Antibody Targets Deep-Seated KRAS Cancer Mutations
Updated
Written By
Shantell Kirkendoll
Senior Science Writer, Duke University School of Medicine
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How Cancer Tumors Hijack the Body’s Defense System
In the May 10, 2024, issue of the journal Science Immunology, researchers unveiled a previously unknown tactic used by cancer tumors to dodge the body’s immune system.The analysis by cancer researchers at Duke University School of Medicine and University of North Carolina at Chapel Hill is a step forward in understanding why some cancers do not respond to immunotherapy.They discovered that a specific type of cell that usually rallies to help the body fight foreign invaders can suddenly operate differently, and instead allow cancer to grow unchecked. Using mouse models, the team found dendritic cells can be successfully manipulated to prevent their rogue transformation.“By disrupting the mechanisms that enable tumors to evade immune detection, we aim to expand the cancer patient population who can benefit from immunotherapy,” said senior study author and medical oncologist at Duke Cancer Institute Brent A. Hanks, MD, PhD, who has appointments in the Department of Medicine and Department of Pharmacology and Cancer Biology at Duke.What causes the dendritic cells to shift roles starts with a strategy employed by tumors. Cancer tumors produce high levels of lactate that can reprogram healthy dendritic cells into what scientists termed “mregDCs.”Unlike their healthy counterparts, mregDCs act as traitors, suppressing the body’s immune response, making it harder for the body to attack cancer cells.“Probably the most surprising finding was that mregDCs aren’t just poor stimulators of T cells needed for an immune response, but they are also capable of blocking other conventional cells from doing their job of initiating an immune response,” said lead study author Michael P. Plebanek, PhD, a postdoctoral associate and cancer immunologist at Duke School of Medicine.Authors note that tumors likely employ a variety of strategies to evade immune detection. But the discovery could lead to a new approach for targeted cancer therapies.Lead study author: Michael P. Plebanek, PhDSenior study author: Brent A. Hanks, MD, PhDAdditional authors include Yue Xue, PhD; Y-Van Nguyen; Nicholas C. DeVito, MD; and Balamayooran Theivanth, PhD, of the Duke Department of Medicine Division of Medical Oncology; Georgia Beasley, MD, in the Duke Department of Surgery; and Alisha Holtzhausen, PhD, of UNC-Chapel Hill School of Medicine.
Cracking the Code: Charlotte Patient Benefits from DCI Precision Cancer Medicine Research
Charlotte-area resident Vickie Johnson, 72, was diagnosed with colon cancer in 2018 after seeking care twice for abdominal pain. First, she was diagnosed with appendicitis and had her appendix out. Then, when her pain persisted beyond the recovery period, she received a new diagnosis. A scan at the ER showed a possible tumor. She went back to her appendix surgeon, had the mass in her colon removed, and was referred to a hospital oncologist. He referred her to a second surgeon who performed an even more aggressive surgery to remove all the remaining cancer in her colon and got her started on chemotherapy.Unfortunately, after each chemotherapy infusion she experienced severe chest pain. As she described it, “terrible spasms like I was having a heart attack.” Her oncologist didn’t have a plan b. “Finally, he said ‘I'm sorry, there's nothing I can do. We'll just test your blood every so often and get a scan every six months,’” Johnson shared. She wasn’t ready to give up, and as it turned out she didn’t need to.Johnson’s next area oncologist — Justin Favaro, MD, PhD — who'd done his medical training at Duke, brought a cardio-oncologist onboard the care team. The two providers tweaked the chemotherapy regimen she’d been on with the first oncologist; adjusting the dosage so her heart would be able to tolerate it. That worked, but successive treatments didn’t make any headway against her cancer.Johnson had begun 2019 in treatment for newly diagnosed colon cancer and ended that year with the death of her husband and progression of her cancer. During 2020, she’d endured another chemotherapy regimen but with no success. Cancer metastases remained in her liver and her lungs.Patients with metastatic colorectal cancer who have progressed on standard chemotherapy receive limited benefit from the available standard of care options. Johnson had genomic testing done and it turned out her cancer was hardwired with a KRAS G12C mutation, an alteration found in 3 to 4% of all metastatic colorectal cancer cases. Favaro said there was one more option.In the summer of 2021, he referred Johnson for enrollment in CodeBreaK 101, an early-stage clinical trial (phase 1b/2) at Duke Cancer Institute testing a new approach to treating KRAS G12C-mutated solid tumor cancers — a new KRAS G12C inhibitor drug (sotorasib) in combination with other anti-cancer therapies of choice, including FDA-approved antibodies, immunotherapy, and chemotherapy drugs. DCI was one of the first institutions worldwide to open this trial, which had launched in December 2019.Duke Cancer Institute GI medical oncologist and Associate Professor of Medicine John Strickler, MD, was Duke site principal investigator. Strickler is a colon cancer specialist who co-leads the DCI Precision Cancer Medicine and Investigational Therapeutics Research Program and the Molecular Tumor Board.Johnson said she had “no hesitation” about her decision and was grateful when she qualified for recruitment to the study under the care of Strickler.“This was the option. Nothing else was working,” Johnson recalled.
Related News
How Cancer Tumors Hijack the Body’s Defense System
In the May 10, 2024, issue of the journal Science Immunology, researchers unveiled a previously unknown tactic used by cancer tumors to dodge the body’s immune system.The analysis by cancer researchers at Duke University School of Medicine and University of North Carolina at Chapel Hill is a step forward in understanding why some cancers do not respond to immunotherapy.They discovered that a specific type of cell that usually rallies to help the body fight foreign invaders can suddenly operate differently, and instead allow cancer to grow unchecked. Using mouse models, the team found dendritic cells can be successfully manipulated to prevent their rogue transformation.“By disrupting the mechanisms that enable tumors to evade immune detection, we aim to expand the cancer patient population who can benefit from immunotherapy,” said senior study author and medical oncologist at Duke Cancer Institute Brent A. Hanks, MD, PhD, who has appointments in the Department of Medicine and Department of Pharmacology and Cancer Biology at Duke.What causes the dendritic cells to shift roles starts with a strategy employed by tumors. Cancer tumors produce high levels of lactate that can reprogram healthy dendritic cells into what scientists termed “mregDCs.”Unlike their healthy counterparts, mregDCs act as traitors, suppressing the body’s immune response, making it harder for the body to attack cancer cells.“Probably the most surprising finding was that mregDCs aren’t just poor stimulators of T cells needed for an immune response, but they are also capable of blocking other conventional cells from doing their job of initiating an immune response,” said lead study author Michael P. Plebanek, PhD, a postdoctoral associate and cancer immunologist at Duke School of Medicine.Authors note that tumors likely employ a variety of strategies to evade immune detection. But the discovery could lead to a new approach for targeted cancer therapies.Lead study author: Michael P. Plebanek, PhDSenior study author: Brent A. Hanks, MD, PhDAdditional authors include Yue Xue, PhD; Y-Van Nguyen; Nicholas C. DeVito, MD; and Balamayooran Theivanth, PhD, of the Duke Department of Medicine Division of Medical Oncology; Georgia Beasley, MD, in the Duke Department of Surgery; and Alisha Holtzhausen, PhD, of UNC-Chapel Hill School of Medicine.
Cracking the Code: Charlotte Patient Benefits from DCI Precision Cancer Medicine Research
Charlotte-area resident Vickie Johnson, 72, was diagnosed with colon cancer in 2018 after seeking care twice for abdominal pain. First, she was diagnosed with appendicitis and had her appendix out. Then, when her pain persisted beyond the recovery period, she received a new diagnosis. A scan at the ER showed a possible tumor. She went back to her appendix surgeon, had the mass in her colon removed, and was referred to a hospital oncologist. He referred her to a second surgeon who performed an even more aggressive surgery to remove all the remaining cancer in her colon and got her started on chemotherapy.Unfortunately, after each chemotherapy infusion she experienced severe chest pain. As she described it, “terrible spasms like I was having a heart attack.” Her oncologist didn’t have a plan b. “Finally, he said ‘I'm sorry, there's nothing I can do. We'll just test your blood every so often and get a scan every six months,’” Johnson shared. She wasn’t ready to give up, and as it turned out she didn’t need to.Johnson’s next area oncologist — Justin Favaro, MD, PhD — who'd done his medical training at Duke, brought a cardio-oncologist onboard the care team. The two providers tweaked the chemotherapy regimen she’d been on with the first oncologist; adjusting the dosage so her heart would be able to tolerate it. That worked, but successive treatments didn’t make any headway against her cancer.Johnson had begun 2019 in treatment for newly diagnosed colon cancer and ended that year with the death of her husband and progression of her cancer. During 2020, she’d endured another chemotherapy regimen but with no success. Cancer metastases remained in her liver and her lungs.Patients with metastatic colorectal cancer who have progressed on standard chemotherapy receive limited benefit from the available standard of care options. Johnson had genomic testing done and it turned out her cancer was hardwired with a KRAS G12C mutation, an alteration found in 3 to 4% of all metastatic colorectal cancer cases. Favaro said there was one more option.In the summer of 2021, he referred Johnson for enrollment in CodeBreaK 101, an early-stage clinical trial (phase 1b/2) at Duke Cancer Institute testing a new approach to treating KRAS G12C-mutated solid tumor cancers — a new KRAS G12C inhibitor drug (sotorasib) in combination with other anti-cancer therapies of choice, including FDA-approved antibodies, immunotherapy, and chemotherapy drugs. DCI was one of the first institutions worldwide to open this trial, which had launched in December 2019.Duke Cancer Institute GI medical oncologist and Associate Professor of Medicine John Strickler, MD, was Duke site principal investigator. Strickler is a colon cancer specialist who co-leads the DCI Precision Cancer Medicine and Investigational Therapeutics Research Program and the Molecular Tumor Board.Johnson said she had “no hesitation” about her decision and was grateful when she qualified for recruitment to the study under the care of Strickler.“This was the option. Nothing else was working,” Johnson recalled.