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Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma
BACKGROUND: The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256838/ https://www.ncbi.nlm.nih.gov/pubmed/34215687 http://dx.doi.org/10.1136/jitc-2020-002123 |
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author | Mustafa, Nurulhuda Nee, Adina Huey Fang Chooi, Jing Yuan Toh, Sabrina Hui Min Chung, Tae-Hoon Selvarajan, Viknesvaran Fan, Shuangyi Ng, Siok Bian Poon, Michelle Chan, Esther Lee, Joanne Chee, Yen Lin Jeyasekharan, Anand D Zhou, Longen Yang, Jennifer Chng, Wee Joo |
author_facet | Mustafa, Nurulhuda Nee, Adina Huey Fang Chooi, Jing Yuan Toh, Sabrina Hui Min Chung, Tae-Hoon Selvarajan, Viknesvaran Fan, Shuangyi Ng, Siok Bian Poon, Michelle Chan, Esther Lee, Joanne Chee, Yen Lin Jeyasekharan, Anand D Zhou, Longen Yang, Jennifer Chng, Wee Joo |
author_sort | Mustafa, Nurulhuda |
collection | PubMed |
description | BACKGROUND: The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL. METHODS: CD38 expression was studied via immunohistochemistry, multiplex immunofluorescence and correlated with clinical characteristics of the patient. The therapeutic efficacy of daratumumab was studied in vitro via CellTiter-Glo (CTG) assay, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and in vivo, via a patient-derived xenograft mouse model of NKTL, both as a single agent and in combination with L-asparaginase. Signaling mechanisms were characterized via pharmacologic treatment, RNA silencing, flow cytometry and corroborated with public transcriptomic data of NKTL. RESULTS: Epstein-Barr virus-positive NKTL patients significantly express CD38 with half exhibiting high expression. Daratumumab effectively triggers Fc-mediated ADCC and CDC in a CD38-dependent manner. Importantly, daratumumab monotherapy and combination therapy with L-asparaginase significantly suppresses tumor progression in vivo. Ablation of complement inhibitory proteins (CIP) demonstrate that CD55 and CD59, not CD46, are critical for the induction of CDC. Notably, CD55 and CD59 expression were significantly elevated in the late stages of NKTL. Increasing the CD38:CIP ratio through sequential CIP knockdown, followed by CD38 upregulation via All-Trans Retinoic Acid treatment, potently augments complement-mediated lysis in cells previously resistant to daratumumab. The CD38:CIP ratio consistently demonstrates a statistically superior correlation to antitumor efficacy of daratumumab than CD38 or CIP expression alone. CONCLUSION: This study characterizes CD38 as an effective target for a subset of NKTL patients and the utilization of the CD38:CIP ratio as a more robust identifier for patient stratification and personalisation of treatment. Furthermore, elucidation of factors which sensitize the complement-mediated response provides an alternative approach toward optimizing therapeutic efficacy of daratumumab where CDC remains a known limiting factor. Altogether, these results propose a strategic rationale for further evaluation of single or combined daratumumab treatment in the clinic for NKTL. |
format | Online Article Text |
id | pubmed-8256838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-82568382021-07-23 Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma Mustafa, Nurulhuda Nee, Adina Huey Fang Chooi, Jing Yuan Toh, Sabrina Hui Min Chung, Tae-Hoon Selvarajan, Viknesvaran Fan, Shuangyi Ng, Siok Bian Poon, Michelle Chan, Esther Lee, Joanne Chee, Yen Lin Jeyasekharan, Anand D Zhou, Longen Yang, Jennifer Chng, Wee Joo J Immunother Cancer Basic Tumor Immunology BACKGROUND: The potential therapeutic efficacy of daratumumab in natural killer T-cell lymphoma (NKTL) was highlighted when its off-label usage produced sustained remission in a patient with highly refractory disease. This is corroborated recently by a phase II clinical trial which established that daratumumab monotherapy is well tolerated and displayed encouraging response in relapsed/refractory NKTL patients. However, little is known regarding the molecular factors central to the induction and regulation of the daratumumab-mediated antitumor response in NKTL. METHODS: CD38 expression was studied via immunohistochemistry, multiplex immunofluorescence and correlated with clinical characteristics of the patient. The therapeutic efficacy of daratumumab was studied in vitro via CellTiter-Glo (CTG) assay, complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and in vivo, via a patient-derived xenograft mouse model of NKTL, both as a single agent and in combination with L-asparaginase. Signaling mechanisms were characterized via pharmacologic treatment, RNA silencing, flow cytometry and corroborated with public transcriptomic data of NKTL. RESULTS: Epstein-Barr virus-positive NKTL patients significantly express CD38 with half exhibiting high expression. Daratumumab effectively triggers Fc-mediated ADCC and CDC in a CD38-dependent manner. Importantly, daratumumab monotherapy and combination therapy with L-asparaginase significantly suppresses tumor progression in vivo. Ablation of complement inhibitory proteins (CIP) demonstrate that CD55 and CD59, not CD46, are critical for the induction of CDC. Notably, CD55 and CD59 expression were significantly elevated in the late stages of NKTL. Increasing the CD38:CIP ratio through sequential CIP knockdown, followed by CD38 upregulation via All-Trans Retinoic Acid treatment, potently augments complement-mediated lysis in cells previously resistant to daratumumab. The CD38:CIP ratio consistently demonstrates a statistically superior correlation to antitumor efficacy of daratumumab than CD38 or CIP expression alone. CONCLUSION: This study characterizes CD38 as an effective target for a subset of NKTL patients and the utilization of the CD38:CIP ratio as a more robust identifier for patient stratification and personalisation of treatment. Furthermore, elucidation of factors which sensitize the complement-mediated response provides an alternative approach toward optimizing therapeutic efficacy of daratumumab where CDC remains a known limiting factor. Altogether, these results propose a strategic rationale for further evaluation of single or combined daratumumab treatment in the clinic for NKTL. BMJ Publishing Group 2021-07-02 /pmc/articles/PMC8256838/ /pubmed/34215687 http://dx.doi.org/10.1136/jitc-2020-002123 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Mustafa, Nurulhuda Nee, Adina Huey Fang Chooi, Jing Yuan Toh, Sabrina Hui Min Chung, Tae-Hoon Selvarajan, Viknesvaran Fan, Shuangyi Ng, Siok Bian Poon, Michelle Chan, Esther Lee, Joanne Chee, Yen Lin Jeyasekharan, Anand D Zhou, Longen Yang, Jennifer Chng, Wee Joo Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title | Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title_full | Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title_fullStr | Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title_full_unstemmed | Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title_short | Determinants of response to daratumumab in Epstein-Barr virus-positive natural killer and T-cell lymphoma |
title_sort | determinants of response to daratumumab in epstein-barr virus-positive natural killer and t-cell lymphoma |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256838/ https://www.ncbi.nlm.nih.gov/pubmed/34215687 http://dx.doi.org/10.1136/jitc-2020-002123 |
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