Breaking News
January 17, 2018 - Lactation May Lower T2D Risk in Younger Women
January 17, 2018 - New Atopic Dermatitis Yardstick provides practical guidance and management insights
January 17, 2018 - New biodegradable pressure sensor could help monitor serious health conditions
January 17, 2018 - HSS orders Sectra’s 3D pre-operative planning solution for improving patient outcomes
January 17, 2018 - Study identifies six new genes regions associated with diabetes
January 17, 2018 - Women do not receive timely diagnosis for heart disease
January 17, 2018 - AbbVie’s Upadacitinib Shows Positive Results as Monotherapy in Phase 3 Rheumatoid Arthritis Study, Meeting All Primary and Key Secondary Endpoints
January 17, 2018 - Should President Trump’s Physical Include a Cognitive Screen?
January 17, 2018 - Could gene therapy someday eliminate HIV?
January 17, 2018 - Researchers identify new anti-inflammatory drug target
January 17, 2018 - Loxo Oncology Initiates Rolling Submission of New Drug Application to U.S. Food and Drug Administration for Larotrectinib for the Treatment of TRK Fusion Cancers
January 17, 2018 - Trunk Imaging Tied to Higher Nephrectomy Risk
January 17, 2018 - Campaigners incensed at failings in Africa AIDS war
January 17, 2018 - Research opens door to development of new treatment for type 2 diabetes
January 17, 2018 - Bariatric surgery extends lifespan in obese patients, shows study
January 17, 2018 - Bristol-Myers Squibb Receives FDA Approval for Opdivo (nivolumab) as Adjuvant Therapy in Patients with Completely Resected Melanoma with Lymph Node Involvement or Metastatic Disease
January 17, 2018 - Ewww Moments in the ER: That’s Improbable!
January 17, 2018 - Methods from optogenetics, machine learning should help improve treatment options for stroke patients
January 17, 2018 - Booze may help or harm the heart, but income matters
January 17, 2018 - Three-dimensional organization of genome plays key role in gene expression, cell fate
January 17, 2018 - Scientists identify six new gene regions that may help treat type 1 diabetes
January 17, 2018 - Top nutrients needed to boost mood and energy levels on Blue Monday
January 17, 2018 - Scientists develop unique technique to map elasticity of cell components
January 17, 2018 - Obesity surgery reduces the risk of death by half finds new study
January 17, 2018 - Raw Meat Not the Safest Choice for Your Dog or for You
January 17, 2018 - Men who lack HSD17B4 gene may be more susceptible to treatment-resistant prostate cancer
January 17, 2018 - High-Dose Aspirin Preferred for Kawasaki’s
January 17, 2018 - Study suggests risk management approach to combat EMS fatigue
January 17, 2018 - A new therapy against obesity
January 17, 2018 - Doctors warn against holding your nose and closing your mouth to contain a sneeze
January 17, 2018 - Measles outbreak alarms public health officials
January 17, 2018 - FDA Slaps Class Warning on Gadolinium Contrast Agents
January 17, 2018 - Distinct human mutations can alter the effect of medicine
January 17, 2018 - ASIT biotech’s new article presents clinical results of gp
January 17, 2018 - Alternative tobacco use by adolescents associated with greater odds of future cigarette smoking
January 17, 2018 - A High-Salt Diet Produces Dementia In Mice
January 17, 2018 - Scientists provide insights into crucial interaction for DNA repair
January 17, 2018 - Sanofi and Regeneron Announce Positive Topline Pivotal Results for PD-1 Antibody Cemiplimab in Advanced Cutaneous Squamous Cell Carcinoma
January 17, 2018 - Morning Break: Pfizer Kills AD/PD Pipeline; Trump Affirms His Mental Health; Humira Pricing Strategy
January 17, 2018 - Researchers see gene influencing performance of sleep-deprived people
January 17, 2018 - Fast food triggers the immune system making it hyperactive
January 17, 2018 - Scientists find increased risk of HIV outbreaks in Ukraine due to war-related migration
January 17, 2018 - New universal flu vaccine moves to clinical trial phase and could be a reality soon
January 17, 2018 - Cocaine de-addiction breakthrough shows promise
January 17, 2018 - FDA Accepts New Drug Application for Seysara (sarecycline) for the Treatment of Moderate to Severe Acne
January 17, 2018 - Robotic Telestenting; BP Cuff Smartwatch; Medicare Bundled Care
January 17, 2018 - New cellular approach found to control progression of chronic kidney disease
January 17, 2018 - Lamprey genes provide clues to repair spinal cord damage, finds study
January 17, 2018 - Tissue-based soft robot could lead to advances in bio-inspired robotics
January 17, 2018 - Mostly the healthy and wealthy Americans use mobile phone apps to track sleep habits
January 17, 2018 - FDA Alert: Varubi (rolapitant) Injectable Emulsion: Health Care Provider Letter
January 16, 2018 - NeuroBreak: Rough Days for Neuroscience Research; Another Migraine Drug Advances
January 16, 2018 - The ‘greatest pandemic in history’ was 100 years ago – but many of us still get the basic facts wrong
January 16, 2018 - Serena Williams Shares Childbirth Ordeal
January 16, 2018 - The Artificial Brain as Doctor
January 16, 2018 - Type 2 diabetes has hepatic origins
January 16, 2018 - Expert discusses how to identify, support individuals with drug or alcohol addiction in workplace
January 16, 2018 - Starting menstruation early increases risk of cardiovascular disease and stroke in later life
January 16, 2018 - CapsoVision receives CE Mark approval for use of CapsoCam Plus System in pediatric patients
January 16, 2018 - Researchers develop new dynamic statistical model to follow gene expressions over time
January 16, 2018 - Alzheimer’s ‘looks like me, it looks like you’
January 16, 2018 - By the Numbers: Physicians’ Economic Impact
January 16, 2018 - Sound Health | NIH News in Health
January 16, 2018 - Modifying baby formula doesn’t prevent type 1 diabetes in children
January 16, 2018 - Energy drinks dangerous for kids
January 16, 2018 - When you need a breast screening, should you get a 3-D mammogram?
January 16, 2018 - Johns Hopkins gets approval to perform HIV positive to HIV positive living donor kidney transplants
January 16, 2018 - The Salk Institute and Indivumed collaborate for cutting-edge cancer research
January 16, 2018 - Study reveals negative long-term effects of heavy cannabis use on brain function and behavior
January 16, 2018 - Many gym-goers injure themselves by pushing harder to be better than friends
January 16, 2018 - Risankizumab Meets All Primary Endpoints Reporting Positive Results in Fourth Pivotal Phase 3 Psoriasis Study
January 16, 2018 - Federal Junk Food Tax Feasible, Study Says
January 16, 2018 - Do girls have stronger teeth than boys?
January 16, 2018 - New high-sensitivity blood tests could aid faster diagnosis and treatment for heart attack
January 16, 2018 - How fatal mitochondrial diseases may strike offspring of families with no history of the conditions
January 16, 2018 - TherapeuticsMD Announces FDA Acceptance of New Drug Application and Prescription Drug User Fee Act (PDUFA) Date for TX-004HR
January 16, 2018 - Morning Break: Food Pharmacies; Obamacare Sign-ups Dip; Top Pot Studies
January 16, 2018 - Blood pressure declines 14 to 18 years before death
January 16, 2018 - ViLim Ball technology helps reduce uncontrollable shaking hands
January 16, 2018 - Researchers use immune-mimicking biomaterial scaffolds to fast track T cell therapies
Researchers find way to improve immunotherapy drugs’ impact while limiting side effects

Researchers find way to improve immunotherapy drugs’ impact while limiting side effects

image_pdfDownload PDFimage_print

By connecting highly effective cancer immunotherapy drugs such as anti-CTLA4 (ipilimumab) and anti-PD-L1 (atezolizumab) to peptides that bind to tissues in and around tumors, a research team based at the University of Chicago found a way to improve the drugs’ impact while limiting treatment-related side effects.

In the last five years, these drugs, known as checkpoint inhibitors, have revolutionized treatment for a wide range of cancers. They can overcome barriers that prevent a patient’s immune system from finding and removing tumor cells. But these drugs, administered through an intravenous drip directly into the blood stream, often trigger troubling autoimmune responses. Two out of three patients receiving this form of immunotherapy have grade-3 or 4 adverse effects. One third of those patients discontinue therapy because of treatment-related problems.

“We wanted to find a more targeted way to give these drugs,” said study author Jeffrey Hubbell, PhD, the Eugene Bell Professor in Tissue Engineering at the University of Chicago. “We felt we could reduce the systemic side effects if we could inject them directly into or around a tumor and, more important, keep them there, concentrating the drug in the place where it ought to go.”

In the November 8, 2017 issue of Science Translational Medicine, Hubbell and colleagues show that injecting the drugs directly into tumor sites reduced systemic side effects and enhanced efficacy. “We weren’t really expecting that both would occur,” Hubbell said. “We were surprised to see such dramatic gains in efficacy.”

The key to improving the performance of these drugs was developing peptides that could anchor the anti-cancer drugs within or adjacent to the tumor environment.

“We had previously discovered a particular peptide sequence that binds to the many components of extra-cellular matrix,” Hubbell said. This led to aggressive screening of related compounds, which led them to a “super-affinity” peptide derived from placenta growth factor-2 (PlGF-2), which has an exceptionally high affinity for extra-cellular matrix proteins.

They were then able to identify the precise part of PlGF-2 (the region 123-144) that does the binding. It links to eight common extra-cellular matrix proteins. So the researchers conjugated the PlGF-2123-144 peptide to the anti-cancer drugs anti-CTLA4 and anti-PD-L1.

Testing in mice showed that both conjugates – PlGF-2123-144 anti-CTLA4 and PlGF-2123-144 anti-PD-L1 – were tethered to the injection site. Very little drug entered the blood stream, where it was barely detectable within three days.

Test results indicate that binding the drugs to the tumor matrix could prevent systemic side effects. Eight out of eight 16-week old non-obese diabetic mice developed autoimmune diabetes after treatment with the standard checkpoint blockade drugs, but none of the mice exposed to the conjugated PlGF-2 checkpoint-blockade drugs developed diabetes.

Further tests on mice showed that the modified drug-antibody model slowed growth of implanted tumors and extended survival. Increasing the dose further slowed tumor growth, boosted the number of cancer-killing T cells entering the tumor environment, and enhanced antitumor activity in nearby tumors.

The modified drugs suppressed tumor growth and prolonged survival in mice with transplanted melanoma and breast cancers. It eradicated breast tumors in 11 out of 16 mice, compared to only five out of 15 mice that responded to treatment with standard anti-CTLA4 and anti-PD-L1.

Only one out of nine mice treated with PlGF-2123-144 anti-CTLA4 and PlGF-2123-144 anti-PD-L1 developed a palpable tumor after being re-challenged with breast tumor cells, an indication that these mice had developed immunologic memory.

“We think we have developed a straightforward way to modify the really important immunotherapy drugs that work remarkably well in some patients but don’t work at all in others,” Hubbell said. “We found that we can enhance efficacy, at least in this mouse model. Perhaps more important, we believe we can reduce the side effects of these remarkable but problematic drugs, allowing patients who need them to remain on the therapy.”

Source:

Novel approach could limit common complications of immunotherapy

Tagged with:

About author

Related Articles