Case Report: Clinical and Serological Hallmarks of Cytokine Release Syndrome in a Canine B Cell Lymphoma Patient Treated With Autologous CAR-T Cells

Overview

Journal Front Vet Sci

Specialty Veterinary Medicine

Date 2022 Jul 28

PMID 35898541

Authors

Matthew J Atherton

Antonia Rotolo

Kumudhini P Haran

Nicola J Mason

Affiliations

Soon will be listed here.

Abstract

Background: Chimeric antigen receptor-T (CAR-T) cells have transformed the treatment of human B cell malignancies. With the advent of CAR-T therapy, specific and in some cases severe toxicities have been documented with cytokine release syndrome (CRS) being the most frequently reported. As dogs develop tumors spontaneously and in an immunocompetent setting, they provide a unique translational opportunity to further investigate the activity and toxicities associated with CAR-T therapy. Although various adoptive cellular therapy (ACT) trials have been documented and several more are ongoing in canine oncology, CRS has not been comprehensively described in canine cancer patients.

Case Presentation: Here we present the clinical and serologic changes in a dog treated with autologous CAR-T for relapsed B cell lymphoma that presented with lethargy and fever 3 days following CAR-T. Multiplexed serum cytokine profiling revealed increases in key cytokines implicated in human CRS including IL-6, MCP-1, IFNγ and IL-10 at or shortly after peak CAR-T levels .

Conclusion: The observations noted in this case report are consistent with CRS development following CAR-T therapy in a canine patient. The dog represents a compelling model to study the pathophysiology of CRS and pre-clinically screen novel therapeutics to prevent and treat this life-threatening condition in the setting of a complex and naturally evolved immune system.

Citing Articles

Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma.

Yoshimoto S, Kudo A, Rotolo A, Foos K, Olenick L, Takagi S iScience. 2024; 27(9):110863.

PMID: 39314237 PMC: 11418608. DOI: 10.1016/j.isci.2024.110863.

Translational History and Hope of Immunotherapy of Canine Tumors.

Bryan J, Maitz C Clin Cancer Res. 2024; 30(19):4272-4285.

PMID: 39042399 PMC: 11444889. DOI: 10.1158/1078-0432.CCR-23-2266.

Limited Clinical Efficacy with Potential Adverse Events in a Pilot Study of Autologous Adoptive Cell Therapy in Canine Oral Malignant Melanoma.

Xia Y, Chi K, Liao A, Lee J Vet Sci. 2024; 11(4).

PMID: 38668417 PMC: 11053650. DOI: 10.3390/vetsci11040150.

Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology.

Rotolo A, Atherton M Clin Cancer Res. 2024; 30(11):2359-2369.

PMID: 38573683 PMC: 11147717. DOI: 10.1158/1078-0432.CCR-23-3690.

Direct comparison of canine and human immune responses using transcriptomic and functional analyses.

Chow L, Wheat W, Ramirez D, Impastato R, Dow S Sci Rep. 2024; 14(1):2207.

PMID: 38272935 PMC: 10811214. DOI: 10.1038/s41598-023-50340-9.

References

Sheth V, Gauthier J . Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2020; 56(3):552-566. PMC: 8592274. DOI: 10.1038/s41409-020-01134-4. View

Parker K, Migliorini D, Perkey E, Yost K, Bhaduri A, Bagga P . Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell. 2020; 183(1):126-142.e17. PMC: 7640763. DOI: 10.1016/j.cell.2020.08.022. View

Atherton M, Morris J, McDermott M, Lichty B . Cancer immunology and canine malignant melanoma: A comparative review. Vet Immunol Immunopathol. 2016; 169:15-26. DOI: 10.1016/j.vetimm.2015.11.003. View

Panjwani M, Smith J, Schutsky K, Gnanandarajah J, OConnor C, Powell Jr D . Feasibility and Safety of RNA-transfected CD20-specific Chimeric Antigen Receptor T Cells in Dogs with Spontaneous B Cell Lymphoma. Mol Ther. 2016; 24(9):1602-14. PMC: 5113111. DOI: 10.1038/mt.2016.146. View

Rutgen B, Hammer S, Gerner W, Christian M, de Arespacochaga A, Willmann M . Establishment and characterization of a novel canine B-cell line derived from a spontaneously occurring diffuse large cell lymphoma. Leuk Res. 2010; 34(7):932-8. DOI: 10.1016/j.leukres.2010.01.021. View

Hay K, Hanafi L, Li D, Gust J, Liles W, Wurfel M . Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017; 130(21):2295-2306. PMC: 5701525. DOI: 10.1182/blood-2017-06-793141. View

Siegler E, Kenderian S . Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies. Front Immunol. 2020; 11:1973. PMC: 7485001. DOI: 10.3389/fimmu.2020.01973. View

Teachey D, Lacey S, Shaw P, Melenhorst J, Maude S, Frey N . Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discov. 2016; 6(6):664-79. PMC: 5448406. DOI: 10.1158/2159-8290.CD-16-0040. View

Marcucci K, Jadlowsky J, Hwang W, Suhoski-Davis M, Gonzalez V, Kulikovskaya I . Retroviral and Lentiviral Safety Analysis of Gene-Modified T Cell Products and Infused HIV and Oncology Patients. Mol Ther. 2017; 26(1):269-279. PMC: 5763152. DOI: 10.1016/j.ymthe.2017.10.012. View

10.

Taraseviciute A, Tkachev V, Ponce R, Turtle C, Snyder J, Liggitt H . Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discov. 2018; 8(6):750-763. PMC: 6058704. DOI: 10.1158/2159-8290.CD-17-1368. View

11.

Neelapu S, Locke F, Bartlett N, Lekakis L, Miklos D, Jacobson C . Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017; 377(26):2531-2544. PMC: 5882485. DOI: 10.1056/NEJMoa1707447. View

12.

Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M . Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018; 24(6):739-748. DOI: 10.1038/s41591-018-0036-4. View

13.

Haran K, Lockhart A, Xiong A, Radaelli E, Savickas P, Posey A . Generation and Validation of an Antibody to Canine CD19 for Diagnostic and Future Therapeutic Purposes. Vet Pathol. 2020; 57(2):241-252. PMC: 7462180. DOI: 10.1177/0300985819900352. View

14.

Katlinski K, Gui J, Katlinskaya Y, Ortiz A, Chakraborty R, Bhattacharya S . Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. Cancer Cell. 2017; 31(2):194-207. PMC: 5313042. DOI: 10.1016/j.ccell.2017.01.004. View

15.

LeBlanc A, Atherton M, Bentley R, Boudreau C, Burton J, Curran K . Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet Comp Oncol. 2021; 19(2):311-352. PMC: 8248125. DOI: 10.1111/vco.12677. View

16.

Maude S, Laetsch T, Buechner J, Rives S, Boyer M, Bittencourt H . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018; 378(5):439-448. PMC: 5996391. DOI: 10.1056/NEJMoa1709866. View

17.

Maude S, Barrett D, Teachey D, Grupp S . Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014; 20(2):119-22. PMC: 4119809. DOI: 10.1097/PPO.0000000000000035. View

18.

Giavridis T, van der Stegen S, Eyquem J, Hamieh M, Piersigilli A, Sadelain M . CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018; 24(6):731-738. PMC: 6410714. DOI: 10.1038/s41591-018-0041-7. View

19.

Milone M, Bhoj V . The Pharmacology of T Cell Therapies. Mol Ther Methods Clin Dev. 2018; 8:210-221. PMC: 5852291. DOI: 10.1016/j.omtm.2018.01.010. View

20.

Fesnak A, June C, Levine B . Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer. 2016; 16(9):566-81. PMC: 5543811. DOI: 10.1038/nrc.2016.97. View