Incorporating Immunotherapy with Radiotherapy for Lymphomas

Round 1

Reviewer 1 Report

The review article “Incorporating Immunotherapy with Radiotherapy for Lymphomas” reported that radiotherapy (RT) played an important role for lymphoma treatment even after immunotherapy  (IT)had been developed, and which concurrent or sequential manner was better option between RT and IT remained unclear. This topic is very important for current treatment strategy for lymphomas because radiotherapy could attack not only lymphoma cell but also immune cell in lymphoma disease site. Therefore, I considered that this review article was suitable for acceptance of the journal “lymphatics”. However, I recommended two points for the purpose to improve this article.

1.       The authors could add a table about ongoing clinical trials about RT plus IT if possible.

2.       Which concurrent RT plus IT, RT followed by IT, or IT followed by RT was the best therapeutic option remains unclear because several advantage and disadvantage were present for these three strategy as the authors mentioned, Therefore, I recommended that the author should add a table about “PROS and CONS” for these three treatment strategies.

Author Response

Reviewer 1

1. The authors could add a table about ongoing clinical trials about RT plus IT if possible.

                We now include Table 3 listing a select radiotherapy and immunotherapy trials.

2. Which concurrent RT plus IT, RT followed by IT, or IT followed by RT was the best therapeutic option remains unclear because several advantage and disadvantage were present for these three strategy as the authors mentioned, Therefore, I recommended that the author should add a table about “PROS and CONS” for these three treatment strategies.

                We now list the pros and cons in Figure 3.

Reviewer 2 Report

I would like to thank the handling editor for offering me the opportunity to review the manuscript entitled “Incorporating Immunotherapy with Radiotherapy for Lymphomas” authored by Strati and Spiotto, which is currently under consideration for publication in Lymphatics. I would also like to commend the authors for their scholarly work, which is a review article that discusses integration of immunotherapy with radiotherapy for the treatment of lymphomas. Immunotherapy agents, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy are emerging as new modalities for treating lymphomas. The authors review the mechanisms and efficacy of these immunotherapies in various lymphoma subtypes. They also discuss strategies for targeting the lymphoma microenvironment to stimulate anti-tumour immune responses. Molecular profiling of lymphomas may help select optimal candidates for immunotherapy. While radiotherapy can stimulate anti-tumour immunity, it can also cause systemic and local immunosuppression which may impair immunotherapy efficacy. More conformal radiotherapy techniques may help mitigate these effects. Overall, the authors review the rationale and challenges for combining novel immunotherapies with conventional lymphoma treatments like radiotherapy. They conclude that immunotherapy is a promising new modality for lymphoma, but optimal incorporation with radiotherapy requires further study.

This review article provides a comprehensive and timely overview of incorporating immunotherapy with radiotherapy for lymphomas. The authors demonstrate expertise and up-to-date knowledge of the latest immunotherapies and their application in lymphoma treatment. The manuscript is well-written, logically structured, and cites recent relevant literature.

The review covers pertinent background information on lymphoma biology and standard treatments before delving into specific immunotherapeutic approaches. The authors provide scientifically sound and technically accurate descriptions of the mechanisms of action of immune checkpoint inhibitors, bispecific antibodies, and CAR T-cell therapy. Relevant clinical trial data is appropriately summarized to showcase the efficacy of these emerging modalities.

Discussion of strategies to target the lymphoma microenvironment and how molecular subtyping can guide patient selection adds further value. The authors thoughtfully consider the opportunities and challenges of combining immunotherapies with radiotherapy, given the potential for both immune stimulation and suppression. They draw appropriately from preclinical studies and clinical experience in solid tumours to inform optimal integration in lymphoma.

Overall, this manuscript provides a comprehensive, and engaging overview, synthesizing a complex and evolving field. It underscores the promise of immunotherapy for lymphoma while addressing knowledge gaps regarding incorporation with radiotherapy. The review is scholarly, well-referenced, and offers new insights that can impact clinical practice and guide future research.

While the manuscript provides valuable insights, there are a few areas that could be refined to further augment the quality and impact of the work. Here are some respectful suggestions that could potentially improve the manuscript if the authors choose to implement them:

- When elucidating mechanisms, incorporating a conceptual diagram could greatly enhance reader comprehension, especially for intricate topics like bispecific antibodies and CAR T-cell therapy.

- To facilitate a deeper understanding of newer agents, such as bispecific antibodies and CAR T-cells, it might be beneficial to include a table summarizing efficacy data and response rates from pivotal clinical trials. This would enable readers to swiftly grasp the clinical potential.

- It is suggested that the authors delve into the implications of preclinical data demonstrating radiation-induced immune dysfunction in tumour-draining lymph nodes. Consider discussing its relevance to lymphoma patients undergoing involved nodal radiotherapy and explore if there is any pertinent evidence in this specific disease context.

- Additionally, it would be informative to include references to clinical evidence regarding any observed compromised effects of immunotherapy in radiated lymph node regions among lymphoma patients. Does this phenomenon occur?

- In the section on CAR T-cell-induced lymphopenia, it may be worthwhile to provide a more comprehensive discussion regarding the implications for infections and the necessity of antimicrobial prophylaxis when CAR T-cell therapy is combined with radiotherapy.

- It would be valuable for the authors to offer further insights into their perspective on the most promising strategies for integrating immunotherapy and radiotherapy for lymphomas. What sequences or combinations should be given priority in clinical trials?

- Lastly, it may be helpful to consider the inclusion of a timeline figure illustrating different sequences for integrating immunotherapy and radiotherapy (e.g., radiotherapy first, concurrent administration, immunotherapy first) to aid in visualizing the proposed strategies.

In conclusion, I would like to reiterate my appreciation to both the editor and the authors for the opportunity to review this interesting and informative manuscript. The minor suggestions provided above are aimed at enhancing the clarity and significance of this valuable review. Addressing some pertinent clinical considerations and practice implications could further augment the article's value for readers.

Author Response

Reviewer 2

- When elucidating mechanisms, incorporating a conceptual diagram could greatly enhance reader comprehension, especially for intricate topics like bispecific antibodies and CAR T-cell therapy.

                We now include a conceptual diagram detailing bispecific antibodies, BiTEs and CAR T cell therapy.

- To facilitate a deeper understanding of newer agents, such as bispecific antibodies and CAR T-cells, it might be beneficial to include a table summarizing efficacy data and response rates from pivotal clinical trials. This would enable readers to swiftly grasp the clinical potential.

                 We now include the response rates in Table 2.

- It is suggested that the authors delve into the implications of preclinical data demonstrating radiation-induced immune dysfunction in tumour-draining lymph nodes. Consider discussing its relevance to lymphoma patients undergoing involved nodal radiotherapy and explore if there is any pertinent evidence in this specific disease context.

                Although clinical reports have not extensively studied this area, we discuss how involved site radiotherapy can stimulate abscopal responses which indicate that involved nodal radiotherapy may facilitate anti-lymphoma immune responses. (page 11, paragraph 2-page 12, paragraph 1)

- Additionally, it would be informative to include references to clinical evidence regarding any observed compromised effects of immunotherapy in radiated lymph node regions among lymphoma patients. Does this phenomenon occur?

                Although we are aware of no clinical evidence discussing compromised effects of immunotherapy after radiotherapy for lymphoma, we present evidence that T cells expressed PD-1 after nodal irradiation that could be targeted with lymphoma. (page 11, paragraph 2-page 12, paragraph 1)

- In the section on CAR T-cell-induced lymphopenia, it may be worthwhile to provide a more comprehensive discussion regarding the implications for infections and the necessity of antimicrobial prophylaxis when CAR T-cell therapy is combined with radiotherapy.

                We discuss prophylaxis for CAR T-cell therapy on page 13 paragraph 3.

- It would be valuable for the authors to offer further insights into their perspective on the most promising strategies for integrating immunotherapy and radiotherapy for lymphomas. What sequences or combinations should be given priority in clinical trials?

                We discuss the timing of immunotherapy with radiotherapy with immunotherapy on page 14, paragraph 2.

- Lastly, it may be helpful to consider the inclusion of a timeline figure illustrating different sequences for integrating immunotherapy and radiotherapy (e.g., radiotherapy first, concurrent administration, immunotherapy first) to aid in visualizing the proposed strategies.

                We now include a timeline in Figure 3.