, a postdoctoral researcher in Kaech's lab. "If we can unravel the details of how nerves suppress the body's immune response to cancer and why the exhausted T cells move towards the nerves, we can begin to target this process therapeutically." According to Kaech, the researchers hope to expand their understanding of the exhausted killer T cell environment to learn more about why stress makes us sicker. "We were able to find a new pathway that we can target with beta-blockers to create more resilient killer T cells that resist exhaustion and fight cancer better," says Globig. Since beta-blockers are already clinically used, the team also hopes to implement their proposed cancer-fighting regimen soon in patients with lung cancer. By partnering with clinicians, they hope to study more human cancer tissue samples to enrich their findings and provide further evidence of the efficacy of beta-blockers in cancer treatment. Other authors include Steven Zhao, Jessica Roginsky, Natalia Avina-Ochoa, Filipe Hoffmann, Gokhan Senturk, Dan Chen, Carolyn O'Connor, and Samuel Pfaff of Salk; Vivien Maltez and Ronald Germain of the National Institutes of Health; Juan Guiza, Omkar Chaudhary, Jiawei Wang, Kurt Schalper, and Brinda Emu of the Yale School of Medicine; and Maximilian Heeg of UC San Diego. The work was supported by the German Research Foundation (GL 991/1-1), the NOMIS Foundation, and the National Institutes of Health (grants K00CA222741, 5R01 CA240909, 5R01 CA216101, R37CA245154, R01CA262377, P50CA196530).