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B.S. Hanna et al.
line, enhanced engraftment and efficacy of CLL patient- derived chimeric antigen receptor (CAR) T cells after more than 1 year of treatment with ibrutinib can be also explained by a normalization of T cells associated with a reduction of exhaustion phenotype, secondary to the effective control of CLL by the drug.42 In this study, the authors further show that ex vivo treatment of CLL CAR T cells with ibrutinib does not impact on their proliferation or function. Our data here clearly show that this observa- tion is due to a commonly used stimulation protocol for T cells in vitro in which αCD3 and αCD28 antibodies are combined as stimuli. Co-stimulation of CD8+ T cells with αCD28 was also used by Dubovsky et al. who describe that ibrutinib does not affect TCR signaling and function of these cells.15 This observation was in contrast to results obtained in ITK-deficient mice which show impaired TCR-dependent signaling and CD8+ T-cell effector func- tion in response to viral infections.43 We now show that inhibition of T-cell activity by ibrutinib can be overcome by co-stimulatory signaling mediated by CD28, which is known to be independent of ITK.33 In line with our find- ings, stimulation of ITK-deficient CD8+ T cells with αCD3 only leads to impaired expansion and activity.43
Considering our observations that ibrutinib negatively impacts on the activity of CD8+ T cells, one needs to investigate whether patients under long-term ibrutinib treatment have reduced adaptive immunity. In early clini- cal studies and applications of ibrutinib, this was hard to assess, as treated patients were relapsed and refractory, as well as high-risk CLL who have a profound immune sup- pression and perturbation of both innate and adaptive immunity, and therefore an increased susceptibility to infections is likely to be caused by the disease.44 Only more recently, with the approval of ibrutinib as first-line therapy for CLL, have high rates of infectious complica- tions in patients on ibrutinib monotherapy and in combi- nation with other drugs been observed.45 However, in comparison to the severe effects chemotherapy has on the immune system of patients, ibrutinib is reasonably well- tolerated, and by monitoring the impact of ibrutinib on patients’ immune status, or by preventing immunosup- pressive adverse effects by rational combination treatment approaches with drugs that improve T-cell effector func- tion, outcome for patients can be even further improved. Recent data of clinical trials with the highly selective BTK inhibitor acalabrutinib showed overall response rates of 85% in treatment-naïve CLL patients and 94% in relapsed/refractory cases.46,47 Most adverse events (AE) observed in these trials were mild or moderate (grade 1-2) and were most commonly diarrhea and headache. It was hypothesized that due to its greater selectivity for BTK, acalabrutinib has favorable pharmacokinetic properties and an improved toxicity profile than ibrutinib. Considering, however, the short history of acalabrutinib
treatment compared to ibrutinib, and the lack of a head- to-head comparison of the two drugs in CLL patients, it remains unclear whether the long-term immune side effects of the drugs are comparable.
Interestingly, the immunomodulatory effect of ibrutinib can be even of therapeutic advantage, as shown in patients with relapsed CLL after allogeneic hematopoietic stem cell transplantation, in which ibrutinib was tolerable and effective.48
Our data in the TCL1 AT model show that combining ibrutinib with immune checkpoint blockade leads to enhanced CD8+ T-cell function and reduced CLL progres- sion. Both αPD-1 and αPD-L1 treatment improved the therapeutic effect of ibrutinib, with better results observed with αPD-1. As PD-L1 is expressed by CLL and myeloid cells in this model,25 this antibody has a broader activity compared to αPD-1. Besides blocking the interaction with PD-1, αPD-L1 but not αPD-1 antibodies were shown to modulate myeloid cell subsets within the tumor microen- vironment via activating Fcγ receptors.36 Furthermore, blocking PD-L1 directly on tumor cells dampens their gly- colysis, leaving more available glucose in the extracellular tumor milieu for T cells, which enhances their activity.49
Testing the combination of ibrutinib with immune checkpoint blockade in the mouse model allowed us to monitor tumor load in all organs affected by disease. In line with observations in CLL patients, ibrutinib as single- agent was not able to reduce malignant cells in the BM, which explains why patients and mice relapse if therapy is discontinued. Interestingly, if combined with αPD-1 or αPD-L1, tumor control in the BM was as efficient as in spleen and blood, suggesting that the combination of ibru- tinib with checkpoint blockade might be able to eradicate CLL cells more efficiently, eventually leading to a cure.
Disclosures
No conflicts of interest to disclose.
Contributions
BSH designed the study, performed experiments, analyzed and interpreted data, prepared figures, and wrote the manuscript; HY, YD, PMR and RS performed experiments, analyzed and interpreted data. SS and PL critically advised the study and reviewed the manuscript; MS designed and supervised the study, interpreted data, and wrote the manuscript.
Funding
This study was supported by the German José Carreras Foundation (13R/2018), the German Cancer Aid (grant number 112069), the BMBF-Network “PRECiSe” (031L0076A), the ERA-NET TRANSCAN-2 program JTC 2014–project FIRE- CLL, and the Cooperation Program in Cancer Research of the DKFZ and Israel’s Ministry of Science, Technology and Space. SS was supported by the DFG (SFB1074 subproject B1).
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