Gamma Knife Stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: A Phase II Trial Analysis

Reviewer #1 (Public review):

Summary:

This study presents compelling evidence for a novel treatment approach in a challenging patient population with MSS/pMMR mCRC, where traditional immunotherapy has often fallen short. The combination of SBRT and tislelizumab not only yielded a high disease control rate but also indicated significant improvements in the tumor's immune landscape. The safety profile appears favorable, which is crucial for patients who have already undergone multiple lines of therapy.

Strengths:

The results underscore the potential of leveraging radiation therapy to enhance the effectiveness of immunotherapy, especially in tumor environments previously deemed hostile to immune interventions. Future research should focus on larger cohorts to validate these findings and explore the underlying mechanisms of immune modulation post-treatment.

Weaknesses:

I believe the author's work is commendable and should be considered with some minor modifications:

(1) While the author categorized patients based on the type of RAS mutation and the location of colorectal cancer metastasis, the article does not adequately address how these classifications influence treatment outcomes. Such as whether KRAS or NRAS mutations, as well as the type of metastatic lesions, affect the sensitivity to gamma-ray treatment and lead to varying responses.

(2) In Figure 2, clarification is needed on how the author differentiated between on-target and off-target lesions. I observed that some images depicted both lesion types at the same level, which could lead to confusion.

(3) The author performed only a basic difference analysis. A more comprehensive analysis, including calculations of markers related to treatment efficacy, could offer additional insights for clinical practice.

(4) The transcriptome sequencing analysis provides insights into how stereotactic radiotherapy sensitizes immunotherapy; however, it currently relies on a simple pre- and post-treatment group comparison. It would be beneficial to include additional subgroups to explore more nuanced findings.

(5) The author briefly discusses the effects of changes in tumor fibrosis and angiogenesis on treatment outcomes. Further experiments may be necessary to validate these findings and investigate the underlying mechanisms of immune regulation following treatment.

Reviewer #2 (Public review):

Summary:

This Phase II clinical trial investigates the combination of Gamma Knife Stereotactic Body Radiation Therapy (SBRT) with Tislelizumab for the treatment of metastatic colorectal cancer (mCRC) in patients with proficient mismatch repair (pMMR). The study addresses a critical clinical challenge in the management of pMMR CRC, focusing on the selection of appropriate candidates. The results suggest that the combination of Gamma Knife SBRT and Tislelizumab provides a safe and potent treatment option for patients with pMMR/MSS/MSI-L mCRC who have become refractory to first- and second-line chemotherapy. The study design is rigorous, and the outcomes are promising.

Advantage:

The trial design was meticulously structured, and appropriate statistical methods were employed to rigorously analyze the results. Bioinformatics approaches were utilized to further elucidate alterations in the patient's tumor microenvironment and to explore the underlying factors contributing to the observed differences in treatment efficacy. The conclusions drawn from this trial offer valuable insights for managing advanced colorectal cancer in patients who have not responded to first- and second-line therapies.

Weakness:

(1) Clarity and Structure of the Abstract
- Results Section: The results section should contain important data, I suggest some important sequencing data should be shown to enhance understanding.
(2) As the author using the NanoString assay for transcriptome analysis, more detail should be shown such as the version of R, and the bioinformatics analysis methods.
(3) It is interesting for included patients that PD-L1 increase expression after Gamma Knife Stereotactic Body Radiation Therapy (SBRT) treatment, How to explain it?
(4) It would be helpful to include a brief discussion of the limitations of the study, such as sample size constraints and their impact on the generalizability of the results. This will give readers a more comprehensive understanding of the findings.
(5) Language Accuracy: There are a few instances where wording could be more professional or precise.

Author response:

We would like to express our sincere gratitude to the editor and reviewers for their thoughtful comments and suggestions on our manuscript. Below is our interim response to the reviewers’ public review:

Reviewer 1:

(1) We appreciate the reviewer’s insightful comment on the consideration of RAS mutation type and lesion metastasis site in our study. We will undertake a more comprehensive review of the literature and conduct a detailed analysis to assess how these factors influence treatment efficacy in our cohort.

(2) Regarding the radiotherapy planning process, we will provide further clarification in the revised manuscript. Specifically, we select the target lesion using CT imaging and delineate it by marking the 50% isodose line to define the planning target volume (PTV). In assessing treatment efficacy, we differentiate between target lesions (within the PTV) and off-target lesions (outside the PTV). We will update the figures to include the isodose line display for better clarity.

(3 & 4) We acknowledge the limitations of our study, particularly with respect to the sample size, which may hinder the statistical power required for a comprehensive analysis of treatment effect markers and subgroup variations. Nonetheless, we will continue to refine our analyses in the revised manuscript to provide additional insights and strengthen the conclusions where possible.

(5) During the early stages of our research, our team conducted a series of investigations into the impact of tumor fibrosis and angiogenesis on treatment outcomes. We have accumulated a substantial body of data, and we will summarize these findings in the revised manuscript to provide further context and support for our current study.

Reviewer 2:

(1, 4 & 5) We greatly appreciate the reviewer’s careful reading of the manuscript. We will revise the abstract, methods, and results sections to improve clarity and precision. Additionally, we will refine the overall wording of the manuscript to enhance its scientific rigor and professionalism.

(2) We also appreciate the reviewer’s suggestions regarding the methods and results. These will be incorporated into the revised manuscript, with additional detail in the methods section to clarify our experimental approach and strengthen the discussion of our findings.

(3) This is an intriguing point raised by the reviewer. We agree that the upregulation of PD-L1 expression following SBRT treatment could potentially enhance the efficacy of subsequent immunotherapy. To explore this further, we will conduct a detailed literature review and provide a more in-depth analysis of our data to elucidate the underlying mechanisms.

We trust that the clarifications provided above partially address the reviewers' concerns. We are committed to fully resolving the raised issues through more comprehensive revisions in the subsequent manuscript update.