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Figure 6 from Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti–PD-1 Monotherapy: A Report from the International RRD Consortium

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posted on 2024-02-08, 08:20 authored by Anirban Das, Nicholas R. Fernandez, Adrian Levine, Vanessa Bianchi, Lucie K. Stengs, Jiil Chung, Logine Negm, Jose Rafael Dimayacyac, Yuan Chang, Liana Nobre, Ayse B. Ercan, Santiago Sanchez-Ramirez, Sumedha Sudhaman, Melissa Edwards, Valerie Larouche, David Samuel, An Van Damme, David Gass, David S. Ziegler, Stefan S. Bielack, Carl Koschmann, Shayna Zelcer, Michal Yalon-Oren, Gadi Abede Campino, Tomasz Sarosiek, Kim E. Nichols, Rebecca Loret De Mola, Kevin Bielamowicz, Magnus Sabel, Charlotta A. Frojd, Matthew D. Wood, Jason M. Glover, Yi-Yen Lee, Magimairajan Vanan, Jenny K. Adamski, Sebastien Perreault, Omar Chamdine, Magnus Aasved Hjort, Michal Zapotocky, Fernando Carceller, Erin Wright, Ivana Fedorakova, Alexander Lossos, Ryuma Tanaka, Michael Osborn, Deborah T. Blumenthal, Melyssa Aronson, Ute Bartels, Annie Huang, Vijay Ramaswamy, David Malkin, Adam Shlien, Anita Villani, Peter B. Dirks, Trevor J. Pugh, Gad Getz, Yosef E. Maruvka, Derek S. Tsang, Birgit Ertl-Wagner, Cynthia Hawkins, Eric Bouffet, Daniel A. Morgenstern, Uri Tabori

Delayed response after initial progression on continued anti–PD-1 monotherapy. A, Delayed response after initial progression on nivolumab monotherapy. B, Cyst decompression and biopsy at progression showed a more mitotically active and higher grade tumor with higher TMB and increased CD8 T-cell infiltration. C, Mutation overlap showed minimal overlap of the somatic mutational spectrum between the two time points (200X magnification; scale bars represent 50 µm). D, Normalized expression counts of immune markers before initiation and after progression on anti–PD-1 monotherapy using the NanoString platform (100X magnification, scale bars represent 100 µm; Methods).

Funding

Stand Up To Cancer (SU2C)

St. Baldrick's Foundation (SBF)

History

ARTICLE ABSTRACT

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti–PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS–MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology. Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity.This article is featured in Selected Articles from This Issue, p. 201