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Cited by 30Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentProtein Degradation and Inhibitors

BTK inhibitors, irrespective of ITK inhibition, increase efficacy of a CD19/CD3-bispecific antibody in CLL

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Mhibik, Maissa, Gaglione, Erika M., Eik, David, Kendall, Ellen K., Blackburn, Amy, Keyvanfar, Keyvan, Baptista, Maria Joao, Ahn, Inhye E. +4 more·2021·Blood
DOI 10.1182/blood.2020009686PMC PMC8586964
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Abstract

Bruton tyrosine kinase inhibitors (BTKis) are a preferred treatment of patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, although effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3-bispecific antibody (bsAb) that recruits autologous T-cell cytotoxicity against CLL cells in vitro. Compared with observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared with that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb-induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.

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  • BTK inhibitors increase the efficacy of CD19/CD3 bispecific antibody irrespective of ITK inhibition, an effect of ibrutinib but not acalabrutinib.

    “suggesting that BTKi increases efficacy of CD19/CD3 bsAb irrespective of interleukin-2 inducible T-cell kinase (ITK) inhibition, an effect of ibrutinib but not acalabrutinib (95).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [95]

    The Discussion says BTK inhibitors improve the bispecific antibody’s cytotoxic response irrespective of ITK inhibition. But the Results explicitly report no difference between ibrutinib and acalabrutinib, contrary to the claim that the effect occurs with ibrutinib but not acalabrutinib. (LLM, conf=0.94)

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  • Bispecific antibodies represent a promising therapeutic strategy for relapsed/refractory CLL and a potential combination partner to deepen responses in patients on targeted therapy, especially with BTK inhibitors and venetoclax.

    “Overall, bsAb represent a promising therapeutic strategy for relapsed/refractory CLL, and as a potential combination partner to deepen responses in patients on targeted therapy, especially in conjunction with BTKi and venetoclax (94, 95, 98).”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [95]

    The Discussion (page not available) calls bispecific antibodies combined with BTK inhibitors a promising strategy to consolidate remissions and overcome drug resistance in CLL. The Results include samples from patients with relapsed CLL, but the paper does not establish efficacy in relapsed/refractory patients or address a combination with venetoclax. Its BTK-inhibitor findings are from in vitro experiments and, as the Discussion notes, need clinical testing. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The faster cytotoxic response difference was also observed in T cells from acalabrutinib-treated CLL patients.

    “This differencewas also observed in T cells from acalabrutinib-treated CLL patients”

    From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [95]

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Authors
Mhibik, M., Gaglione, E. M., Eik, D., Kendall, E. K., Blackburn, A., Keyvanfar, K., Baptista, M. J., Ahn, I. E., Sun, C., Qi, J., Rader, C., & Wiestner, A.
Affiliations
  • National Institutes of Health (US)
  • Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
  • Scripps Research Institute (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-11-11
Volume
138
Issue
19
Pages
1843-1854
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020009686
PMC
PMC8586964
OpenAlex
W3165747560
Cited by
30
References
4
Citations by year
2026: 3 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 1
FWCI
2.81
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Keywords
BTK inhibitors, ibrutinib, acalabrutinib, chronic lymphocytic leukemia, ITK, T cell cytotoxicity, CTLA-4, CD200, immunosuppression, ipilimumab, combination immunotherapy, T cell expansion
MeSH terms
Antineoplastic Agents, Immunological, Ipilimumab, Agammaglobulinaemia Tyrosine Kinase, Immune Checkpoint Inhibitors, Adenine, Adult, Aged, Aged, 80 and over, Benzamides, Female, Humans, Male, Middle Aged, Piperidines, Pyrazines, T-Lymphocytes, Leukemia, Lymphocytic, Chronic, B-Cell, CD3 Complex, Antibodies, Bispecific, Antigens, CD19, Protein Kinase Inhibitors

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