Cargando…

A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3K...

Descripción completa

Detalles Bibliográficos
Autores principales: Gadi, Deepti, Griffith, Alec, Tyekucheva, Svitlana, Wang, Zixu, Rai, Vanessa, Vartanov, Alexander, Thrash, Emily, Fernandes, Stacey M, Lehmberg, Timothy Z., Lee, Brandon, Martindale, Stephen P, Machado, John-Hanson, Odejide, Oreofe, Armand, Philippe, Fisher, David C., Arnason, Jon, Davids, Matthew S., Lederer, James A, Brown, Jennifer R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891037/
https://www.ncbi.nlm.nih.gov/pubmed/34743191
http://dx.doi.org/10.1038/s41375-021-01441-9
_version_ 1784661783292674048
author Gadi, Deepti
Griffith, Alec
Tyekucheva, Svitlana
Wang, Zixu
Rai, Vanessa
Vartanov, Alexander
Thrash, Emily
Fernandes, Stacey M
Lehmberg, Timothy Z.
Lee, Brandon
Martindale, Stephen P
Machado, John-Hanson
Odejide, Oreofe
Armand, Philippe
Fisher, David C.
Arnason, Jon
Davids, Matthew S.
Lederer, James A
Brown, Jennifer R.
author_facet Gadi, Deepti
Griffith, Alec
Tyekucheva, Svitlana
Wang, Zixu
Rai, Vanessa
Vartanov, Alexander
Thrash, Emily
Fernandes, Stacey M
Lehmberg, Timothy Z.
Lee, Brandon
Martindale, Stephen P
Machado, John-Hanson
Odejide, Oreofe
Armand, Philippe
Fisher, David C.
Arnason, Jon
Davids, Matthew S.
Lederer, James A
Brown, Jennifer R.
author_sort Gadi, Deepti
collection PubMed
description Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naïve and central memory CD4 T cells and naïve CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.
format Online
Article
Text
id pubmed-8891037
institution National Center for Biotechnology Information
language English
publishDate 2022
record_format MEDLINE/PubMed
spelling pubmed-88910372022-05-06 A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia Gadi, Deepti Griffith, Alec Tyekucheva, Svitlana Wang, Zixu Rai, Vanessa Vartanov, Alexander Thrash, Emily Fernandes, Stacey M Lehmberg, Timothy Z. Lee, Brandon Martindale, Stephen P Machado, John-Hanson Odejide, Oreofe Armand, Philippe Fisher, David C. Arnason, Jon Davids, Matthew S. Lederer, James A Brown, Jennifer R. Leukemia Article Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naïve and central memory CD4 T cells and naïve CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity. 2022-03 2021-11-06 /pmc/articles/PMC8891037/ /pubmed/34743191 http://dx.doi.org/10.1038/s41375-021-01441-9 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: https://www.springernature.com/gp/open-research/policies/accepted-manuscript-terms
spellingShingle Article
Gadi, Deepti
Griffith, Alec
Tyekucheva, Svitlana
Wang, Zixu
Rai, Vanessa
Vartanov, Alexander
Thrash, Emily
Fernandes, Stacey M
Lehmberg, Timothy Z.
Lee, Brandon
Martindale, Stephen P
Machado, John-Hanson
Odejide, Oreofe
Armand, Philippe
Fisher, David C.
Arnason, Jon
Davids, Matthew S.
Lederer, James A
Brown, Jennifer R.
A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title_full A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title_fullStr A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title_full_unstemmed A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title_short A T Cell Inflammatory Phenotype is Associated with Autoimmune Toxicity of the PI3K Inhibitor Duvelisib in Chronic Lymphocytic Leukemia
title_sort t cell inflammatory phenotype is associated with autoimmune toxicity of the pi3k inhibitor duvelisib in chronic lymphocytic leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891037/
https://www.ncbi.nlm.nih.gov/pubmed/34743191
http://dx.doi.org/10.1038/s41375-021-01441-9
work_keys_str_mv AT gadideepti atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT griffithalec atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT tyekuchevasvitlana atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT wangzixu atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT raivanessa atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT vartanovalexander atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT thrashemily atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT fernandesstaceym atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT lehmbergtimothyz atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT leebrandon atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT martindalestephenp atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT machadojohnhanson atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT odejideoreofe atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT armandphilippe atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT fisherdavidc atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT arnasonjon atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT davidsmatthews atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT ledererjamesa atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT brownjenniferr atcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT gadideepti tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT griffithalec tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT tyekuchevasvitlana tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT wangzixu tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT raivanessa tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT vartanovalexander tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT thrashemily tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT fernandesstaceym tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT lehmbergtimothyz tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT leebrandon tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT martindalestephenp tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT machadojohnhanson tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT odejideoreofe tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT armandphilippe tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT fisherdavidc tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT arnasonjon tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT davidsmatthews tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT ledererjamesa tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia
AT brownjenniferr tcellinflammatoryphenotypeisassociatedwithautoimmunetoxicityofthepi3kinhibitorduvelisibinchroniclymphocyticleukemia