{
  "abstract": "Background Recurrent high-grade astrocytomas (rHGA), including IDH-wildtype glioblastoma and IDH-mutant WHO grade 3 and 4 tumors, have poor outcomes and limited treatment options. Immune checkpoint inhibitors (ICI) have shown minimal benefit, largely due to the restrictive blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME) that limit T-cell infiltration. Laser interstitial thermal therapy (LITT), a minimally invasive ablation technique, provides local cytoreduction and transiently disrupts the BBB and TME, potentially ‘heating up’ the cold TME to enhance ICI efficacy.Methods In this Phase 1/randomized Phase 2 trial ( NCT02311582), 54 patients with rHGA were enrolled: 9 in Phase 1 (WHO grade 3/4 tumors) and 45 in Phase 2 (grade 4 astrocytoma, including glioblastoma) at second or later recurrence, underscoring the advanced disease stage of this cohort. Phase 2 patients were initially randomized 1:1 to LITT followed by pembrolizumab (LITT+PEM) or non-LITT surgery (biopsy or resection) followed by pembrolizumab (NLS+PEM). After 21 patients, randomization was halted when emerging evidence indicated limited benefit from adjuvant ICI alone; the remaining 24 patients were then assigned to LITT+PEM. Primary endpoints were safety and recommended Phase 2 dose in Phase 1, and progression-free survival (PFS) in Phase 2. Secondary Phase 2 endpoints included overall survival (OS), response rate, and immunological mechanisms of response.Results In the 21-patient intent-to-treat cohort, LITT+PEM significantly improved survival versus NLS+PEM: median OS was 21.3 versus 6.7 months (HR 0.29; 95% CI, 0.01–0.88; p=0.021) with 54% versus 12.5% alive at 18 months (OS18), and median PFS was 7.8 versus 2.2 months (HR 0.30; 95% CI, 0.10–0.87; p=0.020). In the per-protocol cohort (n=39), LITT+PEM yielded median OS of 11.8 versus 5.2 months (HR 0.17; 95% CI, 0.06–0.49; p=0.0002) with 42% versus 0% OS18, and median PFS of 4.5 versus 1.6 months (HR 0.21; 95% CI, 0.08–0.56; p=0.0006). Among 34 GBM patients, LITT+PEM again outperformed NLS+PEM: median OS 11.1 versus 4.8 months (HR 0.16; 95% CI, 0.05–0.50; p=0.0003) and median PFS 3.9 versus 1.7 months (HR 0.29; 95% CI, 0.10–0.81; p=0.01). The combination was well tolerated. Immune profiling revealed that LITT triggers early activation of SLIT1 +/S100A8+/IL1R2+ non-classical monocytes — a cell population correlated with improved survival — while subsequent pembrolizumab unleashes robust CD8+ T cell proliferation and clonal expansion. Long-term LITT+PEM survivors developed coordinated memory T-cell responses, whereas shorter-surviving patients exhibited stagnant memory pools and exhausted phenotypes.Conclusions Together, these results demonstrate that LITT+PEM is safe, overcomes rHGA’s immunosuppressive barrier, and mobilizes robust anti-tumor immunity.Trial Registration The study’s ClinicalTrials.gov identifier number is NCT02311582Ethics Approval Human subject work was performed in accordance with an approved protocol by the respective internal review boards at the Washington University in St. Louis School of Medicine, the University of Florida College of Medicine, and the University of Southern California Keck School of Medicine, in accordance with the Declaration of Helsinki. An informed consent was obtained from each human participant before study procedures and analysis were performed. All enrollments were completed at Washington University and University of Florida. The correlative analysis was performed at the University of Southern California. The study’s ClinicalTrials.gov identifier number is NCT02311582.",
  "authors": [
    {
      "affiliations": [
        "University of Southern California Keck School of Medicine, Los Angeles, CA, USA"
      ],
      "name": "David D Tran"
    },
    {
      "affiliations": [
        "Mayo Clinic, Saint Louis, MO, USA"
      ],
      "name": "Jian L Campian"
    },
    {
      "affiliations": [
        "University of Southern California, Los Angeles, CA, USA"
      ],
      "name": "Son B Le"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Ashley Ghiaseddin"
    },
    {
      "affiliations": [
        "Washington University in Saint Louis, St. Louis, MO, USA"
      ],
      "name": "Omar H Butt"
    },
    {
      "affiliations": [
        "University of Southern California, Los Angeles, CA, USA"
      ],
      "name": "Harshit Manektalia"
    },
    {
      "affiliations": [
        "University of Southern California, Alhambra, CA, USA"
      ],
      "name": "Dongjiang Chen"
    },
    {
      "affiliations": [
        "University of Florida, Gainesville, FL, USA"
      ],
      "name": "Maryam Rahman"
    },
    {
      "affiliations": [
        "Washington University School of Medicine, St. Louis, MO, USA"
      ],
      "name": "Milan Chheda"
    },
    {
      "affiliations": [
        "Washington University in Saint Louis, St. Louis, MO, USA"
      ],
      "name": "Albert Kim"
    },
    {
      "affiliations": [
        "Washington University in Saint Louis, St. Louis, MO, USA"
      ],
      "name": "Eric Leuthardt"
    }
  ],
  "title": "490 Laser interstitial thermal therapy plus pembrolizumab extends survival and ignites anti-tumor immunity in recurrent high-grade astrocytoma: results from a phase 1/randomized phase 2b trial",
  "uid": "a925b19c-86ad-52c3-9a6f-9b429e2e9a1a"
}