Benefits of Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma

Wenyujing Zhou, Weihong Chen, Xiaochun Wan, Changru Luo, Xin Du, Xiaoqing Li, Qian Chen, Ruiwen Gao, Xiaohan Zhang, Mei Xie, Mingjun Wang, Wenyujing Zhou, Weihong Chen, Xiaochun Wan, Changru Luo, Xin Du, Xiaoqing Li, Qian Chen, Ruiwen Gao, Xiaohan Zhang, Mei Xie, Mingjun Wang

Abstract

Objective: The aim was to study the benefits and risks of anti-CD19 chimeric antigen receptor (CAR) T-cells in adults with B-cell lymphoma. Methods: From October 2015 to October 2021, we treated five patients with B-cell lymphoma, comprising two with mantle cell lymphoma, one case of Burkitt lymphoma, one case of diffuse large B-cell lymphoma, and one case of chronic lymphocytic leukemia/small lymphocytic lymphoma. The patients were given the FC regimen 5 days before the infusion of anti-CD19 CAR T-cells. The median total number of CAR T-cells infusions was 350*10^6 (88*10^6-585*10^6). Results: 1) Patients who received CAR T-cell induction therapy achieved complete remission (CR) in Case 1 and Case 3 and partial remission (PR) in Case 2. Case 3's ATM and D13S25 gene deletions were negative 42 days after CAR T-cell therapy, and molecular biology CR (mCR) and minimal residual disease (MRD) were negative for 5 years and 6 months. The patient in Case 3 was cured. 2) Case 4 patient's TP53 gene mutation became negative 1 month after CAR T-cell therapy. MRD was negative after CAR T-cell therapy at 41 and 42 months in Cases 4 and 5, respectively. 3) Case 1∼Case 3 patients developed cytokine release syndrome (CRS) without encephalopathy syndrome, accompanied with serious adverse events. CRS can be effectively managed with tocilizumab, etanercept, glucocorticoids, and plasmapheresis. Conclusion: Anti-CD19 CAR T-cell therapy is effective in treating relapsed/refractory B-cell lymphoma, and the side effects of CAR T-cell therapy can be properly managed. CAR T-cell therapy has high efficacy and presented no side effects in the treatment of MRD in B-cell lymphoma (NCT03685786, NCT02456350).

Keywords: CD19; CRS; anti-CD19 CAR T-cell; benefit; relapsed/refractory B-cell lymphoma.

Conflict of interest statement

QC was employed by the Company Shenzhen BinDeBioTech Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zhou, Chen, Wan, Luo, Du, Li, Chen, Gao, Zhang, Xie and Wang.

Figures

FIGURE 1
FIGURE 1
Trend of CD19 and CAR.
FIGURE 2
FIGURE 2
Changes in temperature and IL-6 after transfusion of CAR T-cells in patients with CRS.
FIGURE 3
FIGURE 3
Trend of other indirect monitoring indicators.
FIGURE 4
FIGURE 4
Trend of IL-10 and EBV-DNA copies of Case 2.

References

    1. Adachi K., Kano Y., Nagai T., Okuyama N., Sakoda Y., Tamada K. (2018). IL-7 and CCL19 Expression in CAR-T Cells Improves Immune Cell Infiltration and CAR-T Cell Survival in the Tumor. Nat. Biotechnol. 36, 346–351. 10.1038/nbt.4086
    1. Beatty P. R., Krams S. M., Martinez O. M. (1997). Involvement of IL-10 in the Autonomous Growth of EBV-Transformed B Cell Lines. J. Immunol. 158, 4045–4051.
    1. Bonati L. H., Dobson J., Featherstone R. L., Ederle J., van der Worp H. B., de Borst G. J., et al. (2015). Long-term Outcomes after Stenting versus Endarterectomy for Treatment of Symptomatic Carotid Stenosis: the International Carotid Stenting Study (ICSS) Randomised Trial. The Lancet 385, 529–538. 10.1016/s0140-6736(14)61184-3
    1. Carpenito C., Milone M. C., Hassan R., Simonet J. C., Lakhal M., Suhoski M. M., et al. (2009). Control of Large, Established Tumor Xenografts with Genetically Retargeted Human T Cells Containing CD28 and CD137 Domains. Proc. Natl. Acad. Sci. 106, 3360–3365. 10.1073/pnas.0813101106
    1. Chasov V., Mirgayazova R., Zmievskaya E., Khadiullina R., Valiullina A., Stephenson Clarke J., et al. (2020). Key Players in the Mutant P53 Team: Small Molecules, Gene Editing, Immunotherapy. Front. Oncol. 10, 1460. 10.3389/fonc.2020.01460
    1. Cheson B. D., Leonard J. P. (2008). Monoclonal Antibody Therapy for B-Cell Non-hodgkin's Lymphoma. N. Engl. J. Med. 359, 613–626. 10.1056/nejmra0708875
    1. Coiffier B., Sarkozy C. (2016). Diffuse Large B-Cell Lymphoma: R-CHOP Failure-What to Do? Hematol. Am. Soc. Hematol. Educ. Program 2016, 366–378. 10.1182/asheducation-2016.1.366
    1. Crump M., Neelapu S. S., Farooq U., Van Den Neste E., Kuruvilla J., Westin J., et al. (2017). Outcomes in Refractory Diffuse Large B-Cell Lymphoma: Results from the International SCHOLAR-1 Study. Blood 130, 1800–1808. 10.1182/blood-2017-03-769620
    1. Davila M. L., Riviere I., Wang X., Bartido S., Park J., Curran K., et al. (2014). Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci. Transl. Med. 6, 224ra25–225r. 10.1126/scitranslmed.3008226
    1. Davila M. L., Bouhassira D. C. G., Park J. H., Curran K. J., Smith E. L., Pegram H. J., et al. (2014). Chimeric Antigen Receptors for the Adoptive T Cell Therapy of Hematologic Malignancies. Int. J. Hematol. 99, 361–371. 10.1007/s12185-013-1479-5
    1. Davis J. M., Knutson K. L., Strausbauch M. A., Crowson C. S., Therneau T. M., Wettstein P. J., et al. (2010). Analysis of Complex Biomarkers for Human Immune-Mediated Disorders Based on Cytokine Responsiveness of Peripheral Blood Cells. J. Immunol. 184, 7297–7304. 10.4049/jimmunol.0904180
    1. Deeks E. D. (2017). GP2015: An Etanercept Biosimilar. BIODRUGS 31, 555–558. 10.1007/s40259-017-0246-1
    1. Dotti G., Gottschalk S., Savoldo B., Brenner M. K. (2014). Design and Development of Therapies Using Chimeric Antigen Receptor-Expressing T Cells. Immunol. REV. 257, 107–126. 10.1111/imr.12131
    1. Enblad G., Karlsson H., Loskog A. S. I. (2015). CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma. Hum. Gene. Ther. 26, 498–505. 10.1089/hum.2015.054
    1. Essand M., Loskog A. S. I. (2013). Genetically Engineered T Cells for the Treatment of Cancer. J. Intern. Med. 273, 166–181. 10.1111/joim.12020
    1. FDA (2021). FDA Approves Lisocabtagene Maraleucel for Relapsed or Refractory Large B-Cell Lymphoma.
    1. FDA (2017). FDA Approves Tisagenlecleucel for B-Cell ALL and MCL and Tocilizumab for Cytokine Release Syndrome.
    1. Filley A. C., Henriquez M., Dey M. (2018). CART Immunotherapy: Development, Success, and Translation to Malignant Gliomas and Other Solid Tumors. Front. Oncol. 8, 453. 10.3389/fonc.2018.00453
    1. Fischer J., Paret C., El Malki K., Alt F., Wingerter A., Neu M. A., et al. (2017). CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis. J. Immunother. 40, 187–195. 10.1097/cji.0000000000000169
    1. Frey N., Porter D. (2019). Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy. Biol. Blood Marrow Transplant. 25, e123–e127. 10.1016/j.bbmt.2018.12.756
    1. Frey N. V., Porter D. L. (2016). Cytokine Release Syndrome with Novel Therapeutics for Acute Lymphoblastic Leukemia. Hematol. Am. Soc. Hematol. Educ. Program. 2016, 567–572. 10.1182/asheducation-2016.1.567
    1. Giavridis T., van der Stegen S. J. C., Eyquem J., Hamieh M., Piersigilli A., Sadelain M. (2018). CAR T Cell-Induced Cytokine Release Syndrome Is Mediated by Macrophages and Abated by IL-1 Blockade. Nat. Med. 24, 731–738. 10.1038/s41591-018-0041-7
    1. Grupp S. A., Kalos M., Barrett D., Aplenc R., Porter D. L., Rheingold S. R., et al. (2013). Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia. N. Engl. J. Med. 368, 1509–1518. 10.1056/nejmoa1215134
    1. Hay K. A., Hanafi L.-A., Li D., Gust J., Liles W. C., Wurfel M. M., et al. (2017). Kinetics and Biomarkers of Severe Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy. Blood 130, 2295–2306. 10.1182/blood-2017-06-793141
    1. Hunter C. A., Jones S. A. (2015). IL-6 as a keystone Cytokine in Health and Disease. NAT. Immounl. 16, 448–457. 10.1038/ni.3153
    1. Imai C., Mihara K., Andreansky M., Nicholson I. C., Pui C.-H., Geiger T. L., et al. (2004). Chimeric Receptors with 4-1BB Signaling Capacity Provoke Potent Cytotoxicity against Acute Lymphoblastic Leukemia. Leukemia 18, 676–684. 10.1038/sj.leu.2403302
    1. Irons R. D., Le A. T. (2008). Dithiocarbamates and Viral IL-10 Collaborate in the Immortalization and Evasion of Immune Response in EBV-Infected Human B Lymphocytes. Chemico-Biological Interactions 172, 81–92. 10.1016/j.cbi.2007.11.005
    1. Kochenderfer J. N., Dudley M. E., Kassim S. H., Somerville R. P. T., Carpenter R. O., Stetler-Stevenson M., et al. (2015). Chemotherapy-refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated with Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor. J. Clin. Oncol. 33, 540–549. 10.1200/jco.2014.56.2025
    1. Kotch C., Barrett D., Teachey D. T. (2019). Tocilizumab for the Treatment of Chimeric Antigen Receptor T Cell-Induced Cytokine Release Syndrome. Expert Rev. Clin. Immunol. 15, 813–822. 10.1080/1744666x.2019.1629904
    1. Lee D. W., Gardner R., Porter D. L., Louis C. U., Ahmed N., Jensen M., et al. (2014). Current Concepts in the Diagnosis and Management of Cytokine Release Syndrome. Blood 124, 188–195. 10.1182/blood-2014-05-552729
    1. Li X., Chen W. (2019). Mechanisms of Failure of Chimeric Antigen Receptor T-Cell Therapy. Curr. Opin. Hematol. 26, 427–433. 10.1097/moh.0000000000000548
    1. Liu Y., de Waal Malefyt R., Briere F., Parham C., Bridon J. M., Banchereau J., et al. (1997). The EBV IL-10 Homologue Is a Selective Agonist with Impaired Binding to the IL-10 Receptor. J. Immunol. 158, 604–613.
    1. Lysenko L., Lesnik P., Nelke K., Gerber H. (2017). Immune Disorders in Sepsis and Their Treatment as a Significant Problem of Modern Intensive Care. Postepy Hig Med. Dosw (Online) 71, 703–712.
    1. Malekzadeh P., Pasetto A., Robbins P. F., Parkhurst M. R., Paria B. C., Jia L., et al. (2019). Neoantigen Screening Identifies Broad TP53 Mutant Immunogenicity in Patients with Epithelial Cancers. J. Clin. Invest. 129, 1109–1114. 10.1172/jci123791
    1. Martinez F. O., Helming L., Gordon S. (2009). Alternative Activation of Macrophages: an Immunologic Functional Perspective. Annu. Rev. Immunol. 27, 451–483. 10.1146/annurev.immunol.021908.132532
    1. Maude S. L., Teachey D. T., Porter D. L., Grupp S. A. (2015). CD19-targeted Chimeric Antigen Receptor T-Cell Therapy for Acute Lymphoblastic Leukemia. Blood 125, 4017–4023. 10.1182/blood-2014-12-580068
    1. Montero J. C., Seoane S., Ocaña A., Pandiella A. (2011). Inhibition of SRC Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors. Clin. Cancer Res. 17, 5546–5552. 10.1158/1078-0432.ccr-10-2616
    1. Murthy H., Iqbal M., Chavez J. C., Kharfan-Dabaja M. A. (2019). Cytokine Release Syndrome: Current Perspectives. Itt Vol. 8, 43–52. 10.2147/itt.s202015
    1. Neelapu S. S., Tummala S., Kebriaei P., Wierda W., Gutierrez C., Locke F. L., et al. (2018). Chimeric Antigen Receptor T-Cell Therapy - Assessment and Management of Toxicities. Nat. Rev. Clin. Oncol. 15, 47–62. 10.1038/nrclinonc.2017.148
    1. Nishimoto N., Kishimoto T. (2008). Humanized Antihuman IL-6 Receptor Antibody, Tocilizumab. Handb Exp. Pharmacol., 151–160. 10.1007/978-3-540-73259-4_7
    1. Norelli M., Camisa B., Barbiera G., Falcone L., Purevdorj A., Genua M., et al. (2018). Monocyte-derived IL-1 and IL-6 Are Differentially Required for Cytokine-Release Syndrome and Neurotoxicity Due to CAR T Cells. Nat. Med. 24, 739–748. 10.1038/s41591-018-0036-4
    1. Park J. H., Geyer M. B., Brentjens R. J. (2016). CD19-targeted CAR T-Cell Therapeutics for Hematologic Malignancies: Interpreting Clinical Outcomes to Date. Blood 127, 3312–3320. 10.1182/blood-2016-02-629063
    1. Porter D., Frey N., Wood P. A., Weng Y., Grupp S. A. (2018). Grading of Cytokine Release Syndrome Associated with the CAR T Cell Therapy Tisagenlecleucel. J. Hematol. Oncol. 11, 35. 10.1186/s13045-018-0571-y
    1. Pulè M. A., Straathof K. C., Dotti G., Heslop H. E., Rooney C. M., Brenner M. K. (2005). A Chimeric T Cell Antigen Receptor that Augments Cytokine Release and Supports Clonal Expansion of Primary Human T Cells. Mol. Ther. 12, 933–941. 10.1016/j.ymthe.2005.04.016
    1. Ruella M., Kenderian S. S., Shestova O., Fraietta J. A., Qayyum S., Zhang Q., et al. (2016). The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Responses against Mantle Cell Lymphoma. Clin. Cancer Res. 22, 2684–2696. 10.1158/1078-0432.ccr-15-1527
    1. Samanta M., Iwakiri D., Takada K. (2008). Epstein-Barr Virus-Encoded Small RNA Induces IL-10 through RIG-I-Mediated IRF-3 Signaling. Oncogene 27, 4150–4160. 10.1038/onc.2008.75
    1. Stephan M. T., Ponomarev V., Brentjens R. J., Chang A. H., Dobrenkov K. V., Heller G., et al. (2007). T Cell-Encoded CD80 and 4-1BBL Induce Auto- and Transcostimulation, Resulting in Potent Tumor Rejection. Nat. Med. 13, 1440–1449. 10.1038/nm1676
    1. Sterner R. M., Sakemura R., Cox M. J., Yang N., Khadka R. H., Forsman C. L., et al. (2019). GM-CSF Inhibition Reduces Cytokine Release Syndrome and Neuroinflammation but Enhances CAR-T Cell Function in Xenografts. Blood 133, 697–709. 10.1182/blood-2018-10-881722
    1. Tanaka T., Narazaki M., Kishimoto T. (2016). Immunotherapeutic Implications of IL-6 Blockade for Cytokine Storm. Immunotherapy 8, 959–970. 10.2217/imt-2016-0020
    1. Teachey D. T., Lacey S. F., Shaw P. A., Melenhorst J. J., Maude S. L., Frey N., et al. (2016). Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-Cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov. 6, 664–679. 10.1158/-16-0040
    1. Titov A., Valiullina A., Zmievskaya E., Zaikova E., Petukhov A., Miftakhova R., et al. (2020). Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment. Cancers (Basel) 12. 10.3390/cancers12010125
    1. Wang Z., Han W. (2018). Biomarkers of Cytokine Release Syndrome and Neurotoxicity Related to CAR-T Cell Therapy. Biomark Res. 6, 4. 10.1186/s40364-018-0116-0

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj