Tag: Cancer Immunotherapy

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  • Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

    Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

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    Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

    The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these “liquid biopsies” can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system’s defense to recognize and fight cancer. 

    “We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., senior co-author of the study and associate professor of oncology and director of the thoracic oncology biorepository at Johns Hopkins.

    Anagnostou is also leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” she says.

    The findings, reported in a paper published March 19 in Nature Medicine, emerged from a clinical trial examining the safety and efficacy of two immunotherapy drugs -; nivolumab and relatlimab -;as part of pre-operative treatment for patients with operable esophageal and gastroesophageal junction cancer.

    Patients with gastroesophageal cancer who have successfully completed the standard treatment of chemoradiotherapy followed by surgery unfortunately often see a resurgence of the disease. Therefore, researchers are looking for new immunotherapy approaches, as well as more accurate ways to assess tumors’ response to treatment.

    Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer. By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients.”


    Vincent Lam, M.D., senior study co-author, director of the Esophageal Cancer Research Program and an assistant professor of oncology at Johns Hopkins

    The trial included 32 patients with operable esophageal or gastroesophageal junction cancer, who received nivolumab either alone or in combination with relatlimab prior to and during their standard treatment of chemotherapy and radiation. The drugs tested are both immune checkpoint inhibitors, which prevent cancer cells from dampening the body’s anti-cancer immune response. Researchers used liquid biopsies -; tests that monitor trace levels of tumor DNA shed into the bloodstream -;at different timepoints during treatment. They also measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses.

    About 40% of those in the nivolumab arm and 21.4% in the combination arm had a pathological complete response, meaning there was no evidence of cancer at the time of surgery. Over half of patients in both arms had a major pathological response, meaning less than 10% of cancer cells were remaining at the time of surgery.

    “Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after two years,” Lam says. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after two years. Notably, patients with undetectable ctDNA at different timepoints following immunotherapy had significantly longer cancer-free survival.” 

    The findings “open the door for more personalized treatment,” says lead study author Ronan Kelly, M.D., M.B.A., chief of oncology at Baylor Scott & White Health – North Texas. Kelly was at Johns Hopkins at the time of the study. “We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol,” he says. “If we see ctDNA is still there, and they don’t have robust T cell response, these are the patients who may benefit most from additional treatment.”

    The study adds to a growing collection of evidence showing the value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For example, another recent study from Anagnostou’s lab, along with a ctDNA-adaptive clinical trial led by Johns Hopkins investigators, showed that ctDNA clearance can predict the success of immunotherapy treatment in patients with advanced lung cancer.

    “You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum,” says Anagnostou. “We think it’s the future.”

    Additional study co-authors were Blair Landon, Dipika Singh, Jenna Canzoniero, Archana Balan, Russell Hales, K Ranh Voong, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Kristen Marrone, Gavin Pereira, Nisha Rao, Aryan Borole, Katerina Karaindrou, Zineb Belcaid, James White, Suqi Ke, Eun Ji Shin, Elizabeth Thompson, Kellie Smith, Chen Hu and Josephine Feliciano of Johns Hopkins. Experts from the Allegheny Health Network Cancer Institute also contributed to the work.

    The study was supported by Bristol Myers Squibb. Translational work was supported in part by the National Institutes of Health (grants CA121113, R37 CA251447), the Cancer Research Institute, Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award.

    Source:

    Journal reference:

    Kelly, R. J., et al. (2024). Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine. doi.org/10.1038/s41591-024-02877-z.

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  • New immunotherapy borrows cancer’s tricks to unleash powerful T cells

    New immunotherapy borrows cancer’s tricks to unleash powerful T cells

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    Immunotherapies using engineered T cells have ushered in a new era in cancer treatment, but they have their limits. They may cause side effects or stop working, and they do not work at all against 90% of cancers. 

    Now, scientists at UC San Francisco and Northwestern Medicine may have found a way around these limitations by borrowing a few tricks from cancer itself. 

    By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potentcy to engineered T cells. The team inserted a gene for this unique mutation into normal human T cells, which made them more than 100 times more potent at killing cancer cells. They kept the tumors at bay for many months, showing no signs of becoming toxic.

    While current immunotherapies work only against cancers of the blood and bone marrow, the new approach was able to kill solid tumors derived from skin, lung and stomach tissues in mice. The team has already begun working toward testing this new approach in people.

    The breakthrough was inspired by the martial arts principle of using an opponent’s strength against them, said Kole Roybal, PhD, a co-author of the study and associate professor in microbiology and immunology. 

    We’ve used the mutations that give cancer cells their staying power to engineer what we call a ‘Judo T-cell therapy’ that can survive and thrive in the harsh conditions that tumors create.” 


    Kole Roybal, PhD, co-author of the study and associate professor in microbiology and immunology

    The study appears Feb. 7 in Nature

    A solution hiding in plain sight

    Immunology has proved difficult against most cancers because a solid tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit. Often, cancerous tumors hijack the body’s immune system, causing it to defend, rather than attack, the cancer. 

    Not only does this impair the ability of regular T cells to target cancer cells, it also undermines the effectiveness of engineered T cells that are used in immunotherapies, which quickly tire against the tumor’s defenses. For immunotherapy treatments to work under those conditions, “We need to give healthy T cells abilities that are beyond what they can naturally achieve,” said Roybal, who is also a member of the Gladstone Institute of Genomic Immunology. 

    Using such T cells from patients with lymphoma, the UCSF and Northwestern teams screened 71 mutations, eventually isolating one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.

    “This approach performs better than anything we’ve seen before,” said Jaehyuk Choi, MD, PhD, an associate professor of medical dermatology, as well as biochemistry and molecular genetics, at Northwestern University Feinberg School of Medicine. 

    “Our discoveries empower T cells to kill multiple cancer types and have the potential to offer cures to people who have a poor prognosis,” he said, noting that because cell therapies live and grow inside the patient, they can provide long-term immunity against cancer.

    In collaboration with the Parker Institute for Cancer Immunotherapy and venture capital firm Venrock, Roybal and Choi have launched a new company, Moonlight Bio, to realize the potential of their “judo” approach. Their first project is developing a lung cancer therapy that they hope to begin testing in people within the next few years.

    “We see this as the starting point,” Roybal said. “There’s so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases.”

    Source:

    Journal reference:

    Garcia, J., et al. (2024). Naturally occurring T cell mutations enhance engineered T cell therapies. Nature. doi.org/10.1038/s41586-024-07018-7.

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