Safety and pathologic response of neoadjuvant pulsed electric field ablation and systemic therapy in early-stage resectable lung cancer: case series

Abstract

The VIGOR study was designed to evaluate the pathologic response of soft tissue ablated with pulsed electric fields (PEFs) in non-small cell lung cancer (NSCLC) patients who are candidates for surgical resection following standard of care (SOC) neoadjuvant use of checkpoint inhibitor treatment plus platinum doublet chemotherapy (NCT05583188). The safety of adding PEF to this pathway of care was also evaluated. The primary endpoint was the pathologic response. Secondary endpoints included the rate of R0 (complete) resection, as well as the frequency, duration, and causes of any surgery cancellations or delays. Exploratory endpoints included the profiling of circulating immunocytes post ablation by flow cytometry. The study enrolled 5 patients and PEF energy was successfully delivered to targeted lesions in the lung. No issues were observed when accessing the tumor for delivery of PEF energy, and no device-related serious adverse events (SAEs) were observed. All patients initiated neoadjuvant therapy as planned. Four of five patients underwent surgical resection. Pathological assessment was performed on resected tumors and revealed that out of the four surgical patients three were pathologic complete response (pCR) and one had major pathologic response (MPR). In summary, this study supports the safety and feasibility of PEF ablation in NSCLC patients prior to neoadjuvant treatment with immune checkpoint blockade plus platinum doublet chemotherapy and planned surgical resection.

Neoadjuvant chemotherapy with or without immunotherapy has emerged as a standard treatment approach for selected patients with resectable non-small cell lung cancer (NSCLC), with the greatest benefit observed in patients with PD-L1-expressing tumors, enhancing antitumor immunity and targeting micrometastatic disease. The Phase III CheckMate-816 trial demonstrated that nivolumab plus platinum-based chemotherapy improved pathologic complete response (pCR: 24% vs. 2.2%) and event-free survival (EFS: 31.6 vs. 19.0 months) compared to chemotherapy alone, particularly in stage IIIA disease (1-3). Beyond systemic therapy, local tumor ablation techniques that preserve antigenic integrity may further enhance antitumor immunity. The Aliya^® Pulsed Electric Fields (PEF) system is a minimally invasive ablation approach that delivers electric pulses through a single monopolar needle. Preclinical (4) and clinical (5-7) evidence with this form of ablation indicates it may also produce an immunostimulatory post-ablative tumor microenvironment. We hypothesized that giving the ablation before neoadjuvant chemo-immunotherapy would augment immune responses and improve pathologic response. The study was conducted in accordance with the ISO 14155:2020, ICH-GCP (E6), and Declaration of Helsinki and its subsequent amendments. The study was approved by the WCG Institutional Review Board (No. 202224904). All participating hospitals were informed of and agreed to the study. All patients provided written informed consent. Herein, we report safety, pathologic response, and exploratory immune data from the VIGOR study (NCT05583188; https://clinicaltrials.gov/study/NCT05583188?term=NCT05583188&viewType=Card&rank=1), a prospective, single-arm, multi-center (Mayo Clinic, Rochester, University of Pennsylvania, and Temple University) treat-and-resect study for adult patients with stage IIB–IIIA NSCLC. Tumors were ablated prior to standard of care (SOC) neoadjuvant nivolumab plus platinum doublet chemotherapy, and surgery (Figure 1A, Figure S1). We present this article in accordance with the TREND and AME Case Series reporting checklists (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0299/rc).

Figure 1.

Treatment schema and representative CT imaging prior to Aliya PEF and prior to surgical resection. (A) Study design and treatment timeline. Day 0 included CT imaging, diagnostic biopsy, and Aliya PEF ablation. Blood samples were collected at baseline and post-PEF (days 3 and 10). Neoadjuvant nivolumab plus platinum-doublet chemotherapy was administered every 3 weeks for three cycles, followed by pre-resection imaging, surgical resection (~week 14), and post-resection follow-up (~week 18). Blood samples were also collected at each SOC visit, immediately prior to administration of neoadjuvant therapy. (B) (Left panel) Baseline CT scan of a 3.2 cm × 2.8 cm nodule (yellow arrow) in the left upper lobe from patient V02 (NSCLC squamous cell carcinoma). Eight activations were delivered to the target lesion via percutaneous access. (Right panel) Pre-resection CT scan of the ablated nodule captured approximately 12 weeks post-ablation demonstrated the residual tumor bed (0.9 cm × 0.7 cm, yellow arrow). The lesion was surgically removed by a minimally invasive lobectomy as originally planned and was subsequently determined via histopathological assessment to be a pathologic complete response with no remaining viable tumor cells. CT, computed tomography; NSCLC, non-small cell lung cancer; PEF, pulsed electric field; Rx, resection; SOC, standard of care.

Adult patients with untreated suspected or confirmed NSCLC stage IIB–IIIA who were surgical candidates were enrolled. SOC biopsies were conducted for pathological confirmation of NSCLC (8), and to establish the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutation status. SOC neoadjuvant systemic treatment was delivered according to tumor histology and after confirming negative EGFR and ALK mutation status.

The primary endpoint was pathologic response (percentage of residual viable tumor) of the resected ablated lesion and lymph nodes. Secondary clinical endpoints included the rate of R0 resection and frequency of surgery cancellation or delay. The safety endpoints were the rate of device-related, PEF procedure-related, and other serious adverse events (SAEs).

The Aliya Generator and Aliya Ablation Device (Galvanize Therapeutics Inc., Redwood City, CA, USA) are FDA 510(k) cleared (K212871) for surgical ablation of soft tissue. The energy was delivered percutaneously (Figure 1B) in a single anesthetic session with a 50% ablation coverage goal to balance unablated tumor preservation with the ability to assess the effects of ablation in combination with neoadjuvant therapy. Pre-procedural planning was performed taking into account the targeted lesion size and the ablation zone before the initiation of the procedure in order to determine the percentage of the ablation coverage. Additional technical information on histopathology, systemic therapy administration, and immunophenotyping is provided in Appendix 1.

Patient demographics and procedural characteristics of the five ablated patients are presented in Table 1. All patients had confirmed NSCLC stage IIB–IIIA with malignant lymph nodes. All patients were discharged post-procedure (on the same day as, or the day following the procedure), except in one case where the patient developed a pneumothorax deemed related to the percutaneous ablation procedure, which required 9-day hospitalization but resolved without sequelae.

Table 1. Demographics, baseline, procedural characteristics and surgical approach.

Variables	Values
Median age (years) at consent [range]	64.8 [60–72]
Sex
Female	4
Male	1
Malignancy designation prior to PEF ablation
NSCLC adenocarcinoma	4
NSCLC squamous cell carcinoma	1
Ablated lesion location
RUL	2
LUL	3
Total lesions ablated with PEF	5
Mean ablated lesion size-longest diameter ± SD (range) (cm)	2.0±0.8 (1.0–3.2)
PEF ablation procedural access
Percutaneous	5
Anesthesia
General	3
Conscious sedation	2
Number of patients with surgical resection†	4
Surgical approach
Minimally invasive	2
Thoracotomy	2
Surgical procedure
Lobectomy	3
Bilobectomy	0
Pneumonectomy	1
Number of patients with surgical approach as planned‡	3
Number of days between ablation and surgery (mean ± SD)	103.8±19.6

Data are presented as n unless otherwise specified. ^†, 1 patient discontinued neoadjuvant treatment and did not undergo surgical resection of the ablated lesion due to ongoing debility and intolerance of neoadjuvant drug treatment. ^‡, one patient underwent lobectomy instead of pneumonectomy and the reason for the change was not provided. LUL, left upper lobe; NSCLC, non-small cell lung cancer; PEF, pulsed electric field; RUL, right upper lobe; SD, standard deviation.

Three of five patients received neoadjuvant nivolumab plus pemetrexed/carboplatin, and 2 received nivolumab plus paclitaxel/carboplatin (Table S1). Three patients completed the 3 cycles planned and two discontinuations were recorded; one because of neoadjuvant drug toxicity (pneumonitis, nephritis, and hepatitis) and one because of ongoing debility with intolerance of neoadjuvant drug treatment. The latter did not undergo surgical resection for the same reasons.

All four surgical patients had an R0 resection (all margins noted as negative for invasive tumor). Two surgeries were delayed due to factors unrelated to the ablation (one due to continued smoking, one due to surgical availability), and one was cancelled as noted above. All surgeries proceeded as planned, except one that was downstaged from pneumonectomy to a parenchymal-sparing lobectomy (Table 1, Table S2).

Adverse events (AEs) deemed possibly, probably, or definitely related to the study device, study procedures, or neoadjuvant therapy are summarized in Tables S2,S3. Overall, one SAE (pneumothorax Grade 2) and three Grade 1 AEs (2 hemoptysis, 1 pneumothorax) were considered related to the procedure or device, and are known/anticipated risks associated with percutaneous ablation procedures/device use. AEs deemed related to the neoadjuvant therapy were known/anticipated risks associated with the systemic therapy per product labeling.

Pathologic assessment of the resected specimens demonstrated a pCR in 3 of the 4 patients, with no residual viable tumor detected, per the site-directed pathological evaluation and as confirmed by the independent pathologist. The remaining patient achieved a major pathologic response (MPR) with 8% residual viable tumor.

The extent of fibrosis/stroma and necrosis is summarized in Table 2. Representative images are presented in Figure 2A. Additionally, no viable tumor was identified by site pathologists in any of the sampled lymph nodes in all patients, including those designated by the site as sentinel lymph nodes (3 patients). Mild-to-moderate lymphocyte infiltration was observed in the remaining tumor bed, and the presence of tertiary lymphoid structures (TLS) was also evident in all resected samples, including TLS with germinal centers (GCs) in one tumor (Figure 2B).

Table 2. Site-independent pathologic response evaluation.

Patient ID	Pathologic response	Histological sample type	Viable tumor (%)	Necrosis (%)	Stroma (%)	Overall pathologic response	Grade of inflammation
V01	MPR	PEF-ablated tumor (s1)	0	0	100	8% residual viable tumor, 92% fibrosis	Mild
		PEF-ablated tumor (s2)	5	0	95		Moderate
		PEF-ablated tumor (s3)	10	0	90		Mild
		Sentinel lymph node (s4)	Tumor-negative lymph node
V02	pCR	PEF-ablated tumor (s1)	0	45	55	55% necrosis, 45% fibrosis, 0% viable tumor	Moderate
		PEF-ablated tumor (s2)	0	45	55		Moderate
		PEF-ablated tumor (s3)	0	75	25		Moderate
		Sentinel lymph node (s4)	Tumor-negative lymph node
V03	pCR	PEF-ablated tumor (s1)	0	0	100	100% fibrosis	Mild
		PEF-ablated tumor (s2)	0	0	100		Mild
		PEF-ablated tumor (s3)	0	0	100		Mild
		Sentinel lymph node (s4)	Tumor-negative lymph node
V04	pCR	PEF-ablated tumor (s1)	0	0	100	60% necrosis, 40% fibrosis	Mild
		PEF-ablated tumor (s2)	0	10	90		Moderate
		PEF-ablated tumor (s3)	0	95	5		Moderate

Each specimen was evaluated to determine the relative proportions of viable tumor, necrosis, and stroma (fibrosis and inflammation) and expressed as percentages totaling 100. Pathologic response was assigned according to IASLC criteria, with MPR defined as ≤10% residual viable tumor and pCR defined as the absence of any viable tumor in both the primary lesion and sampled lymph nodes. Inflammation was graded based on lymphocytic infiltration. IASLC, International Association for the Study of Lung Cancer; MPR, major pathologic response; pCR, pathologic complete response.

Figure 2.

Examples of viable tumor, necrosis, fibrosis, and tertiary lymphoid structures in resected tumors. (A) Representative images of H&E-stained tissue sections from patient V01 (MPR) and V04 (pCR) with annotations highlighting the area of residual tumor (green box), necrotic (blue box) and fibrotic (red box) tissue post ablation and neoadjuvant SOC treatment. (B) Representative images of TLS and TLS + GC observed in resected tissue from patient V02. Black dashed boxes indicate the regions shown at higher magnification. GC, germinal center; H&E, hematoxylin and eosin; MPR, major pathologic response; pCR, pathologic complete response; SOC, standard of care; TLS, tertiary lymphoid structures.

Immunophenotyping was performed by flow cytometry. This analysis revealed temporal modulation of adaptive immune cell populations, including increased T lymphocyte activation, reduced T-cell exhaustion, fewer regulatory T-cells (Tregs) as well as increased plasma cells and plasmablasts (Figure 3, Table S4, Figures S2,S3). These immune changes were observed consistently across all 4 patients and reflect previously reported patterns (6.7).

Figure 3.

Individual patient immune-cell responses over time. Scatter plots depict the fold-change values, normalized to each patient’s baseline (blue line), for immune populations that changed in the same direction in all four patients for at least one time point. Rx, resection; SOC, standard of care.

In summary, this case series supports the feasibility of Aliya PEF ablation in patients with stage IIB–IIIA NSCLC prior to neoadjuvant chemoimmunotherapy. The energy was delivered safely with minimal AEs, without impact to the planned surgical resection or exacerbating neoadjuvant-related toxicity. While a limitation of this study is the small number of patients, it offers insight into potential signal finding in patients receiving PEF ablation prior to neoadjuvant chemoimmunotherapy. In addition to the limited sample size, the relatively short duration of follow-up is a key limitation that precludes definitive conclusions regarding long-term efficacy.

In CheckMate-816, the pCR rate of the nivolumab plus chemotherapy group was approximately 24% overall (1). In the present study, 3 of 4 patients achieved pCR; however, given the limited sample size, these findings are descriptive and lack statistical power.

Analysis of immune cell dynamics following treatment revealed distinct patterns across multiple lymphocyte populations. In all four patients, several immune subsets demonstrated consistent modulation over time: activated CD4⁺ T-cells and plasma cells were consistently upregulated, whereas regulatory T-cells were reduced. The sustained increase in effector T-cells (activated CD4⁺) and concurrent suppression of Tregs across all four patients suggest a shift toward a pro-inflammatory immune milieu. The upregulation of plasma cells indicates humoral immune activation. These findings, in conjunction with the observation of TLS and TLS with GC (Figure S4), suggest that this form of ablation, when delivered prior to nivolumab plus chemotherapy, may elicit an adaptive immune response characterized by coordinated activation and differentiation of both T- and B-lymphocyte populations.

While preliminary, the results in this small patient cohort are encouraging and support further investigation into the potential synergistic effects of this specialized energy with chemoimmunotherapy.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the ISO 14155:2020, ICH-GCP (E6), and Declaration of Helsinki and its subsequent amendments. The study was approved by the WCG Institutional Review Board (No. 202224904). All participating hospitals were informed of and agreed to the study. All patients provided written informed consent.