Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

Fraietta, Joseph A.; Beckwith, Kyle A.; Patel, Prachi; Ruella, Marco; Zheng, Zhaohui; Barrett, David M.; Lacey, Simon F.; Melenhorst, J. Joseph; McGettigan, Shannon E.; Cook, David; Zhang, Changfeng; Xu, Jun; Do, Priscilla; Hulitt, Jessica; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Gill, Saar; Porter, David L.; Woyach, Jennifer A.; Long, Meixiao; Johnson, Amy J.; Maddocks, Kami J.; Muthusamy, Natarajan; Levine, Bruce L.; June, Carl H.; Byrd, John C.; Maus, Marcela V.

doi:10.1182/blood-2015-11-679134

Cited by 409 publications

(373 citation statements)

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“…Another recent study investigating the effect of ibrutinib on chimeric antigen receptor-expressing T cells demonstrated that defects in T-cell proliferation and activation were improved after 5 to 11 cycles of ibrutinib therapy. 37 Thus, it is possible that direct elimination of CLL through ibrutinib Bruton's tyrosine kinase targeting reduces T-cell exhaustion, leading to more effective T-cell immunity.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Ryan

Sahaf

Logan

et al. 2016

Blood

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• Ibrutinib provided effective salvage therapy in CLL relapse post-alloHCT, resulting in sustained MRD negativity without GVHD development.• Ibrutinib selectively depleted pre-germinal B cells and Th2 helper cells and may enhance donor Th1 T-cell-mediated GVL effects.Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. (Blood. 2016;128(25):2899-2908

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Section: Discussionmentioning

confidence: 99%

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Ryan

Sahaf

Logan

et al. 2016

Blood

Self Cite

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“…Combining CAR T cells with targeted agents that have immune modulating activity may also prove beneficial. For example, recent work has demonstrated that CAR T cells made from patients with CLL have greater proliferative potential when harvested after prolonged treatment with ibrutinib and that ibrutinib enhances CAR T cell activity in mouse models [71]. The last several decades have seen dramatic innovation in CAR design, manufacturing, and clinical applications.…”

Section: Discussionmentioning

confidence: 99%

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

Roberts

Better

Bot

et al. 2017

Leukemia & Lymphoma

106

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“…They found that CAR T-cell function is not impaired with the exposure of ibrutinib in vitro and in fact simultaneous administration improves tumor clearance, CAR T-cell engraftment and survival in human xenograft models of resistant ALL and CLL. This finding indicates that clinical trials with combination therapy are warranted as ibrutinib enhances CAR T-cell function [15]. Targeting BCL-2 through venetoclax is a significant first step approach can be acquired for the therapeutic strategy in CLL.…”

Section: Short Communicationmentioning

confidence: 99%

Combination Therapy for Chronic Lymphoid Leukemia

Barik¹

2016

J Cancer Sci Ther

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Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

Abstract: Key Points Ibrutinib treatment of CLL enhances the generation of CAR T cells for adoptive immunotherapy. Concurrent ibrutinib therapy improves the engraftment and therapeutic efficacy of anti-CD19 CAR T cells in mouse models.

Cited by 409 publications

References 51 publications

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

Axicabtagene ciloleucel, a first-in-class CAR T cell therapy for aggressive NHL

Combination Therapy for Chronic Lymphoid Leukemia

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