Janssen Fang

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, which is a cancer primarily affecting the lymphatic system.¹ This disease involves “hijacking” cellular mechanisms of differentiation and maturation within the germinal center of lymphoid organs. Currently, the standard treatment for DLBCL is R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy.² Although R-CHOP treatment is considered safe and effective, around 45-50% of individuals will relapse.² The utilization of Chimeric Antigen Receptor (CAR) T cell therapy presents an alternative that could provide greater therapeutic value against B cell cancers and other hemolytic malignancies.³

Objectives: In this literature review, we will explore ways in which CAR T cell anti-tumorigenic responses can be improved via changes in cell architecture.

Search Methods: Online searches on the PubMed database was conducted from 2017 to 2025 using the following keywords: “CAR T cell therapy”, “Interleukins”, “tumorigenic” and “cancer”

Results: Interleukin secretion was shown to enhance CAR T cell activity in tumor-bearing mouse models, especially with regards to IL-36γ and IL-18.^4,5 CAR T cells engineered to express IL-36γ demonstrated increased persistence and IFN-γ production, suggesting improved tumor control, which was confirmed by ELISpot assays and flow cytometry.⁴ IL-18 expressing CAR T cells persisted for over 150 days post-infusion, with elevated IFN-γ levels and PCR confirming gene presence in bone marrow.⁵ The placement of the MyD88/CD40 (MC) costimulatory domain also significantly influenced CAR T cell performance: when included in the CAR construct, surface expression and function were reduced. However, expressing MC as a separate polypeptide using a tricistronic vector enhanced CAR expression and pro-inflammatory cytokine secretion.⁶ Trogocytosis, the transfer of CD19 antigens from tumor cells to CAR T cells, was shown to reduce antigen availability and impair tumor clearance, but this was mitigated by dual targeting with CD19-BBζ and CD22-28ζ CARs, which improved survival in mouse models.⁷ Finally, CRISPR/Cas9-mediated PD-L1 gene knockout in CAR T cells prevented tumor-induced immune suppression and significantly increased tumor clearance and survival time.⁸

Conclusions: Improving CAR T cell anti-tumorigenic responses involves several key strategies, including modifying the cellular architecture, enhancing the secretion of specific cytokines, knocking out inhibitory molecules such as PD-L1, incorporating costimulatory domains, and employing combinatorial antigen targeting to prevent tumor escape. These modifications have shown promise in preclinical models, enhancing CAR T cell persistence, activation, and tumor-killing efficacy. However, further research is needed to better understand the underlying biological mechanisms and evaluate their long-term safety and effectiveness.

Works Cited:

1. Wang Epidemiology and etiology of diffuse large B-cell lymphoma. Seminars in Hematology. 2023;60(5):255-266. doi:10.1053/j.seminhematol.2023.11.004
2. Sehn LH, Salles Diffuse Large B-Cell Lymphoma. New England Journal of Medicine. 2021;384(9):842-858. doi:10.1056/NEJMra2027612
3. Susanibar-Adaniya S, Barta SK. 2021 Update on Diffuse large B cell lymphoma: A review of current data and potential applications on risk stratification and American journal of hematology. 2021;96(5):617-629. doi:10.1002/ajh.26151
4. Li X, Daniyan AF, Lopez A v, Purdon TJ, Brentjens Cytokine IL-36γ improves CAR T-cell functionality and induces endogenous antitumor response. Leukemia. 2021;35(2):506-521. doi:10.1038/s41375-020-0874-1
5. Avanzi MP, Yeku O, Li X, et al. Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune Cell reports. 2018;23(7):2130-2141. doi:10.1016/j.celrep.2018.04.051
6. Collinson-Pautz MR, Chang WC, Lu A, et al. Constitutively active MyD88/CD40 costimulation enhances expansion and efficacy of chimeric antigen receptor T cells targeting hematological malignancies. Leukemia. 2019;33(9):2195-2207. doi:10.1038/s41375-019-0417-9
7. Hamieh M, Dobrin A, Cabriolu A, et CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019;568(7750):112-116. doi:10.1038/s41586-019-1054-1
8. Rupp LJ, Schumann K, Roybal KT, et CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Scientific reports. 2017;7(1):737. doi:10.1038/s41598-017-00462-8