Browsing by Author "Gadalla, Ramy"

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    The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity
    (Elsevier, 2022-12-13) Lukhele, Sabelo; Rabbo, Diala Abd; Guo, Mengdi; Shen, Jian; Elsaesser, Heidi J.; Quevedo, Rene; Carew, Madeleine; Gadalla, Ramy; Snell, Laura M.; Mahesh, Lawanya; Ciudad, M. Teresa; Snow, Bryan E.; You-Ten, Annick; Haight, Jillian; Wakeham, Andrew; Ohashi, Pamela S.; Mak, Tak W.; Cui, Weiguo; McGaha, Tracy L.; Brooks, David G.; Microbiology and Immunology, School of Medicine
    Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.
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    Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
    (BMJ, 2022-03) Lheureux, Stephanie; Matei, Daniela E.; Konstantinopoulos, Panagiotis A.; Wang, Ben X.; Gadalla, Ramy; Block, Matthew S.; Jewell, Andrea; Gaillard, Stephanie L.; McHale, Michael; McCourt, Carolyn; Temkin, Sarah; Girda, Eugenia; Backes, Floor J.; Werner, Theresa L.; Duska, Linda; Kehoe, Siobhan; Colombo, Ilaria; Wang, Lisa; Li, Xuan; Wildman, Rachel; Soleimani, Shirin; Lien, Scott; Wright, John; Pugh, Trevor; Ohashi, Pamela S.; Brooks, David G.; Fleming, Gini F.; Obstetrics and Gynecology, School of Medicine
    Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.