Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer.
Bensch Frederike,van der Veen Elly L,Lub-de Hooge Marjolijn N,Jorritsma-Smit Annelies,Boellaard Ronald,Kok Iris C,Oosting Sjoukje F,Schröder Carolina P,Hiltermann T Jeroen N,van der Wekken Anthonie J,Groen Harry J M,Kwee Thomas C,Elias Sjoerd G,Gietema Jourik A,Bohorquez Sandra Sanabria,de Crespigny Alex,Williams Simon-Peter,Mancao Christoph,Brouwers Adrienne H,Fine Bernard M,de Vries Elisabeth G E
Nature medicine
Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.
10.1038/s41591-018-0255-8
Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression.
Segovia Cristina,San José-Enériz Edurne,Munera-Maravilla Ester,Martínez-Fernández Mónica,Garate Leire,Miranda Estíbaliz,Vilas-Zornoza Amaia,Lodewijk Iris,Rubio Carolina,Segrelles Carmen,Valcárcel Luis Vitores,Rabal Obdulia,Casares Noelia,Bernardini Alejandra,Suarez-Cabrera Cristian,López-Calderón Fernando F,Fortes Puri,Casado José A,Dueñas Marta,Villacampa Felipe,Lasarte Juan José,Guerrero-Ramos Félix,de Velasco Guillermo,Oyarzabal Julen,Castellano Daniel,Agirre Xabier,Prósper Felipe,Paramio Jesús M
Nature medicine
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten; Trp53; Rb1; Rbl1) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
10.1038/s41591-019-0499-y
Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial.
Nature medicine
In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.
10.1038/s41591-021-01579-0