المؤلفون: Sanseviero, Emilio, Taylor, Devon, Tohumeken, Sehmus, Mai, Mimi, Mostafa, Ali, Milo, Marta, Mulgrew, Kathy, Barry, Simon, Fuchs, Serge, Cobbold, Mark, Gabrilovich, Dmitry

المصدر: Regular and Young Investigator Award Abstracts

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.0957Test

المؤلفون: Hardaker, Elizabeth L., Sanseviero, Emilio, Karmokar, Ankur, Taylor, Devon, Milo, Marta, Michaloglou, Chrysis, Hughes, Adina, Mai, Mimi, King, Matthew, Solanki, Anisha, Magiera, Lukasz, Miragaia, Ricardo, Kar, Gozde, Standifer, Nathan, Surace, Michael, Gill, Shaan, Peter, Alison, Talbot, Sara, Tohumeken, Sehmus, Fryer, Henderson

المصدر: Nature Communications; 2/24/2024, Vol. 15 Issue 1, p1-20, 20p

مصطلحات موضوعية: TUMOR microenvironment, IMMUNE checkpoint inhibitors, TYPE I interferons, MYELOID cells, ATAXIA telangiectasia, CYTOTOXIC T cells

مستخلص: The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8⁺ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8⁺ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models. [ABSTRACT FROM AUTHOR]

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المؤلفون: Dave, Hema, Terpilowski, Madeline, Mai, Mimi, Toner, Keri, Grant, Melanie, Stanojevic, Maja, Lazarski, Christopher, Shibli, Abeer, Bien, Stephanie A., Maglo, Philip, Hoq, Fahmida, Schore, Reuven, Glenn, Martha, Hu, Boyu, Hanley, Patrick J., Ambinder, Richard, Bollard, Catherine M.

المصدر: Blood Advances; January 2022, Vol. 6 Issue: 2 p473-485, 13p

مستخلص: Hodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-Ts when given alone or with nivolumab were safe and could elicit antitumor effects in vivo in patients with relapsed/refractory (r/r) HL. Ten patients were infused with TAA-Ts (8 autologous and 2 allogeneic) for active HL (n = 8) or as adjuvant therapy after hematopoietic stem cell transplant (n = 2). Six patients received nivolumab priming before TAA-Ts and continued until disease progression or unacceptable toxicity. All 10 products recognized 1 or more TAAs and were polyfunctional. Patients were monitored for safety for 6 weeks after the TAA-Ts and for response until disease progression. The infusions were safe with no clear dose-limiting toxicities. Patients receiving TAA-Ts as adjuvant therapy remain in continued remission at 3+ years. Of the 8 patients with active disease, 1 patient had a complete response and 7 had stable disease at 3 months, 3 of whom remain with stable disease at 1 year. Antigen spreading and long-term persistence of TAA-Ts in vivo were observed in responding patients. Nivolumab priming impacted TAA-T recognition and persistence. In conclusion, treatment of patients with r/r HL with TAA-Ts alone or in combination with nivolumab was safe and produced promising results. This trial was registered at www.clinicaltrials.gov as #NCT022039303 and #NCT03843294.

المؤلفون: Dave, Hema, Mai, Mimi, Datar, Anushree, Jenkins, Gaye, Pei, Qinglin, Wu, Yue, Keller, Frank G., Castellino, Sharon M., Horton, Terzah M, Bollard, Catherine M.

المصدر: Blood; November 2020, Vol. 136 Issue: 1, Number 1 Supplement 1 p41-42, 2p

مستخلص: Introduction:The role of the immune system and the microenvironment in Hodgkin Lymphoma (HL) has been well established. However, little is known about the effects of treatment on the immune cells in the peripheral blood or the frequency of tumor specific T cell responses to non-EBV HL specific antigens in pediatric and adolescent patients with HL. The goal of this project was to evaluate whether patients had increased tumor specific cytotoxic T cell responses and a pro-inflammatory cytokine milieu after treatment compared to at diagnosis.

المؤلفون: Dave, Hema, Mai, Mimi, Terpilowski, Madeline, Toner, Keri, Stanojevic, Maja, Galligan, Morgan, Shibli, Abeer, Grant, Melanie, Lazarski, Christopher, Maglo, Philip Y, Zhang, Nan, Tanna, Jay, Ambinder, Richard F., Glenn, Martha, Hanley, Patrick, Bollard, Catherine M.

المصدر: Blood; November 2020, Vol. 136 Issue: 1, Number 1 Supplement 1 p18-18, 1p

مستخلص: Background:Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors (Hont JCO 2019). Hence, we evaluated whether TAA-T cells are safe and elicit anti-tumor effects in patients with relapsed/refractory (rel/ref) HL. We further evaluated the safety of Nivolumab following the TAA-T infusion and its effect on the persistence of the TAA-T cells in vivo.