Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

Mueller, Karen Thudium; Maude, Shannon L.; Porter, David L.; Frey, Noelle V.; Wood, Patricia A.; Han, Xiuxin; Waldron, Edward; Chakraborty, Abhijit; Awasthi, Rakesh; Levine, Bruce L.; Melenhorst, J. Joseph; Grupp, Stephan A.; June, Carl H.; Lacey, Simon F.

doi:10.1182/blood-2017-06-786129

Cited by 299 publications

(396 citation statements)

References 27 publications

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“…Persistence of transferred lymphocytes correlates with cancer regression in patients receiving adoptive cell therapy (28, 29). Many investigators are enriching CD62L + T cells from bulk TILs or CAR T-cell cultures, as these central memory T cells are more efficacious than the effector memory CD62L − T cells normally expanded with high dose IL2 under rapid expansion protocols.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo

Majchrzak

Liu

et al. 2018

Cancer Research

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Adoptive T-cell transfer therapy is an FDA-approved treatment for leukemia that relies on the ex vivo expansion and reinfusion of a patient’s immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during ex vivo expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion in vitro. In vivo, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells in vivo. Significance: RORγ agonists can be used in vitro during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.

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Section: Discussionmentioning

confidence: 99%

In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo

Majchrzak

Liu

et al. 2018

Cancer Research

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“…Encouragingly, two of the CD19-targeted CAR-T therapies, Kymriah and Yescarta, have been approved to treat relapsed/refractory (r/r) pediatric, young adult B cell ALL (B-ALL), and certain adult non-Hodgkin lymphomas (NHL) by the US Food and Drug Administration in 2017. Owing to their satisfactory therapeutic effects and clinical safeties [3,[19][20][21], they have successfully become the first two gene therapies approved in the USA. On present trends, it is doubtless that CAR-T therapy will be generalized to more relapsed and refractory malignancy patients in the near future.…”

Section: Introductionmentioning

confidence: 99%

Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy

et al. 2019

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The CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has been widely proved effective on relapsed and refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Meanwhile, CAR-T therapy-related toxicities, including cytokine release syndrome (CRS) and neurological toxicities, are drawing researchers' attention. In addition, our research team notices that coagulopathy and even disseminated intravascular coagulation (DIC) are common problems during CAR-T therapy. In our phase 1/2 clinical trial (NCT02965092), 53 r/r B-ALL patients underwent leukapheresis on day − 11 and received lymphodepleting chemotherapy on day − 7 to day − 5. Finally, they received split infusions of anti-CD19 CAR-T cells on day 0 to day 2. Plasma concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1) were also measured to identify the mechanism of coagulation disorders. The overall 1-month remission rate of the 53 patients was 88.7%. During the treatment course, 19 patients experienced grade 3-4 CRS, 8 patients developed grade 2-3 neurological toxicities. Beyond that, 30 patients (30/53, 56.6%) suffered from coagulation disorders, and half of them should be diagnosed as DIC. Benefiting from replacement and anticoagulant therapy, 14 patients successfully got out of the conditions of DIC. Remarkably, the severity of coagulopathy was positively correlated with CRS grade. What is more, plasma TF and PECAM-1 levels indicated that vascular endothelial factors played key roles in the process of CRS-related coagulopathy. To conclude, coagulation disorders frequently happen during CAR-T therapy. TF and PECAM-1 are of great importance in the etiology and pathogenesis of coagulation problems. Early and proper interventions targeted at CRS-related coagulopathy contribute a lot to the control of side effects in CAR-T therapy.

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“…Furthermore, approximately 10-20% of patients fail to enter remission after receiving anti-CD19 CAR T cell therapy [7][8][9][10] . Loss or modulation of the target antigen [15][16][17] and/or a lack of CAR T cell persistence 18 , as well as product manufacturing failures 19,20 ( fig. 1), are among the more commonly cited impediments to effective CAR T cell therapy.…”

mentioning

confidence: 99%

Mechanisms of resistance to CAR T cell therapy

2019

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Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

Abstract: Key Points Tisagenlecleucel (CTL019) has demonstrated clinical efficacy in relapsed/refractory B-cell ALL and CLL. The cellular kinetic profile of tisagenlecleucel was consistent across the 2 diseases, with higher exposure in responding vs nonresponding patients.

Cited by 299 publications

References 27 publications

In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo

In Vitro Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness In Vivo

Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy

Mechanisms of resistance to CAR T cell therapy

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