humble3d Posted September 27, 2020 Share Posted September 27, 2020 Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer and More... Nikolaos Zacharakis, Harshini Chinnasamy, Mary Black, Hui Xu, Yong-Chen Lu, Zhili Zheng, Anna Pasetto, Michelle Langhan, Thomas Shelton, Todd Prickett, Jared Gartner, Li Jia, Katarzyna Trebska-McGowan, Robert P. Somerville, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff & Steven A. Feldman Nature Medicine volume 24, pages724–730(2018)Cite this article 17k Accesses 194 Citations 2317 Altmetric Metrics details Abstract Immunotherapy using either checkpoint blockade or the adoptive transfer of antitumor lymphocytes has shown effectiveness in treating cancers with high levels of somatic mutations—such as melanoma, smoking-induced lung cancers and bladder cancer—with little effect in other common epithelial cancers that have lower mutation rates, such as those arising in the gastrointestinal tract, breast and ovary1,2,3,4,5,6,7. Adoptive transfer of autologous lymphocytes that specifically target proteins encoded by somatically mutated genes has mediated substantial objective clinical regressions in patients with metastatic bile duct, colon and cervical cancers8,9,10,11. We present a patient with chemorefractory hormone receptor (HR)-positive metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin (IL)-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer, which is now ongoing for >22 months, and it represents a new immunotherapy approach for the treatment of these patients. Access options References 1. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016). Article PubMed CAS Google Scholar 2. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014). Article PubMed CAS Google Scholar 3. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014). Article PubMed CAS Google Scholar 4. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013). Article PubMed PubMed Central CAS Google Scholar 5. Dawood, S. et al. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J. Clin. Oncol. 26, 4891–4898 (2008). Article PubMed PubMed Central Google Scholar 6. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017). Article PubMed PubMed Central CAS Google Scholar 7. Hamanishi, J. et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 33, 4015–4022 (2015). Article PubMed CAS Google Scholar 8. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015). Article PubMed CAS Google Scholar 9. Tran, E. et al. T cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016). Article PubMed PubMed Central CAS Google Scholar 10. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014). Article PubMed CAS Google Scholar 11. Stevanovic, S. et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017). Article PubMed CAS Google Scholar 12. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012). Article PubMed Google Scholar 13. Lefebvre, C. et al. Mutational profile of metastatic breast cancers: a retrospective analysis. PLoS Med. 13, e1002201 (2016). Article PubMed PubMed Central CAS Google Scholar 14. The Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors. Nature 490, 61–70 (2012). Article PubMed Central CAS Google Scholar 15. Dudley, M. E. et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J. Clin. Oncol. 26, 5233–5239 (2008). Article PubMed PubMed Central CAS Google Scholar 16. Abate-Daga, D. et al. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood 122, 1399–1410 (2013). Article PubMed PubMed Central CAS Google Scholar 17. Assadipour, Y. et al. Characterization of an immunogenic mutation in a patient with metastatic triple-negative breast cancer. Clin. Cancer Res. 23, 4347–4353 (2017). Article PubMed CAS Google Scholar 18. Jin, J. et al. Simplified method of the growth of human tumor-infiltrating lymphocytes (TIL) in gas-permeable flasks to numbers needed for patient treatment. J. Immunother. 35, 283–292 (2012). Article PubMed PubMed Central Google Scholar 19. Pasetto, A. et al. Tumor- and neoantigen-reactive T cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol. Res. 4, 734–743 (2016). Article PubMed PubMed Central CAS Google Scholar 20. Cohen, C. J., Zhao, Y., Zheng, Z., Rosenberg, S. A. & Morgan, R. A. Enhanced antitumor activity of murine–human hybrid T cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR–CD3 stability. Cancer Res. 66, 8878–8886 (2006). Article PubMed PubMed Central CAS Google Scholar 21. Haga-Friedman, A., Horovitz-Fried, M. & Cohen, C. J. Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity. J. Immunol. 188, 5538–5546 (2012). Article PubMed CAS Google Scholar 22. Aldrich, J. R. A. Fisher and the making of maximum likelihood. 1912–1922. Stat. Sci. 12, 162–176 (1997). Article Google Scholar Download references Acknowledgements The authors would like to thank A. Mixon and S. Farid of the Surgery Branch FACS Core for assistance with data acquisition and cell sorting, and J. Yang and E. Tran for their valuable discussions. This work was supported by the Center for Cancer Research at the National Cancer Institute (NCI) at the US National Institutes of Health (NIH). Author information Affiliations Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Nikolaos Zacharakis, Harshini Chinnasamy, Mary Black, Hui Xu, Yong-Chen Lu, Zhili Zheng, Anna Pasetto, Michelle Langhan, Thomas Shelton, Todd Prickett, Jared Gartner, Li Jia, Robert P. Somerville, Paul F. Robbins, Steven A. Rosenberg, Stephanie L. Goff & Steven A. Feldman Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA Katarzyna Trebska-McGowan Contributions N.Z. designed and performed the experiments, analyzed and interpreted the data, and co-wrote the manuscript; H.C., M.B. and H.X. performed experiments; Y.-C.L., Z.Z. and A.P. designed and performed experiments for single-cell PCR and sequencing for TCR identification and pairing; R.P.S., M.L. and T.S. maintained and developed clinical-grade lymphocytes for patient infusion; P.F.R., T.P., J.G. and L.J. performed and analyzed WES and RNA-seq data for mutation profiling; K.T.-M. (under the direction of S.L.G. and S.A.R.) was responsible for the clinical care of the patient during protocol treatment; S.A.R. conceived the hypothesis, interpreted the data and co-wrote the manuscript; S.L.G. and S.A.F. coordinated the project, analyzed and interpreted data and co-wrote the manuscript. Corresponding author Correspondence to Steven A. Rosenberg. Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information Supplementary Text and Figures Supplementary Tables 1–5 and Supplementary Figures 1–4 Reporting Summary Rights and permissions Reprints and Permissions About this article Verify currency and authenticity via CrossMark Cite this article Zacharakis, N., Chinnasamy, H., Black, M. et al. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat Med 24, 724–730 (2018). https://doi.org/10.1038/s41591-018-0040-8 Download citation Received15 November 2017 Accepted13 March 2018 Published04 June 2018 Issue DateJune 2018 DOIhttps://doi.org/10.1038/s41591-018-0040-8 Subjects Breast cancer Cancer Cancer immunotherapy Immunotherapy Translational research Further reading New emerging targets in cancer immunotherapy: the role of neoantigens Leticia De Mattos-Arruda, Juan Blanco-Heredia[…] & Julià Blanco ESMO Open (2020) The Cancer Immunotherapy Biomarker Testing Landscape Eric E. Walk, Sophia L. Yohe[…] & Anna B. Berry Archives of Pathology & Laboratory Medicine (2020) Clinicopathological factors associated with tumor-infiltrating lymphocyte reactivity in breast cancer Heejae Lee, Young-Ae Kim[…] & Hee Jin Lee Cancer Immunology, Immunotherapy (2020) Are cancer patients better off if they participate in clinical trials? A mixed methods study Zandra Engelbak Nielsen, Stefan Eriksson[…] & Tove E. Godskesen BMC Cancer (2020) Mutation position is an important determinant for predicting cancer neoantigens Aude-Hélène Capietto, Suchit Jhunjhunwala[…] & Lélia Delamarre Journal of Experimental Medicine (2020) SOURCE: https://www.nature.com/articles/s41591-018-0040-8 --MORE-- https://www.theguardian.com/science/2018/jun/04/doctors-hail-world-first-as-womans-advanced-breast-cancer-is-eradicated --MORE-- KILL CANCER IN HOURS Boffin ( SCIENTIST ) discovers light can be used to destroy tumours in just two hours He combined a single jab with ultraviolet light that causes cancerous cells to self destruct Just one treatment stopped tumours growing, doubling chances of survival A CANCER expert has hit on a way to kill tumours in two hours — using light. The technique involves a single jab with a chemical then a flash of ultraviolet. Cancer cells in lab mice were found to self-destruct, with up to 95 per cent dead in two hours. Professor Matthew Gdovin revealed the cells — which he injected with the chemical compound nitrobenzaldehyde — turned too acidic to survive. He said after patenting his “photodynamic” therapy: “There are many different types of cancers. “The one thing they have in common is their susceptibility to this induced cell suicide. “We are thinking outside the box and finding a way to do what for many is simply impossible.” Just one treatment stopped tumours growing, doubling chances of survival Just one treatment stopped tumours growing, doubling chances of survival... His lab tests showed amazing results against triple negative breast cancer — one of the most aggressive forms. Just one treatment stopped tumours growing, doubling chances of survival. Prof Gdovin, of the University of Texas at San Antonio, said that because the treatment is non- invasive it is ideal for hard to reach cancers such as in the spine or heart. SOURCE: https://www.thesun.co.uk/news/1385404/light-can-kill- cancer-in-just-two-hours/ UTSA researcher develops new, non-invasive method to wipe out cancerous tumors (June 27, 2016) -- Matthew Gdovin, an associate professor in the UTSA Department of Biology, has developed a newly patented method to kill cancer cells. His discovery, described in research published in The Journal of Clinical Oncology, may tremendously help people with inoperable or hard-to-reach tumors, as well as young children stricken with cancer. Gdovin’s top-tier research involves injecting a chemical compound, nitrobenzaldehyde, into the tumor and allowing it to diffuse into the tissue. He then aims a beam of light at the tissue, causing the cells to become very acidic inside and, essentially, commit suicide. Within two hours, Gdovin estimates up to 95 percent of the targeted cancer cells are dead. “Even though there are many different types of cancers, the one thing they have in common is their susceptibility to this induced cell suicide,” he said. Gdovin tested his method against triple negative breast cancer, one of the most aggressive types of cancer and one of the hardest to treat. The prognosis for triple negative breast cancer is usually very poor. After one treatment in the laboratory, he was able to stop the tumor from growing and double chances of survival in mice. “All forms of cancer attempt to make cells acidic on the outside as a way to attract the attention of a blood vessel, which attempts to get rid of the acid,” he said. “Instead, the cancer latches onto the blood vessel and uses it to make the tumor larger and larger.” Chemotherapy treatments target all cells in the body, and certain chemotherapeutics try to keep cancer cells acidic as a way to kill the cancer. This is what causes many cancer patients to lose their hair and become sickly. Gdovin’s method, however, is more precise and can target just the tumor. In the past two years, he’s developed his photodynamic cancer therapy to the point where it’s non-invasive. It now requires just an injection of the nitrobenzaldehyde fluid followed by a flash of an ultraviolet light to cause the cancer-killing reaction. Gdovin has now begun to test the method on drug-resistant cancer cells to make his therapy as strong as possible. He’s also started to develop a nanoparticle that can be injected into the body to target metastasized cancer cells. The nanoparticle is activated with a wavelength of light that it can pass harmlessly through skin, flesh and bone and still activate the the cancer-killing nanoparticle. Gdovin hopes that his non-invasive method will help cancer patients with tumors in areas that have proven problematic for surgeons, such as the brain stem, aorta or spine. It could also help people who have received the maximum amount of radiation treatment and can no longer cope with the scarring and pain that goes along with it, or children who are at risk of developing mutations from radiation as they grow older. “There are so many types of cancer for which the prognosis is very poor,” he said. “We’re thinking outside the box and finding a way to do what for many people is simply impossible.” By Joanna Carver Public Affairs Specialist Gdovin, Matthew J Title: ASSOCIATE PROFESSOR College: COLLEGE OF SCIENCE-DEAN Department: COS BIOLOGY Mailing Address: BIOLOGY - 01860 Building: BSB 1.03.26 Email: [email protected] Phone: (210) 458-5768 Original Press Release University of Texas at San Antonio Yea, though I walk through the valley of the shadow of death I shall fear no evil, because I am the meanest son-of-a-bitch in the valley. Many thanks... --MORE-- Researchers find method to regrow cartilage in the joints In laboratory studies, Stanford School of Medicine researchers have found a way to regenerate the cartilage that eases movement between bones. Researchers at the Stanford University School of Medicine have discovered a way to regenerate, in mice and human tissue, the cushion of cartilage found in joints. Loss of this slippery and shock-absorbing tissue layer, called articular cartilage, is responsible for many cases of joint pain and arthritis, which afflicts more than 55 million Americans. Nearly 1 in 4 adult Americans suffer from arthritis, and far more are burdened by joint pain and inflammation generally. The Stanford researchers figured out how to regrow articular cartilage by first causing slight injury to the joint tissue, then using chemical signals to steer the growth of skeletal stem cells as the injuries heal. The work was published Aug. 17 in the journal Nature Medicine. “Cartilage has practically zero regenerative potential in adulthood, so once it’s injured or gone, what we can do for patients has been very limited,” said assistant professor of surgery Charles K.F. Chan, PhD. “It’s extremely gratifying to find a way to help the body regrow this important tissue.” The work builds on previous research at Stanford that resulted in isolation of the skeletal stem cell, a self-renewing cell that is also responsible for the production of bone, cartilage and a special type of cell that helps blood cells develop in bone marrow. The new research, like previous discoveries of mouse and human skeletal stem cells, were mostly carried out in the laboratories of Chan and professor of surgery Michael Longaker, MD. Articular cartilage is a complex and specialized tissue that provides a slick and bouncy cushion between bones at the joints. When this cartilage is damaged by trauma, disease or simply thins with age, bones can rub directly against each other, causing pain and inflammation, which can eventually result in arthritis. Damaged cartilage can be treated through a technique called microfracture, in which tiny holes are drilled in the surface of a joint. The microfracture technique prompts the body to create new tissue in the joint, but the new tissue is not much like cartilage. “Microfracture results in what is called fibrocartilage, which is really more like scar tissue than natural cartilage,” said Chan. “It covers the bone and is better than nothing, but it doesn’t have the bounce and elasticity of natural cartilage, and it tends to degrade relatively quickly.” The most recent research arose, in part, through the work of surgeon Matthew Murphy, PhD, a visiting researcher at Stanford who is now at the University of Manchester. “I never felt anyone really understood how microfracture really worked,” Murphy said. “I realized the only way to understand the process was to look at what stem cells are doing after microfracture.” Murphy is the lead author on the paper. Chan and Longaker are co-senior authors. For a long time, Chan said, people assumed that adult cartilage did not regenerate after injury because the tissue did not have many skeletal stem cells that could be activated. Working in a mouse model, the team documented that microfracture did activate skeletal stem cells. Left to their own devices, however, those activated skeletal stem cells regenerated fibrocartilage in the joint. But what if the healing process after microfracture could be steered toward development of cartilage and away from fibrocartilage? The researchers knew that as bone develops, cells must first go through a cartilage stage before turning into bone. They had the idea that they might encourage the skeletal stem cells in the joint to start along a path toward becoming bone, but stop the process at the cartilage stage. The researchers used a powerful molecule called bone morphogenetic protein 2 (BMP2) to initiate bone formation after microfracture, but then stopped the process midway with a molecule that blocked another signaling molecule important in bone formation, called vascular endothelial growth factor (VEGF). “What we ended up with was cartilage that is made of the same sort of cells as natural cartilage with comparable mechanical properties, unlike the fibrocartilage that we usually get,” Chan said. “It also restored mobility to osteoarthritic mice and significantly reduced their pain.” As a proof of principle that this might also work in humans, the researchers transferred human tissue into mice that were bred to not reject the tissue, and were able to show that human skeletal stem cells could be steered toward bone development but stopped at the cartilage stage. The next stage of research is to conduct similar experiments in larger animals before starting human clinical trials. Murphy points out that because of the difficulty in working with very small mouse joints, there might be some improvements to the system they could make as they move into relatively larger joints. The first human clinical trials might be for people who have arthritis in their fingers and toes. “We might start with small joints, and if that works we would move up to larger joints like knees,” Murphy says. “Right now, one of the most common surgeries for arthritis in the fingers is to have the bone at the base of the thumb taken out. In such cases we might try this to save the joint, and if it doesn’t work we just take out the bone as we would have anyway. There’s a big potential for improvement, and the downside is that we would be back to where we were before.” Longaker points out that one advantage of their discovery is that the main components of a potential therapy are approved as safe and effective by the FDA. “BMP2 has already been approved for helping bone heal, and VEGF inhibitors are already used as anti-cancer therapies,” Longaker said. “This would help speed the approval of any therapy we develop.” Joint replacement surgery has revolutionized how doctors treat arthritis and is very common: By age 80, 1 in 10 people will have a hip replacement and 1 in 20 will have a knee replaced. But such joint replacement is extremely invasive, has a limited lifespan and is performed only after arthritis hits and patients endure lasting pain. The researchers say they can envision a time when people are able to avoid getting arthritis in the first place by rejuvenating their cartilage in their joints before it is badly degraded. “One idea is to follow a ‘Jiffy Lube’ model of cartilage replenishment,” Longaker said. “You don’t wait for damage to accumulate — you go in periodically and use this technique to boost your articular cartilage before you have a problem.” Longaker is the Deane P. and Louise Mitchell Professor in the School of Medicine and co-director of the Institute for Stem Cell Biology and Regenerative Medicine. Chan is a member of the Institute for Stem Cell Biology and Regenerative Medicine and Stanford Immunology. Other Stanford scientist taking part in the research were professor of pathology Irving Weissman, MD, the Virginia and D. K. Ludwig Professor in Clinical Investigation in Cancer Research; professor of surgery Stuart B. Goodman, MD, the Robert L. and Mary Ellenburg Professor in Surgery; associate professor of orthopaedic surgery Fan Yang, PhD; professor of surgery Derrick C. Wan, MD; instructor in orthopaedic surgery Xinming Tong, PhD; postdoctoral research fellow Thomas H. Ambrosi, PhD; visiting postdoctoral scholar Liming Zhao, MD; life science research professionals Lauren S. Koepke and Holly Steininger; MD/PhD student Gunsagar S. Gulati, PhD; graduate student Malachia Y. Hoover; former student Owen Marecic; former medical student Yuting Wang, MD; and scanning probe microscopy laboratory manager Marcin P. Walkiewicz, PhD. The research was supported by the National Institutes of Health (grants R00AG049958, R01 DE027323, R56 DE025597, R01 DE026730, R01 DE021683, R21 DE024230, U01HL099776, U24DE026914, R21 DE019274, NIGMS K08GM109105, NIH R01GM123069 and NIH1R01AR071379), the California Institute for Regenerative Medicine, the Oak Foundation, the Pitch Johnson Fund, the Gunn/Olivier Research Fund, the Stinehart/Reed Foundation, The Siebel Foundation, the Howard Hughes Medical Institute, the German Research Foundation, the PSRF National Endowment, National Center for Research Resources, the Prostate Cancer Research Foundation, the American Federation of Aging Research and the Arthritis National Research Foundation. SOURCE: http://med.stanford.edu/news/all-news/2020/08/Researchers-find-method-to-regrow-cartilage-in-the-joints.html?fbclid=IwAR38z9ygTVRe5ZMR5DABr2x9rDtj-UwgeA52xFCYA0oMjgheKh7jpbz3-u4 Link to comment Share on other sites More sharing options...
freeforever03 Posted September 28, 2020 Share Posted September 28, 2020 Fantastic article. It appears that we are making giant leaps in the area of cancer treatment and joint re[pair. Link to comment Share on other sites More sharing options...
Recommended Posts
Archived
This topic is now archived and is closed to further replies.