Additive Intralesional Interleukin-2 Improves Progression-Free Survival in a Distinct Subgroup of Melanoma Patients with Prior Progression under Immunotherapy
Round 1
Reviewer 1 Report
In their well-written manuscript Rafei-Shamsabadi et al. present data on a small cohort (n=27) of metastatic melanoma patients after PD-1/CTLA-4 failure and their response to intralesional IL-2. Alongside clinical data inclduing differential blood count the authors present a thorough immunohistochemical analysis for CD4, CD8, PD-1, and PD-L1 of some pre-/post-treatment tissue specimens (n=16). Thereby, the authors conclude that responses to second-line IL-2 were frequent in loco-regional mets (74%) but less likely in distant mets (37%). An increase of absolute eosinophil count (in the peripheral blood) and a presence of CD8+ TILs in posttreatment mets associated with a favorable response and extended PFS.
There are only minor points to address by the authors:
- Please include a table in supplemntal materials listing all 27 patients with relevant primary data that were included into this study.
- Please add Neutrophil-to-Lymphocyte Ratio (NLR), and S100 as possible surrogate markers to your study.
- Please briefly discuss the relevance the biomarkers of this study (CD4, CD8, PD-1, PD-L1, NLR, S100) could have as pre-treatment markers maybe suitable for selection.
Author Response
Please see the attachment for point-by-point response to all reviewers comments.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Feedback:
- Well written
- Unique cohort (limited data on IL-2 intralesional RR post PD-1 progression) and in melanoma patients treated with subcut/nodal mets (previous reports largely describe ITM only)
- Relevant given increasing number of pts who are PD-1 progressors or who develop IO tox and require other therapies
Suggestions for improvement:
- More details required in the methods or as supplemental information to explain the number of IL2 injections given in the study for patients in the retrospective cohort, timing of IHC assessment, and nature of lesions injected (% that were nodal vs ITM vs subcut)
- There is limited data on safety of nodal injections so some toxicxity data on this would be helpful for the field
- Suggest removal of data from the CUP pt as they are not strictly melanoma, as well as reporting the cutaneous melanomas separately in all tables where appropriate
- What % had abscopal response? (alluded to in line 150 but no details/data given).
- Did the authors look at M2 macrophages? They might certainly be important in mediating resistance
- Do the authors have information about the average dose /pt/session or / lesion? this would be an important addition
Minor:
Phase ‘compared to 22(81%) with BRAF WT’ line 124 redundant
Fro supplm Figure S2 – describe ‘under IL-2’ photos/IHC how many doses did they receive?
Author Response
Please see the attachment for point-by-point response to all reviewers comments.
Author Response File: Author Response.pdf
Reviewer 3 Report
the work is potentially interesting
however, the study with 27 respondents is really very small to obtain statistically significant findings
In addition, some parameters were observed that were performed only in some subjects
Author Response
Please see the attachment for point-by-point response to all reviewers comments.
Author Response File: Author Response.pdf
Round 2
Reviewer 3 Report
the study did not increase the number of respondents as previously suggested.
A very small number of respondents do not contribute significantly and well to the documented results obtained in any study, so they cannot here either.
Bearing in mind that this violates every principle of proportionality of data processing in the set of individual values of respondents and making irrelevant conclusions, I believe that working with a small number of respondents should not be accepted at all for publication in journals with high impact factor.
