CAR-T Cells in Canada; Perspective on How to Ensure We Get Our Value’s Worth

Round 1

Reviewer 1 Report

CAR-T cell therapy is an innovative treatment approach to combat cancer, especially in the cases of B cell lymphoma and acute lymphoblastic leukemia.  Despite the revolution in the field, CAR-T cell therapy is still in the early stages of implementation, thus many questions need to be addressed before it becomes broadly available to cancer patients. In this perspective paper, the authors provide their opinion on different aspects of CAR-T cell therapy, including the clinical effectiveness, drug review process in Canada, funding, and cost of treatment. The points raised about the cost and complexity of manufacturing are of a great value and should be carefully considered by the scientific community working on CAR-T cell therapies. Overall, the manuscript is well-written, easy to follow, and clearly provides the authors’ view on this subject.  I am confident that the manuscript will be well-received by the readers of Current Oncology.

Author Response

I thank the reviewer for having reviewed the manuscript and for his/her comments.  No specific corrections were made based on comments.

Reviewer 2 Report

In their current perspective authors discuss the use of CAR-T cells in Canada with emphasis on regulatory and reimbursement policies. The topic and overall idea are interesting. Few suggestions are listed below for the authors to address the concerns of a reader.

The manuscript could benefit from adopting a neutral tone with regards to the use of CAR-T cells as in the current version it seems like authors are more or less recommending against the use of CAR-T cells. As more and more data is generated, authors statements on uncertain long-term benefits and cost-effectiveness of CAR-T cells, could become inaccurate. In fact, authors based their perspective on handful of papers published 4-5 years back when abundant literature has been generated in the last couple of years. Authors need to review recently published literature and tone down their narrative. To present an unbiassed opinion, authors need to base their narrative on at least 70-100 articles instead of just 21 articles.

While it is acceptable for the authors to focus on regulatory status of CAR-T cells in Canada, authors need to be mindful of approvals in neighboring US as well. In that context, authors could have also added discussion on CAR-T cells for multiple myeloma where the response rates are almost 100% and durability of response is very encouraging.

Page 2, line 48: It is not completely accurate that the percentage of patients who had leukopheresis but did not receive CAR-T cells is poorly reported. Almost all of the clinical trials do report the patient flow through consort diagram. If authors believe that the data is not properly reported, the respective sentence should be supported by references to studies that did not report percentage of patients who did not receive CAR-T cells.

Authors statement that phase III RCT data and cost-effectiveness data is not available for tisa-cel and axi-cel is not accurate. Phase III study results have been published for both drugs (see Bishiop et al DOI: 10.1056/NEJMoa2116596 and Locke et al 10.1056/NEJMoa2116133 for example) and patient reported outcomes as well as cost-effectiveness analysis have been published for both drugs (e.g. Elsawy et al DOI: 10.1182/blood.2022015478 and Choe et al  DOI: 10.1001/jamanetworkopen.2022.45956). Authors need to revise the manuscript accordingly.

Authors could consider commenting on dose considerations using the references Dasyam et al 2020 (https://doi.org/10.1111/bcp.14281), Stefanski et al 2023 (https://doi.org/10.1182/bloodadvances.2022007246), Rotte et al 2022 (http://dx.doi.org/10.1136/jitc-2022-005678) Barros et al 2021 (https://doi.org/10.3390/cancers13122941) and Frigault et al 2023 (https://doi.org/10.1186/s13046-022-02540-w).

Page 2, line 70: did authors mean 840 million Canadian dollars? If yes, authors need to be clear because 840 million USD is not accurate.

Section 4: Drug review process in Canada seems out of context and aligns with CAR-T cell review only towards the end of the section. Authors could consider revising the section.

Sections 5, 6, 7 and 8 seem to be written with bias against CAR-T cell therapies. For example, heading of section 5 itself says “uncertainty around clinical benefit”. Authors need to consider latest literature and make their message neutral.

Author Response

Please fine enclosed the answers and corrections for the second reviewer.

Author Response File: Author Response.docx

Reviewer 3 Report

In this perspective manuscript, the authors discuss the value of CAR T-based therapies in Canada and address the challenges facing this cancer treatment approach. The manuscript is well written, and should be of great interest to the readers. Nevertheless, it is necessary for the authors to include the ABSTRACT in the text.

Author Response

Attached is a copy of the abstract, as suggested by the reviewer

Author Response File: Author Response.docx

Reviewer 4 Report

This is an interesting perspective on CAR-T cell therapy in hematology and oncology. They address important topics on Manufacturing and delivery of CAR-T cells, Clinical Effectiveness of CAR-T cells, the current scenario in Canada with cost analysis, and uncertainty around clinical benefit.

The manuscript is well-written and of current clinical significance and relevance. However, the manuscript would benefit and could be further improved by discussing the role of CAR-T cell therapy in other oncological settings. Since recently is emerging the role of immunotherapy with immune checkpoints inhibitors, the authors could discuss some examples of potential applications of CAR-T cell therapy such as hepatocellular carcinoma, one of the most frequent cancers worldwide, whose treatment is dramatically changing with immunotherapy alone or combined with tyrosine kinase inhibitors but also with encouraging data from CAR-T therapy, as recently well described (TKIs in combination with immunotherapy for hepatocellular carcinoma. Expert Rev Anticancer Ther. 2023 Feb 16. doi: 10.1080/14737140.2023.2181162; Hepatocellular Carcinoma: Current Therapeutic Algorithm for Localized and Advanced Disease. J Oncol. 2022 Dec 31;2022:3817724).

Author Response

Please find attached the answers to Reviewer 4.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

No comments

Author Response

The authors agreed with the reviewer’s comments and have amended the manuscript accordingly.

'In the BELINDA trial, where tisagenlecleucel was compared head-to-head with SOC, CAR-T therapy was not superior compared to SOC (15), probably due, at least in part, to the fact that patients enrolled in the BELINDA trial have higher risk features than those enrolled in the ZUMA-7 trial, thus possibly skewing the results unfavorably for CAR-T therapy (Roschewski M et al., NEJM 2022)'.