Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript synthesizes the biological rationale for CAR-T cell therapy selection in PTCL, highlighting emerging clinical evidence for key CAR targets and engineering strategies that could enhance the therapeutic outcomes. 
Additionally, it presents an integrated hematology perspective on how CAR-based therapies may be positioned concerning transplantation and the evolving landscape of targeted agents for relapsed or refractory cases. 
However, there are minor issues that need to be addressed before publication. 
- some paragraphs contain redundancy and can be shortened for clarity. 
- it is important to discuss the role of radiotherapy as a bridging strategy before transplantation. 
- are there any initiatives aimed at developing biology-driven therapy individualization for CAR-T cell therapy to predict patient responses prior to treatment? 
The conclusion section should also be condensed to under 100-150 words, if possible.

Author Response

Comment. Some paragraphs contain redundancy and can be shortened.

Response. Redundant passages have been tightened (Sections 1.5 and 1.8), and the Conclusion has been condensed.

Comment. Discuss the role of radiotherapy as a bridging strategy before transplantation.

Response. Radiotherapy is now discussed in Section 2.5 as a bridging modality during the manufacturing window, drawing on its established use in B-cell CAR-T (Pinnix et al.), with the caveat that the frequently disseminated presentation of PTCL limits localized approaches and that T-cell-specific data remain scarce.

Comment. Are there initiatives for biology-driven individualization to predict response before treatment?

Response. This is addressed in the new Section 1.10, which proposes pretreatment predictive tools — molecular subtyping, quantitative/spatial antigen-density assessment, detection of circulating disease, and ctDNA/MRD monitoring — and argues for building these into trial eligibility and endpoints rather than applying them post hoc.

Comment. Condense the Conclusion to 100–150 words.

Response. The Conclusion has been rewritten and condensed to approximately 170 words; it can be tightened further to fall strictly within 150 words if the editor prefers.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper is well-written and provides a comprehensive, updated literature review of the field. The manuscript is solid, and I only have a few minor comments primarily concerning the figures.

Minor Comments:

1. The authors must ensure strict correspondence between the acronyms used in the images and those in the figure legends. Specifically:

   • In Figure 1, please correct ALCC to ALCL.

   • In Figure 2, please correct CRISP to CRISPR.

2.  The authors should explicitly state the source or tools used to generate their diagrams. Please clarify whether the figures were created using platforms like BioRender, synthesized via AI generation tools, or designed by the authors themselves. If applicable, appropriate licensing or acknowledgments should be added.

Author Response

Comment. Figure 1: correct ALCC to ALCL. Figure 2: correct CRISP to CRISPR.

Response. Both labels have been corrected. Figure 1 has additionally been redesigned as an original scientific schematic (see R2, comment 5).

Comment. State the source/tools used to generate the diagrams (BioRender / AI / author-made) and add licensing/acknowledgments.

Response. A statement has been added to the Acknowledgments: the schematic figures are original vector diagrams designed by the authors and were not produced by AI image-generation tools; AI assistance was limited to language editing and preliminary drafts, all subsequently verified by the authors.

Reviewer 3 Report

Comments and Suggestions for Authors

Irimia et al. present a review article on cellular immunotherapies for T-cell lymphoma (TCL), discussing various cell-based therapeutic approaches, including CAR-T cells and NK cell therapies, as well as their potential applications, limitations, and future directions. While the topic is timely and clinically relevant, the manuscript lacks sufficient depth, breadth, and critical analysis. A few comprehensive reviews on cellular immunotherapy for TCL have already been published, and the current article does not provide substantial new insights or a rigorous synthesis of the literature. As written, the review offers only a superficial overview of the field and fails to meaningfully advance readers' understanding of current challenges and emerging opportunities.

Comments

1. The review lacks sufficient scope and novelty and does not provide a comprehensive or critical evaluation of the field. Given the availability of recent disease-specific reviews on cellular immunotherapies for TCL, the authors should clearly articulate how their review differs from and adds to the existing literature. Currently, the manuscript contributes little beyond summarizing already well-established concepts.
2. In Section 1.1, the rationale presented as if immunotherapy required because conventional chemotherapy does not work. This justification is overly simplistic.
3. In section 1.2, the discussion is largely restricted to PTCL-NOS, while other major TCL subtypes receive little to no attention. Furthermore, the extensive intertumoral and intratumoral heterogeneity characteristic of TCL is not adequately addressed. For example, CD30 expression among ostensibly CD30-positive TCLs can be highly variable, which may significantly influence patient selection, therapeutic response, and resistance mechanisms. The authors should discuss how biological heterogeneity impacts immunotherapy development and clinical outcomes.
4. In section 1.3, the manuscript does not adequately address T-cell aplasia, one of the major challenges associated with T-cell-directed cellular therapies. Strategies currently under investigation to mitigate or overcome treatment-induced T-cell aplasia should be discussed in detail. This issue represents a critical barrier to successful clinical implementation and an important area of ongoing research.
5. In section 1.5, this section is covered very superficially. Much of the information presented has already been summarized in recent disease-specific reviews. The authors neither provide a comprehensive literature analysis nor offer new perspectives. As a result, the section appears redundant and adds little value for readers seeking an updated understanding of the field.
6. In section 1.6, the discussion of TRBC-targeted approaches lacks sufficient depth. The authors should include additional TRBC1-targeted therapies currently under preclinical and clinical evaluation. Furthermore, TRBC2-targeted strategies are not discussed despite representing a potentially important therapeutic avenue for a subset of patients. The review should also address limitations, safety concerns, resistance mechanisms, and recent advancements in this rapidly evolving area.
7. In section 1.7, a substantial body of literature related to CD30-targeted cellular therapies in TCL has been omitted. The current discussion is superficial and incomplete. In particular, tumor heterogeneity in CD30 expression remains a major challenge that may contribute to suboptimal or incomplete responses. The authors should provide a more balanced discussion of the limitations of current approaches and potential strategies being developed to overcome these challenges.
8. In section 1.8.1, the discussion is largely limited to CD7-directed CAR-NK approaches. However, several additional CAR-NK strategies targeting antigens such as CD5, CD4, TRBC1, or other TCL-associated targets are being explored in preclinical and early clinical studies. These approaches should be included to provide a more comprehensive overview of the field.
9. The manuscript contains a few typographical and formatting inconsistencies that should be carefully corrected during revision.

Overall, the topic is highly relevant and important; however, the manuscript requires substantial revision before it can be considered for publication. A more comprehensive, critical, and up-to-date analysis of the literature is needed. The authors should expand the discussion of biological rationale, disease heterogeneity, therapeutic limitations, emerging targets, and ongoing developments to provide a meaningful and authoritative review of cellular immunotherapies for T-cell lymphomas.

 

Author Response

We thank Reviewer 4 for pressing us on depth and novelty. In response we have added an explicit statement of the review’s contribution and substantially expanded the sections identified.

Scope and novelty — how does this review differ from existing ones?

Response. A statement of novelty has been added to the Introduction, and the new Section 1.10 articulates the specific contribution: rather than cataloguing constructs, the review organizes antigen selection around the molecular subclassification of PTCL and presents this target-to-subtype mapping as an explicit, falsifiable framework, stating throughout where rationale ends and evidence begins.

Section 1.1 — the rationale (“chemotherapy does not work”) is oversimplified.

Response. The rationale has been made more precise: rather than a blanket statement that chemotherapy fails, the Introduction now specifies the chemorefractory, transplant-ineligible population — with its distinct, quantified prognosis — as the target population for cellular therapy, and the novelty statement frames the biological rationale accordingly.

Section 1.2 — restricted to PTCL-NOS; heterogeneity (e.g., variable CD30) not addressed.

Response. Biological heterogeneity is now treated as a cross-cutting theme: Section 1.7 adds a dedicated discussion of intertumoral and intratumoral CD30 heterogeneity and its consequences for patient selection and resistance; Section 2.1 addresses antigen heterogeneity as a pre-existing route to escape; and Section 1.10 integrates subtype heterogeneity (GATA3/TBX21, AITL, ALCL, ENKTL) into target selection.

Section 1.3 — T-cell aplasia mitigation strategies not addressed.

Response. A new paragraph in Section 1.3 details mitigation strategies under investigation: antigen-sparing and clonal-restricted designs; time-limited CAR activity (transient mRNA CARs, drug-regulated constructs, inducible caspase-9 safety switches); consolidative allogeneic HSCT; and non-T effectors such as CAR-NK. The durability-versus-aplasia trade-off is stated explicitly as the central unresolved tension.

Section 1.5 — superficial.

Response. Section 1.5 has been tightened and its CD5 biology explicitly linked to the antigen-heterogeneity and subtype-selection arguments developed in Sections 2.1 and 1.10; we are happy to expand specific clinical datasets further if the reviewer identifies priority references.

Section 1.6 — TRBC depth insufficient; TRBC2 not discussed; limitations/resistance missing.

Response. Section 1.6 has been expanded with a paragraph that (i) identifies the TRBC2-restricted population, which is not addressed by TRBC1-directed products and for which dedicated constructs remain undeveloped — a genuine gap; and (ii) sets out the strategy’s limitations: dependence on mutually exclusive constant-region expression, escape via loss or dual expression, immature durability data, and the companion-diagnostic requirement.

Section 1.7 — CD30 literature superficial; expression heterogeneity a major challenge.

Response. A new paragraph in Section 1.7 addresses CD30 expression heterogeneity (bimodal, dim/partial outside ALCL; Bossard et al., Sabattini et al.), its mechanistic link to antigen-density-dependent CAR activity and CD30-low escape, and the resulting insufficiency of a binary “CD30-positive” eligibility criterion, motivating quantitative assessment and dual-targeting.

Section 1.8.1 — limited to CD7-directed CAR-NK; add CD5/CD4/TRBC1.

Response. Section 1.8.1 now adds CD5-directed and CD4-directed CAR-NK approaches (the latter relevant to AITL and CD4-expressing PTCL-NOS) and notes clonal-restricted TRBC1-directed NK constructs as a rational but as-yet-undeveloped avenue, with the general principle that any NK-expressed target still requires genomic disruption in the effector to prevent NK fratricide.

Typographical and formatting inconsistencies.

Response. These have been corrected (detailed under Reviewer 2, language and formatting).

We thank the editors and reviewers once again; we believe the revised manuscript is substantially more balanced, deeper, and more useful, and we hope it is now suitable for publication.

Reviewer 4 Report

Comments and Suggestions for Authors

This is a well-organized and timely review on a difficult, underserved topic. I enjoyed reading through the manuscript; but more detailed discussion would be beneficial. 

My main concern is that the review presents T-ALL/T-LBL data in the trial without separating mature PTCL data, which inflates the apparent maturity of the evidence, especially for CD7 CART trial. Several lineage-specific barriers that are central to whether CAR-T is even feasible in T-cell lymphoma are not discussed, and the overall tone is more optimistic than the data support. The figures are less scientific schematics.

major comments

1. Most of the efficacy data cited is from T-ALL/T-LBL, not mature PTCL. This runs through the entire CD7 section. The 87% CR rate (ref 27) is a pooled figure from 200 patients with CD7+ hematologic malignancies that are overwhelmingly T-ALL/T-LBL; that meta-analysis does not report a mature-PTCL subgroup, so a PTCL-specific CR cannot actually be derived from it.  I would ask the authors to separate T-ALL/T-LBL from mature PTCL for every efficacy claim, to label pooled or lymphoblastic-dominant figures as such.

2. Several major barriers specific to T-cell lymphoma are missing. The abstract lists fratricide, T-cell aplasia, and product contamination, three other problems should be addressed as well:

• Antigen loss is common in advanced disease — CD7 and CD5 are frequently downregulated, creating a pre-existing antigen-negative population available for escape. This is especially relevant given the authors' own statement that CD7 is positive in only ~25% of nodal T-cell lymphomas, which is hard to reconcile with presenting CD7 as a universal target.
• Leukemic/circulating disease is common in Sézary syndrome, ATLL, T-PLL, HSTCL, and certain PTCL; those patients are often excluded from the trials due to circulating disease, but they often represent the group that needs the novel therapies most. 
• Baseline lymphopenia from disease and prior therapy limits both the feasibility and the quality of autologous manufacturing. This is actually a strong argument for the allogeneic platforms the authors favor.

3. Lymphodepletion is not discussed. This is a significant omission. Almost every cited trial uses fludarabine/cyclophosphamide carried over directly from B-cell CAR-T, with no T-cell-specific optimization; even the PTCL-specific NS7CAR-T study used standard flu 30 / cy 300 × 3. This matters because fludarabine is itself durably T-lymphotoxic, so the "profound and prolonged T-cell aplasia" the authors attribute to the CAR is really a combination of baseline lymphopenia, lymphodepleting conditioning, and on-target depletion.  The authors should add a discussion of conditioning and its contribution to toxicity. 

4. The tone is too optimistic. "Substantially reduced these obstacles," and the conclusion's framing ("from biological frustration to significant clinical promise," "increasingly within reach," "replicate the success of CD19") overstate where things stand. Fratricide has been solved at the manufacturing level, but the downstream consequences have not: prolonged cytopenias, infectious deaths (including the EBV-DLBCL case the authors themselves cite), short follow-up, small numbers, highly selective populations, and dependence on consolidative allo-HSCT to rescue aplasia, which means most of this is a bridge rather than definitive therapy. I would tone this down and add a dedicated section that pulls together the T-lineage-specific barriers (antigen loss, leukemic contamination, apheresis-limited lymphopenia, lymphodepletion, and reliance on T-ALL data). That would make the review considerably more balanced and more useful.

5. The figures are decorative. All four appear to be decorative without details in depicting pathogenesis/structure/area to improve. there are mislabeled texts in the figure as well. "Off-the-Stelf," "ALCC," "Angioimuniblisich," "CD0," "Extrandal". those figures might not be necessary. 

6. A couple of the survival figures need correcting or contextualizing.

• The <6-month median OS for r/r disease is in line with the International T-Cell Project (~5.8 months), and reflects a mostly refractory, transplant-ineligible population. Relapsed and transplant-eligible patients do considerably better (3-year survival after relapse ~48% with transplant vs ~18% without; COMPLETE registry ~12.3 months refractory and ~29.1 months relapsed). I would frame it as survival in refractory/transplant-ineligible disease — which is exactly the group CAR-T is meant to bridge.
• minor points

1. please check reference for The bridge-to-transplant statement -> ref 14 (Amador, IHC subclassification)
2. please check on The hPSC-derived CD7-knockout CAR-NK study reference -> Osorio-Rodríguez (ref 50) but appears to be Lin et al. (ref 45)
3. The ROR1 phase I is described as 104 patients, which seems too high for ref 52 — please verify..

language edits

• "ROHAG17V" should be RHOA G17V; "TCRB1/TCRB2" should be TRBC1/TRBC2 (and is correct elsewhere in the text — inconsistent).
• Duplicate references: 1=2, 8=37, 10=20, 14=17, 16=60, 35=36. Ref 24 (Gocke) is incomplete. Garbled entries at refs 42, 49, and 61 .
• Citation style is inconsistent
• Section 1.3 heading has a doubled "and"; the GATA3 subsection is unnumbered.
• Typos: "Aditionallyn the" → "Additionally, in the"; "relaying maily" → "relying mainly"; "promint" → "prominent"; "alctivity" → "activity"; "a 80%" → "an 80%"; "corroborated with the fact that" and "to preventing GvHD" are ungrammatical; run-together words ("andon," "thatCD70," "theirpotential"); and the broken phrase "the broader treatment landscape, - r as a bridge."
• Redundancy: CD5 as a negative regulator of TCR signaling is stated twice in consecutive sentences (1.5); "central effector cells / central role" repeats in the NK section.

Author Response

We thank Reviewer for a detailed and accurate critique, which reshaped the manuscript. We agree with the central point — that lymphoblastic and mature-PTCL evidence must not be conflated, and that several lineage-specific barriers were under-represented — and have addressed it comprehensively.

Major comment 1 — Separate T-ALL/T-LBL from mature PTCL for every efficacy claim; the 87% CR is pooled, lymphoblastic-dominant.

Response. Addressed throughout Section 1.4. The Abstract now states that, for the pan-T targets, the most robust efficacy data still derive largely from T-cell lymphoblastic disease. The 87% figure is now explicitly described as a pooled complete-remission rate from a cohort overwhelmingly comprising T-ALL/T-LBL, with no mature-PTCL subgroup reported, so that a PTCL-specific CR rate cannot be derived from it. The RD13-01 trial is reframed as a mixed CD7-positive population, and Section 2.5 makes the extrapolation caveat explicit.

Major comment 2 — Missing barriers: antigen loss; leukemic/circulating disease; baseline lymphopenia; and the CD7 “~25%” vs universal-target contradiction.

Response. A new Section 2 has been added. Section 2.1 addresses antigen loss/heterogeneity as a pre-existing route to escape (CD7 and CD5 frequently downregulated at baseline); Section 2.2 addresses leukemic/circulating disease (Sézary, ATLL, T-PLL, HSTCL) and the resulting exclusion of the patients who most need therapy; Section 2.3 addresses apheresis-limited lymphopenia and frames it, as the reviewer suggests, as an argument for allogeneic platforms. The internal contradiction has been resolved: the “~25%” figure has been removed, and the text now states that CD7 is frequently downregulated or lost in nodal PTCL (Went et al.), that CAR activity is antigen-density-dependent, and that CD7 status should guide eligibility rather than be presumed universal (Sections 1.4 and 2.1).

Major comment 3 — Lymphodepletion is not discussed.

Response. A dedicated Section 2.4 has been added. It notes that essentially every cited trial uses fludarabine/cyclophosphamide carried over unmodified from B-cell CAR-T (including the PTCL-oriented NS7CAR-T regimen, flu 30 / cy 300 × 3), that fludarabine is itself durably T-lymphotoxic, and that the profound aplasia usually attributed to on-target CAR activity is more accurately a composite of baseline lymphopenia, conditioning, and on-target depletion. Conditioning is identified as a modifiable, understudied variable.

Major comment 4 — The tone is too optimistic; add a dedicated barriers section.

Response. The tone has been recalibrated. In the Abstract, “substantially reduced these obstacles” is replaced by “begun to address these obstacles… while their downstream clinical consequences… remain incompletely resolved.” The Conclusion has been rewritten and condensed (~170 words): the phrases “biological frustration,” “increasingly within reach” and “replicate the success of CD-19” have been removed, and the field is now framed as functioning, for the pan-T targets, largely as a bridge to allogeneic HSCT rather than as definitive therapy. The requested dedicated barriers section is Section 2.

Major comment 5 — The figures are decorative and mislabeled.

Response. Figure 1 has been redesigned as an original scientific schematic that maps molecular subtype → target → anti-fratricide strategy → residual barrier → maturity of evidence, replacing the previous decorative artwork; the mislabeled text (e.g., “Off-the-Stelf,” “ALCC,” “Angioimuniblisich,” “CD0,” “Extrandal”) has been corrected, and the figure source is now stated.

Major comment 6 — Contextualize the survival figures (refractory/transplant-ineligible framing).

Response. The Introduction now frames the poor survival explicitly as that of chemorefractory, transplant-ineligible disease (median overall survival ≈ 5.5 months after relapse without transplantation; Mak et al.), and states that relapsed, transplant-eligible patients fare considerably better (Brink et al.), so that CAR-T is positioned precisely as therapy for the refractory/transplant-ineligible group it is meant to serve.

Minor points.

Response. The bridge-to-transplant statement no longer relies on ref. 14 (Amador); consolidative allogeneic HSCT after CD7 CAR-T is now supported by an appropriate reference (Xu et al., Section 2.5). The hPSC-derived CD7-knockout CAR-NK citation has been corrected. The ROR1 phase I trial (NCT02706392) is corrected from “104 patients” to 21 patients with CLL, triple-negative breast cancer and NSCLC — no T-cell lymphoma (Section 1.9.2).

Language and formatting.

Response. “ROHAG17V” is corrected to RHOA G17V, and “TCRB1/TCRB2” to TRBC1/TRBC2 (Section 1.6). The duplicate references (1=2, 8=37, 10=20, 14=17, 16=60, 35=36), the incomplete Gocke reference (former ref 24, replaced by Went et al.), and the garbled entries (refs 42, 49, 61) have been corrected in the reference manager, and the citation style is now uniformly bracketed. The Section 1.3 heading is corrected to “Biological Impediments: Fratricide and T-Cell Aplasia”; the previously unnumbered GATA3 subsection has been repurposed and numbered as Section 1.10. All flagged typographical errors (“Aditionallyn the,” “relaying maily,” “promint,” “alctivity,” “a 80%,” “andon,” “thatCD70,” “theirpotential,” “corroborated with the fact that,” “to preventing GvHD,” and the broken phrase “the broader treatment landscape, - r as a bridge”) have been corrected. The two redundancies noted (CD5 as a negative regulator, Section 1.5; “central … central” in the NK section) have been removed.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Authors addressed most comments, and the revised manuscript has improved substantially. However, a few minor issues should still be addressed.

1. Line 268: This sentence is unclear and should be revised for clarity: “A binary ‘CD30-positive’ eligibility criterion is therefore insufficient; quantitative or spatial assessment of CD30, and dual-targeting to cover CD30-low fractions, are more rational than uniform application, and the striking results in ALCL and Hodgkin should be extrapolated to the broader PTCL space only with caution.”

 

2. Line 394: The opening part of this sentence is difficult to follow: “The preceding sections argue, target by target, for a principle the field has not yet operationalized: that antigen selection in PTCL should be informed by molecular subtype rather than applied uniformly.”

 

3. Line 400: This sentence would benefit from clarification: “In AITL the follicular-helper program (ICOS, CD10) and the TET2/RHOA-G17V background define a different targetable surface; in ALCL CD30 is near-constitutive; in ENKTL EBV-associated programs bring CD38 and CD70 into range.”

 

4. Line 414: This sentence is overly dense and difficult to follow. Consider revising for readability: “Operationalizing this framework requires pretreatment tools that predict response rather than describe it retrospectively: molecular subtyping by immunohistochemistry or expression profiling to assign GATA3/TBX21 and follicular-helper programs; quantitative and spatial assessment of target-antigen density, given the density-dependence of CAR activity and the CD30 and CD7 heterogeneity discussed above (Sections 1.7 and 2.1); detection of circulating disease to flag apheresis-contamination risk (Section 2.2); and ctDNA and minimal-residual-disease monitoring to identify emerging antigen-negative clones early.”

 

Author Response

Manuscript ID: cancers-4376707

Title: Targeting Peripheral T-Cell Lymphomas with Chimeric Antigen Receptor Therapy: Mechanistic Challenges, Clinical Landscape, and Future Engineering Perspectives

 

 

Authors addressed most comments, and the revised manuscript has improved substantially. However, a few minor issues should still be addressed.

1. Line 268: This sentence is unclear and should be revised for clarity: “A binary ‘CD30-positive’ eligibility criterion is therefore insufficient; quantitative or spatial assessment of CD30, and dual-targeting to cover CD30-low fractions, are more rational than uniform application, and the striking results in ALCL and Hodgkin should be extrapolated to the broader PTCL space only with caution.”

 

Response: We thank the reviewer for pointing out this oversight. We simplified the paragraph. Now it reads: “A caveat specific to CD30 deserves emphasis. Across a series of 376 non-cutaneous PTCLs, CD30 expression by immunohistochemistry was heterogeneous both across and within entities, correlating closely with mRNA levels. The expression was bimodally distributed, separating high- from low-expressing cases, with roughly half of non-anaplastic PTCLs positive at a 5% threshold against near-uniform positivity in ALCL [43,44] Because CAR activity is antigen-density-dependent (Section 2.1), this heterogeneity, dim and partial outside ALCL, plausibly underlies the more modest and less durable responses seen beyond ALCL and constitutes a built-in resistance mechanism, as CD30-low subclones survive and repopulate.  Therefore, a simplistic binary definition of tumoralCD30 positivity is insufficient for the broader PTCLs. Quantitative or spatial assessment of CD30, and dual-targeting to cover CD30-low fractions, are more rational therapeutic approaches. “

(lines 257-259)

 

2. Line 394: The opening part of this sentence is difficult to follow: “The preceding sections argue, target by target, for a principle the field has not yet operationalized: that antigen selection in PTCL should be informed by molecular subtype rather than applied ”

 

Response: We have updated this phrase to make it more logical and easier to follow: “In the preceding sections, we discuss potential individual antigenic CAR-T targets and provide evidence that collectively supports an approach that has yet to be fully translated into clinical practice: antigen selection for CAR-T therapy in PTCL should be individualized according to the molecular features of each disease subtype, rather than relying on a “one-size-fits-all” strategy.”

(lines 394-397)

 

3. Line 400: This sentence would benefit from clarification: “In AITL the follicular-helper program (ICOS, CD10) and the TET2/RHOA-G17V background define a different targetable surface; in ALCL CD30 is near-constitutive; in ENKTL EBV-associated programs bring CD38 and CD70 into range.”

 

Response: We thank the reviewer for the constructive comment. The paragraph now reads: “AITL, a disease driven by TET2/RHOA-G17V alterations, can be targeted using the characteristic T-follicular helper phenotype (ICOS and CD10 expression). In ALCL, the near-constitutive expression of CD30 makes it a particularly attractive target, whereas EBV-associated ENKTL frequently expresses other actionable surface antigens, including CD38 and CD70.”

 

(lines 405-409)

 

4. Line 414: This sentence is overly dense and difficult to follow. Consider revising for readability: “Operationalizing this framework requires pretreatment tools that predict response rather than describe it retrospectively: molecular subtyping by immunohistochemistry or expression profiling to assign GATA3/TBX21 and follicular-helper programs; quantitative and spatial assessment of target-antigen density, given the density-dependence of CAR activity and the CD30 and CD7 heterogeneity discussed above (Sections 1.7 and 1); detection of circulating disease to flag apheresis-contamination risk (Section 2.2); and ctDNA and minimal-residual-disease monitoring to identify emerging antigen-negative clones early.”

 

Response: The section now reads: “Operationalizing this framework requires pretreatment stratification tools. These include molecular subtyping by immunohistochemistry or expression profiling to assign GATA3/TBX21 and follicular-helper differentiation. Additionally, considering the density-dependent CAR activity, as well as CD30 and CD7 heterogenous expression, quantitative and spatial assessment of target-antigen density are essential for target selection. (Sections 1.7 and 2.1). Equally important are detection of circulating disease to determine the risk of apheresis-contamination (Section 2.2); together with ctDNA and minimal-residual-disease monitoring to identify emerging antigen-negative cloness. “

(lines 421-431)