Stem Cells in Regenerative Medicine
- Eva Sykova and Serhiy Forostyak
1: Department of Neuroscience, Institute of Experimental Medicine,
Academy of Science of the Czech Republic, Videnska 1083, Prague, 14220, Czech Republic
2: Department of Neuroscience, 2nd Faculty of Medicine, Charles University,
V Uvalu 84, Prague, 15006, Czech Republic
Abstract
Background: A number of cardiovascular, neurological, musculoskeletal and other diseases have
a limited capacity for repair and only a modest progress has been made in treatment of brain diseases. The discovery of stem cells has opened new possibilities for the treatment of these maladies, and cell therapy now stands at the cutting-edge of modern regenerative medicine and tissue
engineering. Experimental data and the first clinical trials employing stem cells have shown their
broad therapeutic potential and have brought hope to patients suffering from devastating pathologies of different organs and systems.
Aims: Here, we briefly review the main achievements and trends in cell-based therapy, with an
emphasis on the main types of stem cells: embryonic, mesenchymal stromal and induced pluripotent cells.
Discussion: Many questions regarding the application of stem cells remain unanswered, particularly tumorigenicity, immune rejection and danger of gene manipulation. Currently, only MSC
seems to be safe and might be considered to be a leading candidate for human application to treat
pathologies that affect the cardiovascular, neurological and musculoskeletal systems.
Key words: Stem Cells • Embryonic Stem Cells • Mesenchymal Stromal Cells • Induced Pluripotent
Stem Cells • Clinical Trials • PACS: 87.19.L-; 87.19.LW
article original link: click here
References
- Key Statistics for Acute Lymphocytic Leukemia (ALL). 17 October 2018. Accessed 17 March 2024. https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/about/key-statistics.html.
2. Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet Lond Engl. 2013;381(9881):1943-1955.
3. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847.
4. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.
5. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531.
6. Jabbour E, Haddad FG, Short NJ, Kantarjian H. Treatment of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia—from intensive chemotherapy combinations to chemotherapy-free regimens: a review. JAMA Oncol. 2022;8(9):1340-1348.
7. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.
8. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448.
9. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet Lond Engl. 2021;398(10299):491-502.
10. Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2862-2871.
11. Roddie C, Dias J, O’Reilly MA, 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(30):3352-3363.
12. Hay KA, Gauthier J, Hirayama AV, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy. Blood. 2019;133(15):1652-1663.
13. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet Lond Engl. 2015;385(9967):517-528.
14. Ortiz-Maldonado V, Rives S, Español-Rego M, et al. Factors associated with the clinical outcome of patients with relapsed/refractory CD19+ acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy. J Immunother Cancer. 2021;9(12):e003644.
15. Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019;25(9):1408-1414.
16. Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322-3331.
17. Laetsch TW, Maude SL, Rives S, et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA Trial. J Clin Oncol. 2023;41(9):1664-1669.
18. Mueller KT, Maude SL, Porter DL, et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood. 2017;130(21):2317-2325.
19. Schultz LM, Baggott C, Prabhu S, et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a Pediatric Real-World Chimeric Antigen Receptor Consortium Report. J Clin Oncol. 2022;40(9):945-955.
20. Lee DW, Santomasso BD, Locke FL, et al. ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638.
21. Wayne AS, Huynh V, Hijiya N, et al. Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2023;108(3):747-760.
22. Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449-459.
23. Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123-2138.
24. Roloff GW, Aldoss I, Kopmar NE, et al. Brexucabtagene autoleucel in adults with relapsed/refractory B-cell ALL: outcomes and novel insights from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA) [abstract]. Blood. 2023;142(suppl 1):1030.
25. Roloff G, Faramand R, Aldoss I, et al. Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL. J Clin Oncol. 2023;41(16 suppl):7001.
26. Roddie C, Pinto JDA, O’Reilly MA. Safety, efficiency and long-term follow-up of AUTO1, a fast-off rate CD19 CAR in relapsed/refractory B-cell acute lymphoblastic leukaemia and other B-cell malignancies [abstract]. Blood. 2022;140(suppl 1):7452-7453.
27. Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel (obe-cel, AUTO1) for relapsed/refractory adult B-cell acute lymphoblastic leukemia (R/R B-ALL): pooled analysis of the ongoing FELIX phase Ib/II study [abstract]. Blood. 2023;142(suppl 1):222.
28. Jabbour E, Tholouli E, Sandhu KS, et al. Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study [abstract]. J Clin Oncol. 2024;42(16 suppl):6504.
29. Jacoby E, Ghorashian S, Vormoor B, et al. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia. 2022;36(6):1525-1532.
30. Qi Y, Zhao M, Hu Y, et al. Efficacy and safety of CD19-specific CAR T cell–based therapy in B-cell acute lymphoblastic leukemia patients with CNSL. Blood. 2022;139(23):3376-3386.
31. Holland EM, Yates B, Ling A, et al. Characterization of extramedullary disease in B-ALL and response to CAR T-cell therapy. Blood Adv. 2022;6(7):2167-2182.
32. Zhang X, Zhang G, Li W, et al. Factors associated with outcomes among refractory/relapsed TP53-mutated/chromosome 17p deletion acute B-cell lymphoblastic leukemia (B-ALL) patients treated with CD19-targeted chimeric antigen receptor (CAR)-T therapy [abstract]. Blood. 2021;138(suppl 1):3828.
33. Pan J, Tan Y, Deng B, et al. Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children. Leukemia. 2020;34(12):3382-3387.
34. Mishra AK, Burridge S, Espuelas MO, et al. Practice guideline: preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia. Br J Haematol. 2024;204(5):1687-1696.
35. Feuchtinger T, Bader P, Subklewe M, et al. Approaches for bridging therapy prior to chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic B-lineage leukemia in children and young adults. Haematologica. 2024;109(12):3892-3903.
36. Rubinstein JD, Breese EH, Krupski MC, et al. The choice of either conventional chemotherapy or inotuzumab ozogamicin as bridging regimen does not appear to impact clinical response to CD19-directed CAR-T therapy in pediatric B-ALL. Transplant Cell Ther. 2023;29(5):311.e1-311.e7.
37. Ceolin V, Brivio E, van Tinteren H, et al. Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia. Leukemia. 2023;37(1):53-60.
38. Myers RM, Taraseviciute A, Steinberg SM, et al. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol. 2022;40(9):932-944.
39. Fabrizio VA, Boelens JJ, Mauguen A, et al. Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy. Blood Adv. 2022;6(7):1961-1968.
40. Turtle CJ, Hanafi LA, Berger C, et al. Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptor-modified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia. Blood J. 2015;126(23):3773.
41. Dekker L, Calkoen FG, Jiang Y, et al. Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia. Blood Adv. 2022;6(7):1969-1976.
42. Ghilardi G, Chong EA, Svoboda J, et al. Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas. Ann Oncol. 2022;33(9):916-928.
43. Frey NV, Shaw PA, Hexner EO, et al. Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia. J Clin Oncol. 2020;38(5):415-422.
44. Frey NV, Porter DL. CAR T-cells merge into the fast lane of cancer care. Am J Hematol. 2016;91(1):146-150.
45. Myers RM, Kadauke S, Li Y, et al. Risk-adapted preemptive tocilizumab decreases severe cytokine release syndrome (CRS) after CTL019 CD19-targeted chimeric antigen receptor (CAR) T-cell therapy for pediatric B-cell acute lymphoblastic leukemia (B-ALL). Biol Blood Marrow Transplant. 2020;26(3):920-931.
46. Park JH, Nath K, Devlin SM, et al. CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results. Nat Med. 2023;29(7):1710-1717.
47. Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med. 2019;11(499):eaau5907.
48. Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv. 2019;3(5):711-717.
49. Gu C, Wu Q, Zhang J, et al. Successful treatment of severe cytokine release syndrome after CAR-T therapy by ruxolitinib without compromising CAR-T efficacy. Leuk Lymphoma. 2023;64(2):495-498.
50. Frigault MJ, Maziarz RT, Park JH, et al. Itacitinib for the prevention of immune effector cell therapy-associated cytokine release syndrome: results from the Phase 2 Incb 39110-211 placebo-controlled randomized cohort [abstract]. Blood. 2023;142(suppl 1):356.
51. Sterner RM, Sakemura R, Cox MJ, et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood. 2019;133(7):697-709.
52. Manni S, Del Bufalo F, Merli P, et al. Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies. Nat Commun. 2023;14(1):3423.
53. Zurko JC, Johnson BD, Aschenbrenner E, et al. Use of early intrathecal therapy to manage high-grade immune effector cell-associated neurotoxicity syndrome. JAMA Oncol. 2022;8(5):773-775.
54. Shalabi H, Harrison C, Yates B, Calvo KR, Lee DW, Shah NN. Intrathecal hydrocortisone for treatment of children and young adults with CAR T-cell immune-effector cell-associated neurotoxicity syndrome. Pediatr Blood Cancer. 2024;71(1):e30741.
55. Kim DW, Bukhari A, Lutfi F, et al. Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma. Leuk Lymphoma. 2022;63(6):1339-1347.
56. Lichtenstein DA, Schischlik F, Shao L, et al. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells. Blood. 2021;138(24):2469-2484.
57. Jain T, Knezevic A, Pennisi M, et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv. 2020;4(15):3776-3787.
58. O’Reilly MA, Neill L, Collin SM, et al. High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma. HemaSphere. 2024;8(1):e29.
59. Haidar G, Garner W, Hill JA. Infections after anti-CD19 chimeric antigen receptor T-cell therapy for hematologic malignancies: timeline, prevention, and uncertainties. Curr Opin Infect Dis. 2020;33(6):449-457.
60. Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. 2022;33(3):259-275.
61. Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med. 2024;390(7):584-586.
62. Hamilton MP, Sugio T, Noordenbos T, et al. Risk of second tumors and T-cell lymphoma after CAR T-cell therapy. N Engl J Med. 2024;390(22):2047-2060.
63. Lamble AJ, Schultz LM, Nguyen K, et al. Risk of T-cell malignancy after CAR T-cell therapy in children, adolescents, and young adults. Blood Adv. 2024;8(13):3544-3548.
64. Ozdemirli M, Loughney TM, Deniz E, et al. Indolent CD4+ CAR T-cell lymphoma after cilta-cel CAR T-cell therapy. N Engl J Med. 2024;390(22):2074-2082.
65. Ghilardi G, Fraietta JA, Gerson JN, et al. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med. 2024;30(4):984-989.
66. Shiqi L, Jiasi Z, Lvzhe C, et al. Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T. Mol Ther Oncolytics. 2023;29:107-117.
67. Turicek DP, Giordani VM, Moraly J, Taylor N, Shah NN. CAR T-cell detection scoping review: an essential biomarker in critical need of standardization. J Immunother Cancer. 2023;11(5):e006596.
68. Gkazi SA, Gravett E, Bautista C, Bartram J, Ghorashian S, Adams SP. Clinically applicable assessment of tisagenlecleucel CAR T cell treatment by digital droplet PCR for copy number variant assessment. Int J Mol Sci. 2022;23(14):7573.
69. Pulsipher MA, Han X, Maude SL, et al. Next-generation sequencing of minimal residual disease for predicting relapse after tisagenlecleucel in children and young adults with acute lymphoblastic leukemia. Blood Cancer Discov. 2022;3(1):66-81.
70. Dourthe ME, Rabian F, Yakouben K, et al. Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia. Leukemia. 2021;35(12):3383-3393.
71. Lamble AJ, Moskop A, Pulsipher MA, et al. INSPIRED Symposium Part 2: Prevention and Management of Relapse Following Chimeric Antigen Receptor T Cell Therapy for B Cell Acute Lymphoblastic Leukemia. Transplant Cell Ther. 2023;29(11):674-684.
72. Ganzel C, Wang XV, Rowe JM, et al. At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial. Br J Haematol. 2020;191(1):37-43.
73. Biasco L, Izotova N, Rivat C, et al. Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients. Nat Can (Ott). 2021;2(6):629-642.
74. Finney OC, Brakke HM, Rawlings-Rhea S, et al. CD19 CAR T cell product and disease attributes predict leukemia remission durability. J Clin Invest. 2019;129(5):2123-2132.
75. Leahy AB, Devine KJ, Li Y, et al. Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy. Blood. 2022;139(14):2173-2185.
76. Myers RM, Taraseviciute A, Steinberg SM, et al. Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL. J Clin Oncol. 2021;40(9):932-945.
77. Gabelli M, Oporto-Espuelas M, Bonney DK, et al. Maintenance therapy for early loss of B-cell aplasia after CD19 CAR T-cell therapy. Blood Adv. 2024;8(8):1959-1963.
78. Pan J, Yang JF, Deng BP, et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia. 2017;31(12):2587-2593.
79. Shadman M, Gauthier J, Hay KA, et al. Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy. Blood Adv. 2019;3(20):3062-3069.
80. Nagler A, Labopin M, Dholaria B, et al. Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation. Br J Haematol. 2019;186(5):767-776.
81. Chen LY, Gong WJ, Li MH, et al. Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia. Blood Adv. 2023;7(17):4913-4925.
82. Cassaday RD, Garcia KLA, Fromm JR, et al. Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia. Blood Adv. 2020;4(14):3239-3245.
83. Li AM, Hucks GE, Dinofia AM, et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia [abstract]. Blood. 2018;132(suppl 1):556.
84. Elsallab M, Ellithi M, Hempel S, Abdel-Azim H, Abou-el-Enein M. Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis. Cancer Gene Ther. 2023;30(6):845-854.
85. Sun W, Malvar J, Sposto R, et al. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia & Lymphoma study. Leukemia. 2018;32(11):2316-2325.
86. Wudhikarn K, King AC, Geyer MB, et al. Outcomes of relapsed B-cell acute lymphoblastic leukemia after sequential treatment with blinatumomab and inotuzumab. Blood Adv. 2022;6(5):1432-1443.
87. Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282-1295.
88. Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20-28.
89. Shah NN, Highfill SL, Shalabi H, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I Anti-CD22 CAR T-Cell Trial. J Clin Oncol. 2020;38(17):1938-1950.
90. Pan J, Niu Q, Deng B, et al. CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia. 2019;33(12):2854-2866.
91. Schultz LM, Jeyakumar N, Kramer AM, et al. CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: phase 1b results. Leukemia. 2024;38(5):963-968.
92. Cordoba S, Onuoha S, Thomas S, et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med. 2021;27(10):1797-1805.
93. Shalabi H, Qin H, Su A, et al. CD19/22 CAR T-cells in children and young adults with B-ALL: phase I results and development of a novel bicistronic CAR. Blood. 2022;140(5):451-463.
94. Spiegel JY, Patel S, Muffly L, et al. T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med. 2021;27(8):1416-1431.
95. Gardner R, Annesley C, Finney O, et al. Early clinical experience of CD19 x CD22 dual specific CAR T cells for enhanced anti-leukemic targeting of acute lymphoblastic leukemia [abstract]. Blood. 2018;132(suppl 1):278.
96. Annesley C, Summers C, Pulsipher MA, et al. SCRI-CAR19x22v2 T cell product demonstrates bispecific activity in B-ALL [abstract]. Blood. 2021;138(suppl 1):470.
97. Ghorashian S, Lucchini G, Richardson R, et al. CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL. Blood. 2024;143(2):118-123.
98. Wang T, Tang Y, Cai J, et al. Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial. J Clin Oncol. 2023;41(9):1670-1683.
99. Pan J, Tang K, Luo Y, et al. Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2023;24(11):1229-1241.
100. Gauthier J, Bezerra ED, Hirayama AV, et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood. 2021;137(3):323-335.
101. Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022;10(5):e004483.
102. Xu Q, Shi Y, Xue L, et al. Outcomes of second anti-CD19 CAR T-cell therapy (CART2) in acute B lymphoblastic leukemia and the impact of Allo-HSCT on efficacy. Cell Transplant. 2023;32:09636897231204724.
103. Myers RM, Li Y, Barz Leahy A, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T cells in CAR-naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. J Clin Oncol. 2021;39(27):3044-3055.
104. Zarebski LM, Urrutia M, Goldbaum FA. Llama single domain antibodies as a tool for molecular mimicry. J Mol Biol. 2005;349(4):814-824.
105. Sun Y, Yang XN, Yang SS, et al. Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity. Signal Transduct Targeted Ther. 2023;8(1):445. 12.
106. Benjamin R, Jain N, Maus MV, et al; CALM Study Group. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol. 2022;9(11):e833-e843.
107. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf’ allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19(3):185-199.
108. Chattaraj A, Rehman MEU, Khan I, et al. Safety and efficacy of allogeneic CAR-T cells in B-cell malignancies: a systematic review and meta-analysis. J Clin Oncol. 2022;40(16 suppl):e19530.
109. Yang J, He J, Zhang X, 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(7):104.
110. Klebanoff CA, Crompton JG, Leonardi AJ, et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight. 2017;2(23):e95103.
111. Mehra V, Agliardi G, Dias Alves Pinto J, et al. AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival. J Immunother Cancer. 2023;11(9):e007002.
112. Di M, Long JB, Isufi I, et al. Total costs of care during chimeric antigen receptor T-cell therapy in patients with relapsed/refractory B cell non-Hodgkin lymphoma: a large private insurance claim-based analysis [abstract]. Blood. 2022;140(suppl 1):10818-10819.
113. Castella M, Boronat A, Martín-Ibáñez R, et al. Development of a novel anti-CD19 chimeric antigen receptor: a paradigm for an affordable CAR T cell production at academic institutions. Mol Ther Methods Clin Dev. 2019;12:134-144.
114. Mallapaty S. Cutting-edge CAR-T cancer therapy is now made in India — at one-tenth the cost. Nature. 2024;627(8005):709-710.
115. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022;28(4):735-742.
