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Background: Chimeric antigen receptor (CAR) T cell therapy has been successfully translated to clinical practice for the treatment of B cell malignancies. The suppressive microenvironment of many malignancies is a bottleneck preventing treatment success of CAR T cells in a broader range of tumours. Among others, the immunosuppressive metabolite adenosine is present in high concentrations within many tumours and dampens anti-tumour function of immune cells and consequently therapeutic response. Methods: Here, we present the impact of the selective adenosine A2A and A2B receptor antagonist AB928/etrumadenant on CAR T cell cytokine secretion, proliferation, and cytotoxicity. Using phosphorylation-specific flow cytometry, we evaluated the capability of AB928 to shield CAR T cells from adenosine-mediated signalling. The effect of orally administered AB928 on CAR T cells was assessed in a syngeneic mouse model of colon carcinoma. Results: We found that immunosuppressive signalling in CAR T cells in response to adenosine was fully blocked by the small molecule inhibitor. AB928 treatment enhanced CAR T cell cytokine secretion and proliferation, granted efficient cytolysis of tumour cells in vitro and augmented CAR T cell activation in vivo. Conclusions: Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B‐cell lymphoma or acute lymphoblastic leukemia. Impaired T‐cell fitness of CLL patients may be involved in treatment failure. Less‐differentiated naïve‐like T cells play an important role in CART expansion and long‐term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B‐cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin‐2‐inducible T‐cell kinase (ITK) which is involved in T‐cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T‐cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient‐derived CART cells. Furthermore, ibrutinib enriched CART cells with less‐differentiated naïve‐like phenotype and decreased expression of exhaustion markers including PD‐1, TIM‐3 and LAG‐3. In addition, ibrutinib increased the cytokine release capacity of CLL patient‐derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient‐derived CART cell products. What's new? Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in chronic lymphocytic leukemia (CLL). However, naïve‐like T cells play an important role in CART expansion and long‐term persistence in vivo, and these cells are sparse in CLL patients. Here, the authors show that BTK/ITK inhibition with Ibrutinib during CART cell generation may improve CLL patient‐derived CART cell products and enhance CART cell function. Supplementing CART cell production with ibrutinib increases CART cell yields and enriches CART cells with less‐differentiated phenotypes and lower expression of exhaustion markers, representing a potential avenue to improve the clinical outcome of patients. [ABSTRACT FROM AUTHOR]

Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4 + T helper (T H ) cells > 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels >4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed T H cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper T H cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, p  < 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, p  < 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, p  = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing., Competing Interests: Veit L. Bücklein—AMGEN: Honoraria; Celgene: research funding; Pfizer: Honoraria; Kite/Gilead: research funding, Honoraria; Novartis: Honoraria. consultancy/advisory, BMS: Consultancy/advisory, Takeda: consultancy/advisory. Viktoria Blumenberg—BMS/Celgene: research funding; Kite/Gilead: consultancy, Honoraria, research funding; Janssen: research funding, Honoraria; Novartis: research funding, Honoraria; Roche: consultancy, research funding; Takeda: research funding. Sebastian Kobold—received honoraria from TCR2 Inc., Cymab, Miltenyi, Galapagos, Novartis, BMS, and GSK, is an inventor of several patents in the field of immuno‐oncology, received license fees from TCR2 Inc. and Carina Biotech, received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmBH, Plectonic GmBH, and Arcus Bioscience for work unrelated to the manuscript. Michael von Bergwelt‐Baildon—consultancy, research funding, and Honoraria: MSD Sharp & Dohme, Novartis, Roche, Kite/Gilead, Bristol‐Myers Squibb, Astellas, Mologen, and Miltenyi. Kai Rejeski—Kite/Gilead: research funding, advisory, honoraria, and travel support; Novartis: Honoraria; BMS/Celgene: consultancy, Honoraria; Pierre‐Fabre: Travel Support. Marion Subklewe—receives industry research support from Amgen, BMS/Celgene, Gilead, Janssen, Miltenyi Biotec, Novartis, Roche, Seattle Genetics, and Takeda and serves as a consultant/advisor to AvenCell, CDR‐Life, Ichnos Sciences, Incyte Biosciences, Janssen, Miltenyi Biotec, Molecular Partners, Novartis, Pfizer, and Takeda. She serves on the speakers' bureau at Amgen, AstraZeneca, BMS/Celgene, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. The remaining authors declare no conflict of interest., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)