CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells

Guercio, Marika; Orlando, Domenico; Cecca, Stefano Di; Sinibaldi, Matilde; Boffa, Iolanda; Caruso, Simona; Abbaszadeh, Zeinab; Camera, Antonio; Cembrola, Biancamaria; Bovetti, Katia; Manni, Simona; Caruana, Ignazio; Ciccone, Roselia; Bufalo, Francesca Del; Merli, Pietro; Vinti, Luciana; Girardi, Katia; Ruggeri, Annalisa; Stefanis, Cristiano De; Pezzullo, Marco; Giorda, Ezio; Scarsella, Marco; Vito, Rita De; Barresi, Sabina; Ciolfi, Andrea; Tartaglia, Marco; Moretta, Lorenzo; Locatelli, Franco; Quintarelli, Concetta; Angelis, Biagio De

doi:10.3324/haematol.2019.231183

Cited by 44 publications

(23 citation statements)

References 40 publications

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“…The costimulatory molecules of T cells consist of CD28, inducible costimulatory (ICOS), TNF superfamily member 4 (TNFSF4), and DNAM1 (CD226), and the co-inhibitory molecules contain TIM3, cytotoxic T-lymphocyte associated protein 4 (CTLA4), programmed death-1 (PD1), and lymphocyte activating 3 (LAG3) ( 20 – 24 ). Among these, CD28 and CTLA4 represent the best-studied costimulatory pathways.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia

et al. 2021

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Cancer immunotherapy by immune checkpoint blockade has been effective in the treatment of certain tumors. However, the association between immune checkpoints and autoimmune diseases remains elusive and requires urgent investigation. Primary immune thrombocytopenia (ITP), characterized by reduced platelet count and a consequent increased risk of bleeding, is an autoimmune disorder with a hyper-activated T cell response. Here, we investigated the contribution of immune checkpoint-related single-nucleotide polymorphisms (SNPs), including CD28, ICOS, PD1, TNFSF4, DNAM1, TIM3, CTLA4, and LAG3 to the susceptibility and therapeutic effects of ITP. In this case-control study, 307 ITP patients and 295 age-matched healthy participants were recruited. We used the MassARRAY system for genotyping immune checkpoint-related SNPs. Our results revealed that rs1980422 in CD28 was associated with an increased risk of ITP after false discovery rate correction (codominant, CT vs. TT, OR = 1.788, 95% CI = 1.178–2.713, p = 0.006). In addition, CD28 expression at both the mRNA and protein levels was significantly higher in patients with CT than in those with the TT genotype (p = 0.028 and p = 0.001, respectively). Furthermore, the T allele of PD1 rs36084323 was a risk factor for ITP severity and the T allele of DNAM1 rs763361 for corticosteroid-resistance. In contrast, the T allele of LAG3 rs870849 was a protective factor for ITP severity, and the T allele of ICOS rs6726035 was protective against corticosteroid-resistance. The TT/CT genotypes of PD1 rs36084323 also showed an 8.889-fold increase in the risk of developing refractory ITP. This study indicates that immune checkpoint-related SNPs, especially CD28 rs1980422, may be genetic factors associated with the development and treatment of ITP patients. Our results shed new light on prognosis prediction, disease severity, and discovering new therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia

et al. 2021

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“…31,40 OX40L/OX40 signaling was shown to promote Bcl-xL and Bcl-2 expression essential for long-term T cell survival and in vivo persistence of CAR.CD30T cells. 41,42 AZA down-regulated IL-10 in ALL-2 cells, and OX40 co-stimulation was shown to abrogate IL-10 inhibitory effects on CAR T cells. 19,43 Thus, we focused on exploring the effect of OX40L/OX40 signaling on CAR T cell function.…”

Section: Discussionmentioning

confidence: 94%

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy

Xu¹,

Tse²,

Yang³

et al. 2021

ITT

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Purpose Despite the success of chimeric antigen receptor (CAR) T cells in clinical studies, a significant proportion of responding patients eventually relapsed, with the latter correlating with low CAR T cell expansion and persistence. Methods and Results Using patient-derived xenograft (PDX) mouse models of CD19 + B cell acute lymphoblastic leukemia (B-ALL), we show that priming leukemia-bearing mice with 5-azacytidine (AZA) enhances CAR T cell therapy. AZA given 1 day prior to CAR T cell infusion delayed leukemia growth and promoted CAR T cell expansion and effector function. Priming leukemia cells with AZA increased CAR T cell/target cell conjugation and target cell killing, promoted CAR T cell divisions and expanded IFNγ + effector T cells in co-cultures with CD19 + leukemia Nalm-6 and Raji cells. Transcriptome analysis revealed activation of diverse immune pathways in leukemia cells isolated from mice treated with AZA. We propose that epigenetic priming with AZA induces transcriptional changes that sensitize tumor cells to subsequent CAR T cell treatment. Among the candidate genes up-regulated by AZA is TNFSF4 which encodes OX40L, one of the strongest T cell co-stimulatory ligands. OX40L binds OX40, the TNF receptor superfamily member highly specific for activated T cells. TNFSF4 is heterogeneously expressed in a panel of pediatric PDXs, and high TNFSF4 expression correlated with increased CAR T cell numbers identified in co-cultures with individual PDXs. High OX40L expression in Nalm-6 cells increased their susceptibility to CAR T cell killing while OX40L blockade reduced leukemia cell killing. Conclusion We propose that treatment with AZA activates OX40L/OX40 co-stimulatory signaling in CAR T cells. Our data suggest that the clinical use of AZA before CAR T cells could be considered.

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“…CAR containing inducible co-stimulator (ICOS) generates IL-17-producing effector cells with the characteristic of TH17 cells showing enhanced persistence in vivo [30,37]. OX40 co-stimulatory signaling effectively represses IL-10 secretion, and contributes to counteract self-repression, thus facilitates a prolonged CAR T cells response [31,38]. Toll-like receptor 2 (TLR2)-incorporated CAR T cells demonstrate improved expansion and persistence due to the capacity of generating memory T cells, expressing pro-survival proteins and abolishing the suppression of regulatory T cells [39][40][41].…”

Section: Transmembrane and Intracellular Domainsmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

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CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

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CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells

Cited by 44 publications

References 40 publications

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia

Immune Checkpoint-Related Gene Polymorphisms Are Associated With Primary Immune Thrombocytopenia

Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy

Engineering better chimeric antigen receptor T cells

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