Cryoablation Combined with Programmed Cell Death Protein 1 Inhibitor Pembrolizumab for Advanced Non-small Cell Lung Cancer

doi:10.21203/rs.3.rs-4831983/v1

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Cryoablation Combined with Programmed Cell Death Protein 1 Inhibitor Pembrolizumab for Advanced Non-small Cell Lung Cancer

https://doi.org/10.21203/rs.3.rs-4831983/v1

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Introduction:

To evaluate the efficacy and safety of cryoablation combined with pembrolizumab treatment versus cryoablation alone in patients with advanced non-small cell lung cancer (NSCLC).

Methods

This retrospective study was conducted from February 2018 and October 2021. A total of 90 patients with NSCLC (AJCC stage IIIB/IV) were included, with 36 patients receiving cryoablation combined with pembrolizumab (Group A) and 54 patients receiving cryoablation alone (Group B). The primary outcome measures included objective response rate (ORR), overall survival (OS), and progression-free survival (PFS), immune responses and adverse events serving as secondary endpoints. Risk factors for OS and PFS were identified using univariate and multivariate analyses.

Results

No treatment related deaths were observed. Group A demonstrated a higher ORR (75.0% vs. 61.1%), longer median OS (28.1 months vs. 24.2 months), and longer median PFS (12.8 months vs. 8.4 months) compared to Group B. Additionally, Group A showed significant increases in CD3+, CD4+, and CD8 + T cells, and elevated levels of IL-2, IL-6, TNF-β, and IFN-γ. The multivariate analysis showed the combination of cryoablation and pembrolizumab was an independent prognostic factor for OS and PFS.

Conclusions: Cryoablation combined with pembrolizumab significantly improves clinical outcomes in advanced NSCLC patients compared to cryoablation alone, highlighting the potential of this combination therapy in enhancing anti-tumor immunity and prolonging survival.

Cryoablation

Programmed cell death protein 1 Inhibitor

Pembrolizumab

Advanced non-small cell lung cancer

Combination

Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases and remains a leading cause of cancer-related mortality worldwide (1). Despite advances in targeted therapies and immunotherapies, the prognosis for patients with advanced NSCLC remains poor, with a 5-year survival rate of less than 5% for stage IV disease (2–4). Traditional treatment modalities, including chemotherapy and radiotherapy, have limited efficacy and are often associated with significant toxicity (5–7). Therefore, there is an urgent need for novel therapeutic strategies that can improve outcomes for these patients.

Cryoablation, a minimally invasive procedure that uses argon to destroy cancer cells, has emerged as a promising local treatment for various malignancies, including NSCLC (8–10). This technique not only induces direct tumor cell death but also has the potential to elicit systemic anti-tumor immune responses (11–13). However, the efficacy of cryoablation as a monotherapy is often limited by incomplete tumor eradication and the potential for residual disease. Combining cryoablation with immunotherapy, such as immune checkpoint inhibitors, may enhance the anti-tumor immune response and improve clinical outcomes.

Programmed death-1 (PD-1) inhibitors, such as pembrolizumab, have revolutionized the treatment landscape for advanced NSCLC by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby restoring T-cell activity and promoting anti-tumor immunity (14, 15). Pembrolizumab has demonstrated significant clinical benefits in patients with PD-L1-positive NSCLC, leading to its approval as a first-line treatment for this population (16, 17). However, the response rates to pembrolizumab monotherapy remain suboptimal, particularly in patients with low or negative PD-L1 expression (18).

Given the complementary mechanisms of action of cryoablation and pembrolizumab, we hypothesize that the combination of these two modalities may synergistically enhance anti-tumor immunity and improve clinical outcomes in patients with advanced NSCLC. This study aims to evaluate the efficacy and safety of cryoablation combined with pembrolizumab compared to cryoablation alone in patients with advanced NSCLC. We will assess tumor response, progression-free survival (PFS), overall survival (OS), and immune-related biomarkers to elucidate the potential benefits of this combination therapy.

In summary, this study addresses a critical clinical need by exploring a novel combination therapy for advanced NSCLC. By integrating cryoablation with pembrolizumab, we aim to enhance the anti-tumor immune response and improve patient outcomes. The findings from this study could provide valuable insights into the potential of combining local and systemic therapies for the treatment of advanced NSCLC.

Patients

This retrospective study was approved from the Institutional Ethic Committee of Affiliated Hospital of Shaanxi University of Chinese Medicine and conducted in accordance with the Declaration of Helsinki and the Declaration of Good Clinical Practice. Written informed consent was obtained from each participant. From February 2018 and October 2021, all patients with advanced NSCLC underwent either a combination of cryoablation + pembrolizumab (group A) or cryoablation alone (group B). The inclusion criteria were as follows: (1) Histologically and radiologically verified advanced NSCLC; (2) Stage IIIB/IV, according to the American Joint Committee on Cancer (AJCC) criteria; (3) Patients over 18 years; (4) Sufficient bone marrow, laboratory examination of hepatic, renal and ardio-pulmonary function; (5) Relapsed after multimodal treatment (surgical resection, radiotherapy, or disease progressed after chemotherapy); (7) Life expectancy of at least 3 months; (6) Patients received pembrolizumab therapy for at least 1month after cryoablation in this study. The exclusion criteria were as follows: (1) Patients with distant metastases; (2) previous received anti-PD-1/PD-L1 therapy; (3) platelet count of less than 50×10⁹/L; (4) Severe impairment of pulmonary functions with the maximum voluntary ventilation less than 40%.

Treatment Procedure

Cryoablation

Preoperative imaging was performed to select supine, lateral or oblique position. Intraoperative real-time monitoring of the patient's blood pressure, oxygen saturation, heart rate, and electrocardiogram. Preoperative intravenous access was established for preoperative and intraoperative medications. Under the guidance of CT combined with ultrasound, we determined the location and path of the puncture needle, and planned the level, angle and depth of the puncture into the tumor. Thus, important tissue structures such as the heart, large blood vessels, and trachea were avoided to ensure surgical safety. Local aesthesia was applied at the puncture point with 1% lidocaine injection. The cryoprobe was inserted into the target according to the needle plan designed, and then confirmed by CT/MR scanning. The type and number of cryoprobes are selected according to the morphology, size and location of the lesion, with the aim of obtaining full coverage of the tumor with the "ice ball". Rapid freezing with argon for 15–20 min, rapid rewarming with helium for 2–5 min, and repeated freezing and rewarming were performed. The decision to increase the freezing time was made according to the coverage of the lesion by the "ice ball" on imaging. When the edge of the "ice ball" exceeds the lesion by more than 1cm, it is heated and the cryoprobe is withdrawn. CT or MR scanning was performed for complications such as pneumothorax and hemorrhage.

Pembrolizumab

Patients in group A received pembrolizumab therapy (100 mg/3w). The first dose of pembrolizumab was administered within 2 weeks after cryoablation. Patients received continuous pembrolizumab treatment until intolerance toxicity or progressive disease. The treatment protocol is illustrated in Fig. 1B.

PD-L1 expression analysis

PD- L1 expression was assessed using a proprietary immunohistochemistry assay. We classified PD-L1 expression into three levels: negative PD-L1 expression (TPS < 1%), low PD-L1 expression (TPS 1–49%), and high PD-L1 expression (TPS ≥ 50%).

Flow cytometric analysis

Blood samples of each patient’s blood (2 ml) were collected just before the cryoablation procedure (Pretreatment) and 30 days (Posttreatment) after cryoablation procedure. Flow cytometry techniques (FACS caliber, four-color system, BD Bioscience, CA, US) were used to analyze the absolute number of CD3⁺ T cells (CD3⁺), CD4⁺T cell (CD3⁺CD4⁺), CD8⁺T cell (CD3⁺CD8⁺), Treg cell (CD4⁺CD25⁺CD127dim). A similar method was used to measure serum cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), tumor-necrosis factor-beta (TNF-β), and interferon-γ (IFN-γ).

Collection of clinical data

The tumor response was evaluated based on the mRECIST (28). The objective response rate (ORR) was calculated as follows: ORR = (CR + PR cases) / total cases × 100%.

Follow-up and endpoints assessment

All patients in this study were followed up at 1-, 3-, and 6-months posttreatment and then every three months. Two radiologists independently interpreted all follow-up scan results. Adverse events were evaluated and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The last follow-up was completed on June 16, 2023. The tumor response was assessed using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)(19). The objective response rate (ORR) after 3months posttreatment was calculated which is defined as the percentage of patients with a best overall response of complete response (CR) or partial response (PR). Overall survival (OS) was defined as the time from diagnosis to death or until the last follow-up. progression-free survival (PFS) was defined as the time from diagnosis to disease progression until the last follow-up.

Adverse events, including immune-mediated adverse events, were collected throughout the treatment until 90 days after the last infusion of pembrolizumab. All Adverse events were graded based on the NCI Common Terminology Criteria for Adverse Events v5.0.

Statistical analysis

All statistical analyses were performed and compiled using GraphPad Prism (version 8.01, GraphPad Software, San Diego, CA, USA) and SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA). Categorical variables were compared using the chi-square or Fisher exact test. The continuous data, categorical data, and survival curves of the two groups were compared using the Mann-Whitney test, Fisher's exact test, and log-rank (Mantel-Cox) tests individually. The Cox regression model was used in survival analysis to assess the influence factor of OS and PFS. All statistical tests were two-sided; a p-value < 0.05 was considered statistically significant.

Patient Characteristics

Between February 2018 and October 2021, a total of 387 advanced NSCLC patients were included in this study (Fig. 1). Based on the exclusion criteria, totally 297 patients were excluded due to receiving other treatment (n = 138), tumor metastasis (n = 106), incomplete data, or missing (n = 48). A total of 90 advanced NSCLC patients were finally evaluated in this study: Group A (n = 36) and Group B (n = 54) (Fig. 1A). The baseline characteristics were well balanced between the two groups (Table 1). The median ages were 58 (29–80) and 54 (33–78) in Group A and B, respectively. Male patients had a higher risk than female patients between the two groups. The median tumor sizes were 4.6 cm (range 2.9–8.5) and 4.8 cm (range 3.1–8.7) for patients in groups A and B, respectively. The majority of patients were nonsquamous histology (81.1%) and had former or current smokers (82.2%). In the 90 patients who underwent a PD-L1 expression assay before treatment, 12 (13.3%) patients had PD-L1 negative expression, and 56 (62.2%) had PD-L1 positive expression, including 29 (32.2%) patients more than 50% (≥ 50%) PD-L1 expression (Table 1).

Table 1

Patients characteristics.
Characteristic	Group A (n = 36)	Group B (n = 54)	P Value
Age, year			0.326
≤ 60	25	32
> 60	11	22
Sex
Male	26	35	0.461
Female	10	19
Tumor size (cm)			0.666
2 ~ 5	14	24
≥5	22	30
Tumor pattern			0.660
Squamous	6	11
Nonsquamous	30	43
TNM stage			0.648
IIIA	11	19
IV	25	35
Smoking status			0.736
Former or current	29	45
Never	7	9
PD-L1 TPS			0.371
≥50%	9	20
≥ 1% and < 50%	11	16
< 1%	4	8
Unknown	12	10
Preoperative therapy			0.702
Surgery	14	21
Chemotherapy	10	10
Radiotherapy	9	16
Others	3	7
TNM, tumor node metastasis; PD-L1, programmed death-ligand 1; TPS, tumor proportion score

Adverse Events

As shown in Table 2, there was no treatment-related mortality in either group in our study. Overall, the frequency of adverse events was similar between the two groups. The most common cryoablation treatment-related adverse events were pain (61.1%), nausea (63.9%), vomiting (58.3%) and pneumothorax (33.3%) in group A. The major (grade 3 ~ 4) cryoablation-related adverse events were pneumothorax (5.6%) and hemorrhage (2.7%) in Group A (Table 2). All adverse events were relieved or improved after symptomatic treatment. The most common immune-related adverse events were fatigue (19.4%), pruritus (13.8%), diarrhea (11.1%), nausea (11.1%). The major (grade 3 ~ 4) immune-related adverse events were fatigue (2.7%), pruritus (2.7%), AST increased (2.7%), lipase increased (2.7%), ALT increased (2.7%) in group A, which was resolved after the treatment with a corticosteroid. There were no immune-related adverse events in group B (Table 3).

Table 2

Adverse events related to cryoablation treatment.
Characteristic	Group A (n = 36)		Group B (n = 54)
	All Grade	Grade 3/4	All Grade	Grade 3/4
Pain	22 (61.1%)	0	36 (66.7%)	0
Nausea	23 (63.9%)	0	28 (51.9%)	0
Vomiting	21 (58.3%)	0	32 (59.3%)	0
Pneumothorax	12 (33.3%)	2 (5.6%)	17 (31.5%)	4 (7.4%)
Pleural effusion	7 (19.4%)	0	15 (27.8%)	0
Hemorrhage	9 (25.0%)	1 (2.7%)	22 (40.7%)	2 (3.7%)
Infection	1 (2.7%)	0	2 (3.7%)	0

Table 3

Adverse events related to immune treatment.
Adverse event	Group A (n = 36)
	All Grade	Grade 3/4
Fatigue	7 (19.4%)	1 (2.7%)
Pruritus	5 (13.8%)	1 (2.7%)
Diarrhea	4 (11.1%)	0
Nausea	4 (11.1%)	0
Decreased appetite	2 (5.6%)	0
Hypothyroidism	2 (5.6%)	0
Cough	2 (5.6%)	0
Fever	2 (5.6%)	0
AST increased	2 (5.6%)	1 (2.7%)
Lipase increased	1 (2.7%)	1 (2.7%)
ALT increased	1 (2.7%)	1 (2.7%)
Pneumonitis	1 (2.7%)	0
AST, aspartate transaminase; ALT, alanine aminotransferase

Response

Overall, 11 (30.6%) patients achieved CR, 16 (44.4%) patients received PR, 6 (16.7%) patients developed SD, and 3 (8.3%) patients suffered PD in group A. The tumor response in group B was 10 (18.5%) patients with CR, 23 (42.6%) patients with PR, 9 (16.7%) patients with SD and 12 (22.2%) with PD. The ORR was 75.0% vs. 61.1% (p = 0.045, Table 4) in groups A and B, respectively.

Table 4

Tumor response 3 months posttreatment
Characteristic	Group A (n = 36)	Group B (n = 54)	P Value
CR	11(30.6%)	10(18.5%)
PR	16(44.4%)	23(42.6%)
SD	6(16.7%)	9(16.7%)
PD	3(8.3%)	12(22.2%)
ORR	27(75%)	33(61.1%)	0.045
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate

Immune parameters

We compared the absolute number of immune cells after treatment to investigate possible effects on the tumor immune microenvironment of each treatment. The results demonstrated that the absolute number of CD3⁺T cells (p = 0.033), CD4⁺T cells (p = 0.012), and CD8⁺ T cells (p = 0.003) steadily increased after treatment in group A comparing to group B (Figs. 2A–C), while the proportion of Tregs cells (p = 0.035) decreased (Figs. 2D).

To further investigate the variations of the immune microenvironment, we compared the levels of cytokines in both groups. The data suggested that the IL2 (p = 0.009), IL-6 (p = 0.000), TNF-β (p = 0.001), and IFN-γ (p = 0.014) levels significantly increased after treatment in group A comparing to group B (Fig. 3).

Survival

The median follow-up time was 24.6 months (9.9–41.4 months). The median OS from diagnosis was significantly longer in group A than in group B, respectively (28.1 months vs. 24.2 months, p = 0.009, Fig. 4A). Similarly, the median PFS from diagnosis was significantly longer in group A than in group B, respectively (12.8 months vs. 8.4 months, p = 0.011, Fig. 4B).

Univariate and Multivariate Analyses of OS and PFS

Univariate Cox regression analysis and multivariate Cox regression analysis were used to evaluate the predictors of OS and PFS. As shown in Table 5, tumor size (HR: 1.024, 1.045–1.038, p = 0.025), tumor pattern (HR: 0.645, 0.328–1.525, p = 0.048), PD-L1 TPS (HR: 0.975, 0.415–2.045, p = 0.038), cryoablation plus pembrolizumab (HR: 0.447, 0.238–0.765, p = 0.015) were significantly correlated with OS in the univariate Cox regression analysis. Multivariate analysis showed that the tumor size (HR: 2.056, 1.010–4.256, p = 0.046), PD-L1 TPS (HR: 0.172, 0.042–0.746, p = 0.028) and cryoablation plus pembrolizumab (HR: 0.472, 0.285–0.778, p = 0.006) were predictors of OS (Table 5). Furthermore, PD-L1 TPS (HR: 0.488, 0.214–1.425, p = 0.045) and cryoablation plus pembrolizumab (HR: 1.757, 0.965–3.287, p = 0.047) were also significant prognostic factors for PFS (Table 6).

Table 5

Univariate and multivariate analyses of OS in patients
Characteristic	Univariate analysis		Multivariate analysis
Characteristic	HR (95%CI)	P value	HR (95%CI)	P value
Age (> 60/≤60)	0.724 (0.146–0.786)	0.356
Sex (female/male)	0.354 (0.278–0.628)	0.758
Tumor size (≥ 5/2 ~ 5)	1.024 (1.045–1.038)	0.025	2.056 (1.010–4.256)	0.046
Tumor pattern (squamous/nonsquamous)	0.645 (0.328–1.525)	0.048	0.024 (0.014–0.524)	0.067
TNM stage	0.987 (0.648–1.546)	0.983
Smoking status (Current/former/Never)	1.012 (0.985–1.41)	0.225
PD-L1 TPS (≥ 50%/1–49%)	0.975 (0.415–2.045)	{Novello, 2023 #8}	0.172 (0.042–0.746)	0.028
Preoperative therapy (surgery/chemotherapy/ radiotherapy/others)	1.345 (0.789–2.458)	0.178
Cryoablation (with pembrolizumab/without pembrolizumab)	0.447 (0.238–0.765)	0.015	0.472 (0.285–0.778)	0.006
OS, overall survival; PD-L1, programmed death-ligand 1; HR, hazard ratio; CI, confidence interval;

Table 6

Univariate and multivariate analyses of PFS in patients
Characteristic	Univariate analysis		Multivariate analysis
Characteristic	HR (95%CI)	P value	HR (95%CI)	P value
Age (> 60/≤60)	1.145 (0.561–2.110)	0.656
Sex (female/male)	0.351 (0.212–0.653)	0.751
Tumor size (≥ 5/2 ~ 5)	0.714 (0.484–1.564)	0.428
Tumor pattern (squamous/nonsquamous)	1.124 (0.748–1.658)	0.572
TNM stage	0.942 (0.631–1.412)	0.752
Smoking status (Current/former/Never)	0.946 (0.645–1.412)	0.746
PD-L1 TPS (≥ 50%/1–49%)	0.625 (0.258–1.445)	0.021	0.488 (0.214–1.425)	0.045
Preoperative therapy (surgery/chemotherapy/ radiotherapy/others)	0.615 (0.378–1.224)	0.208
Cryoablation (with pembrolizumab/without pembrolizumab)	1.825 (1.045–3.275)	0.013	1.757 (0.965–3.287)	0.047
PFS, progression free survival; PD-L1, programmed death-ligand 1; HR, hazard ratio; CI, confidence interval;

In this study, we evaluated the efficacy and safety of combining cryoablation with pembrolizumab treatment compared to cryoablation alone in patients with advanced NSCLC. Our main findings indicate that the combination therapy significantly improved ORR and prolonged OS and PFS compared to cryoablation alone. Specifically, patients receiving the combination therapy exhibited a more favorable immune profile, as evidenced by increased levels of CD3 + T cells, CD4 + T cells, and CD8 + T cells, along with elevated serum cytokines such as IL-2 and IFN-γ. These results align with our initial hypothesis that the addition of pembrolizumab, an anti-PD-1 monoclonal antibody, would enhance the anti-tumor immune response initiated by cryoablation. Furthermore, the safety profile of the combination therapy was manageable, with adverse events consistent with those previously reported for pembrolizumab and cryoablation treatments (16, 20). These findings suggest that the integration of cryoablation and pembrolizumab could offer a promising therapeutic strategy for patients with advanced NSCLC.

The primary novelty of this study lies in its comprehensive evaluation of the combined treatment of cryoablation and pembrolizumab in NSCLC patients, a therapeutic approach that has not been extensively explored in previous research. This study uniquely integrates cryoablation, a minimally invasive procedure that induces tumor cell death through argon, with pembrolizumab, an immune checkpoint inhibitor targeting PD-1. The combination aims to enhance anti-tumor immunity by not only directly reducing tumor burden but also by potentially increasing the immunogenicity of the tumor microenvironment. Our findings demonstrate a significant improvement in both OS and PFS in the combination therapy group compared to cryoablation alone, with median OS of 28.1 months versus 24.2 months and median PFS of 12.8 months versus 8.4 months, respectively. This is consistent with the hypothesis that cryoablation can act as an in situ vaccine, enhancing the efficacy of subsequent immunotherapy (21–23). Furthermore, the observed increase in CD3+, CD4+, and CD8 + T cells, along with elevated levels of cytokines such as IL-2, IL-6, TNF-β, and IFN-γ, supports the notion of an augmented immune response post-treatment. These results align with previous studies that have suggested the potential of combining local ablative therapies with systemic immunotherapies to achieve synergistic effects (11, 24, 25). However, our study is among the first to provide robust clinical evidence in a human cohort, thereby filling a critical gap in the current understanding of multimodal treatment strategies for advanced NSCLC (16, 26).

The clinical implications of our study are significant, particularly in the context of treatment strategies for advanced NSCLC. These findings suggest that integrating immunotherapy with local ablative techniques can enhance the anti-tumor immune response, potentially leading to better clinical outcomes. This is particularly relevant given the limited treatment options and poor prognosis associated with advanced NSCLC. The observed increase in CD3 + T cells, CD4 + T cells, and CD8 + T cells, along with elevated levels of cytokines such as IL-2, IL-6, TNF-β, and IFN-γ, underscores the immunomodulatory effects of this combination therapy. These results align with previous studies that have highlighted the synergistic effects of combining local therapies with immune checkpoint inhibitors (14, 27, 28).

However, our study is limited by its retrospective nature and the relatively small sample size. Future research should focus on conducting large-scale, multicenter randomized controlled trials to validate our findings and explore the underlying mechanisms of this combined treatment approach. Additionally, longer follow-up periods are necessary to assess the long-term efficacy and safety of this therapeutic strategy. Understanding the molecular and immunological changes induced by this combination therapy could pave the way for more personalized and effective treatment regimens for NSCLC patients.

In conclusion, our study demonstrates that the combination of cryoablation and pembrolizumab therapy significantly improves the clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) compared to cryoablation alone. These findings suggest that the synergistic effect of cryoablation and immunotherapy could potentially overcome the limitations of monotherapy in treating advanced NSCLC.

Conflicts of interest

All authors report no conflicts of interest in this work.

FUNDING

This study was supported by the Project of Shaanxi Provincial Department of Science and Technology (No. 2022SF-513).

Author Contribution

SW and PW designed the project and edited the manuscript. LW, GW, HY, ZC and XY conducted study selection, dataextraction, statistical analyses, and drafted the main manuscript. All authors contributed to the article and approved thesubmitted version.

Acknowledgements

We thank all patients and their families for their help and support. We thank all my colleagues for their assistance.

Availability of data and material

The dataset generated during and/or analyzed during this study are available from the corresponding author on reasonable request.

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No competing interests reported.

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Cryoablation Combined with Programmed Cell Death Protein 1 Inhibitor Pembrolizumab for Advanced Non-small Cell Lung Cancer

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Abstract

Figures

Introduction

Methods

Patients

Treatment Procedure

Cryoablation

Pembrolizumab

PD-L1 expression analysis

Flow cytometric analysis

Collection of clinical data

Follow-up and endpoints assessment

Statistical analysis

Results

Patient Characteristics

Adverse Events

Response

Immune parameters

Survival

Univariate and Multivariate Analyses of OS and PFS

Discussion

Declarations

Conflicts of interest

FUNDING

Author Contribution

Acknowledgements

Availability of data and material

References

Additional Declarations

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