Abstract 2468: Phase II study of cryoablation and post-progression immune checkpoint inhibition in metastatic melanoma
Authors: Mooradian Meghan J. , Fintelmann Florian J. , LaSalle Thomas J. , Simon Judit , Graur Alexander , Muzikansky Alona , Mino-Kenudson Mari , Shalhout Sophia , Kaufman Howard L. , Jenkins Russell W. , Lawrence Donald , Lawless Aleigha , Sharova Tatyana , Uppot Raul N. , Fang Jacy , Blaum Emily M. , Gonye Anna L. , Gushterova Irena , Boland Genevieve M. , Hacohen Nir , Sade-Feldman Moshe , Sullivan Ryan J. 
Published: March 2024

Abstract
Introduction: Efforts to overcome resistance to immune checkpoint inhibition (ICI) are paramount, and novel combination strategies are in development. Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment that has demonstrated immune modulatory effects. We hypothesized that cryoablation may prime the tumor microenvironment (TME) through direct modulation of the tumor, thereby generating an anti-tumor response in ICI refractory tumors.
Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoint was safety and feasibility, with objective response rate (ORR) and disease control rate (DCR) in non-ablated lesions a key secondary endpoint. To better understand the inflammatory state of TME as well as factors determining response to cryoablation, we performed immunohistochemistry (PD-L1, CD8+ TIL) as well as single-cell RNA-sequencing (ScRNAseq) on evaluable pre- and post-cryoablation biopsies obtained from metastatic sites of 15 patients.
Results: From May 2018 through July 2020, 17 patients were treated. This regimen was feasible with all patients ongoing cryoablation with no unexpected safety signal. The ORR and DCR was 23.5% (95% CI 6.81-49.9) and 41.2% (95% CI 18.44-67.08), respectively, with four patients experiencing PR and three patients SD. Durable control, defined as tumor control ≥6 months, was achieved in 35%. Median progression-free survival (PFS) was 59 days (95% CI 42, 179) with a 6-month PFS rate of 23.5% (95% CI 7.3%, 44.9%). Median overall survival (OS) was 387 days (95% CI 106, 608) with a 1-year OS rate of 53% (95% CI (27.6%, 73%). Correlative analysis demonstrated pre-ablation tumors were uniformly associated with a “cold” TME, as all samples were PD-L1 negative and the majority had low levels of CD8+ TIL, defined as ˂5% of tumor cells associated with CD8+ TILs. ScRNAseq revealed no clear trends of cell type composition to predict best response to cryoablation, however an increase in B/plasma cells was seen in patients with disease control, suggesting these cells may play a role in mounting a durable anti-tumor response after cryoablation.
Conclusion: The anti-tumor efficacy of combining cryoablation and post-progression ICI was superior to what would be expected with the use of post-progression ICI alone with an acceptable safety profile. Our data support further study of this novel, synergistic therapeutic approach.
Citation Format: Meghan J. Mooradian, Florian J. Fintelmann, Thomas J. LaSalle, Judit Simon, Alexander Graur, Alona Muzikansky, Mari Mino-Kenudson, Sophia Shalhout, Howard L. Kaufman, Russell W. Jenkins, Donald Lawrence, Aleigha Lawless, Tatyana Sharova, Raul N. Uppot, Jacy Fang, Emily M. Blaum, Anna L. Gonye, Irena Gushterova, Genevieve M. Boland, Nir Hacohen, Moshe Sade-Feldman, Ryan J. Sullivan. Phase II study of cryoablation and post-progression immune checkpoint inhibition in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2468.