MD Anderson Research Highlights for March 29, 2023

HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Recent developments include microbiome-based biomarkers to predict CAR T cell therapy responses, novel predictive markers of immunotherapy response in gastric cancer, a new combination therapy for a rare salivary gland cancer, a promising treatment combination for high-risk myelodysplastic syndrome, a combination therapy to sensitize ovarian tumors to immunotherapy, and an artificial intelligence model for predicting neoadjuvant treatment response in triple-negative breast cancer.

Microbiome-based biomarkers may be used to predict to CAR T cell therapy response Chimeric antigen receptor (CAR) T cell therapy is a successful treatment option for many cancer patients, but evidence suggests that the gut microbiome may impact its efficacy. Broad-spectrum antibiotics given prior to CAR T cell therapy are necessary to prevent infection, but they also deplete beneficial gut microbes and are associated with poor treatment response as well as an increased risk of toxicities. To further understand this complicated relationship, researchers including Neeraj Saini, M.D., and Robert Jenq, M.D., examined German and U.S. cohorts of B-cell lymphoma patients receiving CAR T cell therapy. By investigating non-antibiotic-disrupted microbiomes, the researchers developed a machine-learning algorithm that can predict long-term response to CAR T therapy using microbiome-based biomarkers. These biomarkers could help in optimizing patient selection or tailoring follow-up treatment, potentially improving patient outcomes. Learn more in Nature Medicine. 

Immune biomarker may be linked with immunotherapy responses in gastric cancer
A specific subtype of gastric cancer — gastric signet ring cell carcinoma (GSRCC) — is associated with higher rates of metastasis and recurrence as well as resistance to immunotherapy. One major component affecting immune response is the tumor immune microenvironment (TIME), which is poorly understood in GSRCC. To characterize the TIME, researchers led by Han Liang, Ph.D., used single-cell transcriptomic and proteomic analysis of advanced GSRCC and non-GSRCC tumors. They found that exhausted CD8⁺ T cells and their product, CXCL13, play critical roles in shaping the TIME and may be predictive indicators of treatment response. The study found impairment of these T cells and resulting downstream effects might be responsible for the poor immune response seen in GSRCC, suggesting that targeting CXCL13 production could be a viable therapeutic strategy. Learn more in Gastroenterology.

Combination therapy shows potential as novel treatment for adenoid cystic carcinoma Most patients with adenoid cystic carcinoma (ACC), a rare salivary gland cancer, develop recurrent or metastatic (R/M) disease even with aggressive local therapy, leaving them with limited treatment options. While there is no standard of care for R/M ACC, therapies targeting VEGFR have increased T cell infiltration in lab models, and combination therapy with VEGFR and immune checkpoint inhibitors is effective in renal cell and endometrial carcinoma. Based on this, researchers led by Renata Ferrarotto, M.D., conducted a Phase II trial evaluating the combination of the VEGFR inhibitor axitinib plus the PD-L1 inhibitor avelumab in 28 patients with progressive R/M ACC. The study reached its primary endpoint of at least four partial responses, with an overall response rate of 18% in patients with incurable ACC. The combination had a manageable toxicity profile, meriting further evaluation of this combination therapy. Learn more in the Journal of Clinical Oncology. 

New therapy combination shows promise in patients with untreated high-risk MDS
A novel combination of therapies has demonstrated promising clinical efficacy in patients with untreated high-risk myelodysplastic syndrome (MDS), including those with TP53 mutations. In a Phase Ib study co-led by Naval Daver, M.D., 95 patients with previously untreated high-risk MDS were treated with magrolimab and azacitidine. Magrolimab is a monoclonal antibody that blocks a ‘don’t-eat-me’ signal overexpressed in cancer cells, while azacitidine increases ‘eat me’ signals, thus enhancing phagocytosis of tumor cells. The combination resulted in a complete response rate (CRR) and overall response rate of 33% and 75%, respectively, and the median overall survival (OS) had not yet been reached at a median follow-up of 17.1 months. For patients with TP53 mutations, the CRR was 40% and median OS was 16.3 months. Thirty-four participants were able to receive an allogenic stem-cell transplant, with 77% surviving for at least two years. The combination generally was well tolerated and currently is being evaluated in three ongoing randomized multinational Phase III trials in frontline higher-risk MDS and frontline acute myeloid leukemia. Learn more in the Journal of Clinical Oncology.

Combination therapy improves antitumor response in preclinical ovarian cancer models
Inactivation of tumor suppressor ARID1A occurs frequently in human cancers, including more than half of ovarian clear cell carcinomas. Seeking to make these genetically defined tumors more receptive to immunotherapy, researchers led by Rugang Zhang, Ph.D., showed that ARID1A inactivation sensitizes cells to statin-mediated inhibition of the mevalonate pathway, which is essential for cancer cell survival. Inhibiting the mevalonate pathway drives pyroptosis, a highly inflammatory form of cell death that leads to increased immune cell infiltration. Combining statins with checkpoint blockade suppressed tumor growth and boosted antitumor immunity, suggesting this combination could be translated to treat ARID1A-mutated cancer types by repurposing known drugs. Learn more in Cancer Cell.  

Neural network-based AI model may predict response to neoadjuvant therapy in TNBC
A pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC) is associated with improved outcomes, but only 30-65% of patients achieve a pCR with neoadjuvant chemotherapy. To better predict treatment responses, researchers led by Savitri Krishnamurthy, M.D., and Debu Tripathy, M.D., used an artificial intelligence (AI) model trained using 799 whole-slide images (WSI) of tissue from the National Institute of Health Cancer Genomic Atlas Breast Adenocarcinoma data set. The model used a multiscale convolutional neural network (CNN) extractor — a mathematical grid used for object recognition and classification — to learn variations in tumors. The researchers used this model on biopsies from patients with TNBC to predict response to neoadjuvant chemotherapy. The positive predictive value for patients who achieved pCR was 73.7% and the negative predictive value for patients who did not achieve pCR was 76.2%.This is the first time WSIs have been used to build CNN-based AI models for predicting response of TNBC, providing a potentially powerful tool to help optimize treatment selection. Learn more in JCO Clinical Cancer Informatics.

MD Anderson highlights from the Society of Gynecologic Oncology 2023 Annual Meeting
The Society of Gynecologic Oncology (SGO) 2023 Annual Meeting, held March 25-28 in Tampa, Fla., featured notable scientific plenary presentations from MD Anderson, including:

• NOW: Neoadjuvant Olaparib Window trial in patients with newly diagnosed BRCA mutant ovarian cancer, presented by Shannon Westin, M.D.
• Laparotomy versus minimally invasive surgery for interval debulking surgery among patients with advanced ovarian cancer, presented by Kirsten Jorgensen, M.D.
• SOLAR: Phase Ib dose expansion of Selumetinib (MEK inhibitor) and OLAparib (PARP inhibitor) combination in solid tumors with RAS pathway alterations and in PARP inhibitor-resistant ovarian cancer, presented by Shannon Westin, M.D.

 Recent awards and honors

• Sharon Dent, Ph.D., professor of Epigenetics and Molecular Carcinogenesis, was inducted into The Greater Houston Women’s Chamber of Commerce Hall of Fame.
• Kristy Brock, Ph.D., professor of Imaging Physics, David Jaffray, Ph.D., chief technology and digital officer, Betty Kim, M.D., Ph.D., professor of Neurosurgery, and Konstantin Sokolov, Ph.D., professor of Imaging Physics, were inducted into the 2023 class of the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows
• Michael Roth, M.D., associate professor of Pediatrics, was awarded the National Cancer Institute (NCI) Director’s Award as part of the NCI National Clinical Trials Network (NCTN) Adolescent & Young Adult Working Group

 In case you missed it
Read below to catch up on recent MD Anderson press releases.

• Florencia McAllister receives TAMEST Mary Beth Maddox Award for pancreatic tumor microbiome research
• Dual immunotherapy plus chemotherapy before surgery improves patient outcomes in operable lung cancer
• Kerin Adelson, M.D., named MD Anderson Chief Quality and Value Officer
• Targeting menin induces responses in acute leukemias with KMT2A rearrangements or NPM1 mutations

 

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