Evaluation of the Efficacy and Safety of Chimeric Antigen Receptor-Modified T (CAR-T) Cell Therapy in Leukemia: A Five-Year Updated Systematic Review and Meta-analysis

I Gede Wikania Wira Wiguna; I Gede Krisna Arim Sadeva; Christo Timothy Mamangdean; Putu Mirah Wahyu Subagia Putri; Kadek Meryndha Kumala Tungga; I Komang Raditya Putra Pratama; Agung Brahmanthya Nadine Kepakisan; Komang Indra Parama Arta; Putu Ari Shanti Dewi; I Gede Putu Supadmanaba; Desak Made Wihandani

doi:10.31584/jhsmr.20251201

Authors

I Gede Wikania Wira Wiguna Graduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia.
I Gede Krisna Arim Sadeva Graduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia.
Christo Timothy Mamangdean Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
Putu Mirah Wahyu Subagia Putri Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
Kadek Meryndha Kumala Tungga Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
I Komang Raditya Putra Pratama Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
Agung Brahmanthya Nadine Kepakisan Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
Komang Indra Parama Arta Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
Putu Ari Shanti Dewi Undergraduated Student, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia
I Gede Putu Supadmanaba Department of Biochemistry, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia.
Desak Made Wihandani Department of Biochemistry, Faculty of Medicine, Udayana University, Denpasar, Bali 80232, Indonesia.

DOI:

https://doi.org/10.31584/jhsmr.20251201

Keywords:

CAR-T cell therapy, efficacy, Leukemia, safety

Abstract

Objective: Despite the progress made by conventional treatments in reducing mortality rates, the significant number of relapsed or refractory patients necessitates the exploration of novel therapies. Recent studies on chimeric antigen receptor T-cell therapy (CAR-T) cells have shown promising outcomes for individuals battling blood cancers. However, the outcomes are still inconsistent due to the structural complexity of CAR-T cells and the rapid development of more advanced versions. This study evaluated the efficacy and safety of various CAR-T cells in Leukemia patients.
Material and Methods: The preferred reporting items for systematic reviews and meta-analysis 2020 protocol was used for the literature search and systematic review. Studies reporting CAR-T cell therapy’s efficacy and safety in Leukemia patients were included. Statistical analyses were performed using R statistical software v.3.3. P-values≤0.05 were considered statistically significant.
Results: Eighteen single-arm clinical trials were included based on the inclusion criteria. Most of the studies involved patients with acute Lymphoblastic Leukemia. CAR-T cell therapy in Leukemia achieved a 79% (95% confidence interval [CI] [69%-87%], I²=74%) complete response, 79% (95% CI [59%-91%], I²=87%) cytokine release syndrome event, 18% (95% CI [9%-33%], I²=72%) immune effector cell-associated neurotoxicity syndrome event rate, 69% (95% CI [47%-85%], I²=82%) minimal residual disease-negative, and a 9% (95% CI [8%-13%], I²=37%) mortality rate.
Conclusion: CAR-T therapy has demonstrated efficient responses in Leukemia patients, reinforcing the positive outcomes observed with favorable toxicities. Further data regarding the durability of CAR-T cell therapy are essential for strengthening our understanding of CAR-T cell efficacy and safety in Leukemia patients.

References

Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117:5019.

Leukemia — Cancer stat facts [homepage on the Internet]. Bethesda: National Institutes of Health; 2022 [cited 2023 Oct 30]. Avaliable from: https://seer.cancer.gov/statfacts/html/leuks.html.

Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 2017;7:e577.

Sermer D, Brentjens R. CAR T-cell therapy: Full speed ahead. Hematol Oncol 2019;37:95–100.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ;2021:372. doi: 10.1136/BMJ.N71.

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ;366:I4898. doi: 10.1136/BMJ.L4898.

Heng G, Jia J, Li S, Zhang Y, Wang T, Liu F, et al. Sustained therapeutic efficacy of humanized anti-CD19 chimeric antigen receptor T cells in relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res 2020;26:1606-15.

Yang J, He J, Zhang X, Liu Y, Zhou S, Wang Z, et al. Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study. Blood Cancer J 2022;12:104.

Long AH, Haso WM, Shern JF, Lee W, Wu M, Wang X, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015;21:581-90.

Jacoby E, Bielorai B, Avigdor A, Zuckerman T, Shouval R, Besser MJ, et al. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol 2018;93:1485-92.

Gong WJ, Qiu Y, Li MH, Chen LY, Li YY, Yu JQ, et al. Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy. Front Immunol 2022;13:922212. doi: 10.3389/fimmu.2022.922212.

Hu Y, Zhou Y, Zhang M, Wang Y, Chen X, Liu H, et al. CRISPR/Cas9-Engineered Universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res 2021;27:2764-72.

Zhao H, Wei J, Wei G, Luo Y, Shi J, Cui Q, et al. Pre-transplant MRD negativity predicts favorable outcomes of CAR-T therapy followed by haploidentical HSCT for relapsed/refractory acute lymphoblastic leukemia: a multi-center retrospective study. J Hematol Oncol 2020;13:42.

Wang J, Mou N, Yang Z, Zhang L, Zhao X, Wei L, et al. Efficacy and safety of humanized anti-CD19 CAR T therapy following intensive lymphodepleting chemotherapy for refractory/relapsed B acute lymphoblastic leukaemia. Br J Haematol 2020;191:212-22.

Dai H, Wu Z, Jia H, Wang X, Wang Y, Zhang H, et al. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J Hematol Oncol 2020;13:30.

Ortíz-Maldonado V, Rives S, Castellà M, Gutiérrez C, Salazar R, Granados I, et al. CART19-BE-01: a multicenter trial of ARI-0001 cell therapy in patients with CD19+ relapsed/refractory malignancies. Mol Ther 2021;29:636-44.

Niu J, Qiu H, Xiang F, Zhang Y, Liu Z, Wang X, et al. CD19/CD22 bispecific CAR-T cells for MRD-positive adult B cell acute lymphoblastic leukemia: a phase I clinical study. Blood Cancer J 2023;13:44.

Li M, Xue S-L, Tang X, Li Y, Wang Y, Xu Z, et al. The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients. Sci Rep 2022;12:378.

Zhao X, Yang J, Zhang X, Liu X, Sun Y, Zhang Y, et al. Efficacy and safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell acute lymphoblastic leukemia. Mol Ther Oncolytics 2020;18:272–81.

Jiang H, Li C, Yin P, Wang H, Zhang Y, Liu Y, et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: an open-label pragmatic clinical trial. Am J Hematol 2019;94:1113–22.

Lu W, Wei Y, Cao Y, Zhang Y, Chen Y, Wang H, et al. CD19 CAR-T cell treatment conferred sustained remission in B-ALL patients with minimal residual disease. Cancer Immunol Immunother 2021;70:3501–11.

Roddie C, Dias J, O’Reilly MA, Reshmi S, Maloney D, Hosing C, et al. Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. J Clin Oncol 2021;39:3352–63.

Davila ML, Brentjens RJ. CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Clin Adv Hematol Oncol 2016;14: 802–8.

Ma F, Ho JY, Du H, Li J, Zhang Y, Wang H, et al. Evidence of long-lasting anti-CD19 activity of engrafted CD19 chimeric antigen receptor-modified T cells in a phase I study targeting pediatrics with acute lymphoblastic leukemia. Hematol Oncol 2019;37:601–8.

Zhang Y, Chen H, Song Y, Liu W, Xu X, Li X, et al. Chimeric antigen receptor T-cell therapy as a bridge to haematopoietic stem cell transplantation for refractory/relapsed B-cell acute lymphoblastic leukemia. Br J Haematol 2020;189:146–52.

Jiang H, Li C, Yin P, Zhang X, Liu Y, Wang J, et al. Anti-CD19 chimeric antigen receptor-modified T-cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia: an open-label pragmatic clinical trial. Am J Hematol 2019;94:1113–22.

Frey NV, Shaw PA, Hexner EO, Lacey SF, Porter DL, Schuster SJ, et al. Optimizing chimeric antigen receptor T-Cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol 2020;38:415–22.

Itzhaki O, Jacoby E, Nissani A, Baruch R, Shapira-Frommer R, Schachter J, et al. Head-to-head comparison of in-house produced CD19 CAR-T cell in ALL and NHL patients. J Immunother Cancer 2020;8:e000148. doi: 10.1136/JITC-2019-000148.

Niu J, Qiu H, Xiang F, Zhang Z, Zhou H, Li Y, et al. CD19/CD22 bispecific CAR-T cells for MRD-positive adult B cell acute lymphoblastic leukemia: a phase I clinical study. Blood Cancer J 2023;13:1-4.