P16.07 Immuno-Modulatory Effects of Ceralasertib in Combination with Durvalumab in NSCLC with Progression on Anti-PD(L)1 Treatment (HUDSON)

Hernández, Maurenis; Besse, Benjamin; Awad, Mark M.; Forde, Patrick M.; Thomas, Mark G.; Park, K.; Goss, G.; Rizvi, Naiyer A.; Cosaert, Jan; Szűcs, Zoltán; Mortimer, Peter G.; Hobson, R.; Ambrose, Helen; Hayward, C.; Dressman, M.; Dean, E; Coenen-Stass, Anna M.L.; Barrett, Carl; Heymach, John V.; Sachsenmeier, Kris F.

doi:10.1016/j.jtho.2021.01.553

Cited by 3 publications

(2 citation statements)

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“…Consistent with these findings, similar reduction and recovery dynamics of T-cells were observed in advanced NSCLC patients treated with ceralasertib plus durvalumab in HUDSON trial 13 , 16 , 17 . To further characterize the mechanisms of action of ATR inhibition on T-cells, in vitro analysis was performed on CD3/CD28 stimulated, proliferating T-cells isolated from the peripheral bloods of healthy individuals.…”

Section: Resultssupporting

confidence: 80%

“…Until recently, the role of therapeutics targeting the DNA damage response such as PARP, ATR, DNA-PK and ATM for cancer treatment has largely focused on the tumor cells. Pre-clinically, the role of ATRi via direct targeting of tumors (predominantly in model systems without an immune component) with DDR-defects, oncogene induced replication stress, or in combination with chemotherapy, radiation, or PARP inhibitors have been well documented 1 , 2 , 10 , 11 , 16 , 17 . Here, we show that the ATRi ceralasertib has potential to deliver a broad and profound impact in the TIME promoting T-cell activity, and influencing the number and function of myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

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The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment

Hardaker,

Sanseviero,

Karmokar

et al. 2024

Nat Commun

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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.

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Section: Resultssupporting

confidence: 80%