Peter Edward Fecci

Laser interstitial thermal therapy (LITT) is a local surgical treatment for brain metastases (BM). Here, we present and discuss the main radiologic findings and challenges related to LITT-treated BM. Prior to LITT, imaging features are useful for prognostic stratification and patient selection, as well as treatment planning. During the LITT session, intra-procedural imaging is acquired immediately at the beginning of the procedure for tumor delineation, during the ablation to monitor treatment using MR thermometry, and immediately post-LITT to evaluate the ablated region. Images obtained during the LITT procedure are useful to estimate the extent of ablation, either by analyzing the real-time thermometry data or by comparing pre- and post-ablation images. In the months following LITT, follow-up scans exhibit characteristic imaging patterns for responding versus progressing lesions, which should be accounted for during post-LITT surveillance. In light of these patterns, and considering the strategies adopted by previous LITT studies, we propose dedicated criteria for local radiologic response and local radiologic progression in clinical trials, by adapting the RANO-BM criteria for local therapies to a “dual baseline” framework dedicated to LITT-treated BM. Finally, we provide suggestions for the adoption of standardized post-LITT imaging protocols based on the current consensus.

Radiation necrosis (RN) remains a challenging complication of upfront radiotherapy for both brain metastases and primary tumors. Despite the development of an array of advanced imaging modalities to differentiate RN from true tumor progression, tissue diagnosis remains the gold standard. Synergizing artificial intelligence to assist with imaging and intraoperative pathologic diagnosis may represent a fruitful future direction. Similarly, laser interstitial thermal therapy is an attractive alternative for RN management when the costs and complications of chronic steroids or bevacizumab are considered. Current evidence suggests that an angio-inflammatory cascade is responsible for RN development; tissue-based studies and preclinical modeling are needed to reveal targetable causal mechanisms that may support clinical risk stratification and treatment.

Pathways of interest were defined from a custom GMT file based on signatures taken from the mouse NanoString nCounter Immune Exhaustion Panel

Bulk RNA sequencing log2 fold change and adjusted p-values between WT and KO samples per gene.

Purpose:Exhaustion represents a collection of programmed T-cell differentiation states and an important mode of T-cell dysfunction. T-cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor thymocyte selection–associated HMG box (TOX). Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete.Experimental Design:Single-cell RNA sequencing was used to evaluate the expression of TNF receptors on human and murine tumor-infiltrating CD8+ T cells. Flow cytometry was utilized to assess exhaustion markers and TNF receptors on CD8+ T cells. Bulk RNA sequencing was used to demonstrate the role of TNFR2 on the overall exhaustion profile. Finally, the effect of TNFR2 on the overall antitumor response was established using TNFR2-knockout (KO) mice and an antagonist.Results:We reveal that upregulation of TNFR2 coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Loss of TNFR2 affords a novel population of T cells that expresses TIM3 but possesses diminished TOX levels and contains functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2-KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2-KO mice demonstrate improved T cell–dependent control of tumor and chronic lymphocytic choriomeningitis infection, whereas pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models.Conclusions:Our data place TNFR2 signaling as a potential upstream regulator of TOX expression in T cells and propose TNFR2 antagonism as a novel immunotherapeutic strategy.

Median time to humane endpoint for subcutaneous (sc) implantation of E0771 and CT2A-Trp2 or intracranial (ic) implantation of CT2A-Trp2 or CT2A. Median survival was not reached in the aTNFR2/aPD1 combination group following intracranial CT2A-Trp2 as 12 out of 20 survived long-term (more than 60 days) and intracranial CT2A (6/10 survived).

Background: Stereotactic radiosurgery (SRS) remains the standard of care for brain metastases (BM), offering effective local control with fewer neurocognitive side effects. However, distinguishing radiation necrosis (RN) from local recurrence (LR) is challenging in lesions that enlarge post-SRS. Identifying clinical and treatment-related factors associated with RN vs LR may improve decision-making. Prior smaller studies have suggested time to progression may help differentiate RN from LR; we aimed to reassess this observation and explore other factors in a larger cohort. Methods: We retrospectively analyzed patients treated with SRS for BM between 2011 and 2022 who later underwent biopsy, with or without LITT, for imaging-suspected RN vs LR. Data included demographics, clinicopathologic characteristics, SRS-treatment parameters, and biopsy results. Results: Among the identified 145 patients with 151 progressive lesions, biopsy confirmed RN in 93 (61.6%) and LR in 58 (38.4%). A subset of lesions (n = 108) had complete dosimetric data. Median age at SRS was 62 years, with a median SRS-biopsy interval of 13 months. The median prescribed dose was 20 Gy for single-fraction and 27.5 Gy for hypofractionated regimens. Multivariable models identified age ≥65 and SRS to biopsy interval ≥9 months as predictors of RN in the full cohort. In the subset group with detailed dosimetric data, V12Gy ≥ median (4.64 cm³) additionally predicted RN and improved model fit. Conclusion: We identified older age, a longer SRS to biopsy interval, and higher V12Gy as predictors of RN. Our predictive models incorporate these variables and may support clinical decision-making, improve diagnostic accuracy, and optimize patient outcomes.

Purpose: Exhaustion represents a collection of programmed T-cell differentiation states and an important mode of T-cell dysfunction. T-cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor thymocyte selection–associated HMG box (TOX). Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. Experimental Design: Single-cell RNA sequencing was used to evaluate the expression of TNF receptors on human and murine tumor-infiltrating CD8+ T cells. Flow cytometry was utilized to assess exhaustion markers and TNF receptors on CD8+ T cells. Bulk RNA sequencing was used to demonstrate the role of TNFR2 on the overall exhaustion profile. Finally, the effect of TNFR2 on the overall antitumor response was established using TNFR2-knockout (KO) mice and an antagonist. Results: We reveal that upregulation of TNFR2 coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Loss of TNFR2 affords a novel population of T cells that expresses TIM3 but possesses diminished TOX levels and contains functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2-KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2-KO mice demonstrate improved T cell–dependent control of tumor and chronic lymphocytic choriomeningitis infection, whereas pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models. Conclusions: Our data place TNFR2 signaling as a potential upstream regulator of TOX expression in T cells and propose TNFR2 antagonism as a novel immunotherapeutic strategy.

Supplemental Figure 2. Pre- and post-LITT images of patient gliomas