Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Melissa M. Berrien-Elliott; Michelle Becker-Hapak; Amanda F. Cashen; Miriam Jacobs; Pamela Wong; Mark Foster; Ethan McClain; Sweta Desai; Patrick Pence; Sarah A Cooley; Claudio G Brunstein; Feng Gao; Camille N. Abboud; Geoffrey L. Uy; Peter Westervelt; Meagan A. Jacoby; Iskra Pusic; Keith E. Stockerl-Goldstein; Mark A. Schroeder; John F. DiPersio; Patrick Soon-Shiong; Jeffrey S. Miller; Todd A. Fehniger

doi:10.1182/blood.2021011532

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Melissa M. Berrien-Elliott, Michelle Becker-Hapak, Amanda F. Cashen, Miriam Jacobs, Pamela Wong, Mark Foster, Ethan McClain, Sweta Desai, Patrick Pence, Sarah A Cooley, Claudio G Brunstein, Feng Gao, Camille N. Abboud, Geoffrey L. Uy, Peter Westervelt, Meagan A. Jacoby, Iskra Pusic, Keith E. Stockerl-Goldstein, Mark A. Schroeder, John F. DiPersioPatrick Soon-Shiong, Jeffrey S. Miller, Todd A. Fehniger

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

Abstract

Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8⁺ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

Original language	English (US)
Pages (from-to)	1177-1183
Number of pages	7
Journal	Blood
Volume	139
Issue number	8
DOIs	https://doi.org/10.1182/blood.2021011532
State	Published - Feb 24 2022

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: M.M.B.-E. and T.A.F. consult for Wugen (equity) and are inventors of technology that Washington University has licensed to Wugen (royalties). T.A.F. has received research support from Immunity Bio, Compass Therapeutics, HCW Biologics, and Wugen and advises Kiadis, Nkarta, Indapta, and Orca Biosystems. C.B. has received research funds from Gamida Cell and Fate Therapeutics and consults for Allovir (data and safety monitoring board). I.P. is on the advisory board for Incyte, Kadmon, and Syndax. J.S.M. reports consultancy, patents, royalties, and research funding from Fate Therapeutics and GT Biopharma; consultancy for Vycellix; and honoraria and membership on the advisory committees of ONK Therapeutics and Sanofi. P.S.-S. is a majority shareholder of ImmunityBio, Inc., and Altor BioScience, LLC, related to N-803. The remaining authors declare no competing financial interests.

Funding Information:
The authors acknowledge support from Bill Eades, Siteman Flow Cytometry Core; Stephen Oh, Immune Monitoring Laboratory; and Biological Therapy Core Facility of the Siteman Cancer Center supported by the National Institutes of Health National Cancer Institute Cancer Center Support Grant (P30CA91842). T.A.F. reports grants from National Institutes of Health National Cancer Institute (R01CA205239), Leukemia and Lymphoma Society, V Foundation for Cancer Research, and Siteman Cancer Center at Washington University School of Medicine and Children's Discovery Institute. M.M.B.-E. was supported by funding from National Institutes of Health National Cancer Institute (K12CA167540). University of Minnesota studies were supported by funding to J.S.M. from National Institutes of Health National Cancer Institute (P01CA111412, P01CA65493, and R35CA197292). M.M.B.-E., T.A.F., and A.F.C. were also funded by National Institutes of Health National Cancer Institute (grant P50CA171063). P. Wong was supported by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute (T32HL007088). Schemas were created using Biorender.com .

Publisher Copyright:
© 2022 American Society of Hematology

Keywords

Allogeneic Cells/immunology
Antineoplastic Agents/administration & dosage
CD8-Positive T-Lymphocytes/immunology
Female
Hematopoietic Stem Cell Transplantation
Humans
Immunotherapy, Adoptive
Interleukin-15/administration & dosage
Killer Cells, Natural/immunology
Leukemia, Myeloid, Acute/immunology
Male
Recombinant Fusion Proteins/administration & dosage

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Clinical Trial, Phase I
Multicenter Study
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1182/blood.2021011532

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Berrien-Elliott, M. M., Becker-Hapak, M., Cashen, A. F., Jacobs, M., Wong, P., Foster, M., McClain, E., Desai, S., Pence, P., Cooley, S. A., Brunstein, C. G., Gao, F., Abboud, C. N., Uy, G. L., Westervelt, P., Jacoby, M. A., Pusic, I., Stockerl-Goldstein, K. E., Schroeder, M. A., ... Fehniger, T. A. (2022). Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy. Blood, 139(8), 1177-1183. https://doi.org/10.1182/blood.2021011532

Berrien-Elliott, MM, Becker-Hapak, M, Cashen, AF, Jacobs, M, Wong, P, Foster, M, McClain, E, Desai, S, Pence, P, Cooley, SA, Brunstein, CG, Gao, F, Abboud, CN, Uy, GL, Westervelt, P, Jacoby, MA, Pusic, I, Stockerl-Goldstein, KE, Schroeder, MA, DiPersio, JF, Soon-Shiong, P, Miller, JS & Fehniger, TA 2022, 'Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy', Blood, vol. 139, no. 8, pp. 1177-1183. https://doi.org/10.1182/blood.2021011532

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title = "Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy",

abstract = "Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.",

keywords = "Allogeneic Cells/immunology, Antineoplastic Agents/administration & dosage, CD8-Positive T-Lymphocytes/immunology, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunotherapy, Adoptive, Interleukin-15/administration & dosage, Killer Cells, Natural/immunology, Leukemia, Myeloid, Acute/immunology, Male, Recombinant Fusion Proteins/administration & dosage",

author = "Berrien-Elliott, {Melissa M.} and Michelle Becker-Hapak and Cashen, {Amanda F.} and Miriam Jacobs and Pamela Wong and Mark Foster and Ethan McClain and Sweta Desai and Patrick Pence and Cooley, {Sarah A} and Brunstein, {Claudio G} and Feng Gao and Abboud, {Camille N.} and Uy, {Geoffrey L.} and Peter Westervelt and Jacoby, {Meagan A.} and Iskra Pusic and Stockerl-Goldstein, {Keith E.} and Schroeder, {Mark A.} and DiPersio, {John F.} and Patrick Soon-Shiong and Miller, {Jeffrey S.} and Fehniger, {Todd A.}",

note = "Funding Information: Conflict-of-interest disclosure: M.M.B.-E. and T.A.F. consult for Wugen (equity) and are inventors of technology that Washington University has licensed to Wugen (royalties). T.A.F. has received research support from Immunity Bio, Compass Therapeutics, HCW Biologics, and Wugen and advises Kiadis, Nkarta, Indapta, and Orca Biosystems. C.B. has received research funds from Gamida Cell and Fate Therapeutics and consults for Allovir (data and safety monitoring board). I.P. is on the advisory board for Incyte, Kadmon, and Syndax. J.S.M. reports consultancy, patents, royalties, and research funding from Fate Therapeutics and GT Biopharma; consultancy for Vycellix; and honoraria and membership on the advisory committees of ONK Therapeutics and Sanofi. P.S.-S. is a majority shareholder of ImmunityBio, Inc., and Altor BioScience, LLC, related to N-803. The remaining authors declare no competing financial interests. Funding Information: The authors acknowledge support from Bill Eades, Siteman Flow Cytometry Core; Stephen Oh, Immune Monitoring Laboratory; and Biological Therapy Core Facility of the Siteman Cancer Center supported by the National Institutes of Health National Cancer Institute Cancer Center Support Grant (P30CA91842). T.A.F. reports grants from National Institutes of Health National Cancer Institute (R01CA205239), Leukemia and Lymphoma Society, V Foundation for Cancer Research, and Siteman Cancer Center at Washington University School of Medicine and Children's Discovery Institute. M.M.B.-E. was supported by funding from National Institutes of Health National Cancer Institute (K12CA167540). University of Minnesota studies were supported by funding to J.S.M. from National Institutes of Health National Cancer Institute (P01CA111412, P01CA65493, and R35CA197292). M.M.B.-E., T.A.F., and A.F.C. were also funded by National Institutes of Health National Cancer Institute (grant P50CA171063). P. Wong was supported by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute (T32HL007088). Schemas were created using Biorender.com . Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = feb,

day = "24",

doi = "10.1182/blood.2021011532",

language = "English (US)",

volume = "139",

pages = "1177--1183",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "8",

}

TY - JOUR

T1 - Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

AU - Berrien-Elliott, Melissa M.

AU - Becker-Hapak, Michelle

AU - Cashen, Amanda F.

AU - Jacobs, Miriam

AU - Wong, Pamela

AU - Foster, Mark

AU - McClain, Ethan

AU - Desai, Sweta

AU - Pence, Patrick

AU - Cooley, Sarah A

AU - Brunstein, Claudio G

AU - Gao, Feng

AU - Abboud, Camille N.

AU - Uy, Geoffrey L.

AU - Westervelt, Peter

AU - Jacoby, Meagan A.

AU - Pusic, Iskra

AU - Stockerl-Goldstein, Keith E.

AU - Schroeder, Mark A.

AU - DiPersio, John F.

AU - Soon-Shiong, Patrick

AU - Miller, Jeffrey S.

AU - Fehniger, Todd A.

N1 - Funding Information: Conflict-of-interest disclosure: M.M.B.-E. and T.A.F. consult for Wugen (equity) and are inventors of technology that Washington University has licensed to Wugen (royalties). T.A.F. has received research support from Immunity Bio, Compass Therapeutics, HCW Biologics, and Wugen and advises Kiadis, Nkarta, Indapta, and Orca Biosystems. C.B. has received research funds from Gamida Cell and Fate Therapeutics and consults for Allovir (data and safety monitoring board). I.P. is on the advisory board for Incyte, Kadmon, and Syndax. J.S.M. reports consultancy, patents, royalties, and research funding from Fate Therapeutics and GT Biopharma; consultancy for Vycellix; and honoraria and membership on the advisory committees of ONK Therapeutics and Sanofi. P.S.-S. is a majority shareholder of ImmunityBio, Inc., and Altor BioScience, LLC, related to N-803. The remaining authors declare no competing financial interests. Funding Information: The authors acknowledge support from Bill Eades, Siteman Flow Cytometry Core; Stephen Oh, Immune Monitoring Laboratory; and Biological Therapy Core Facility of the Siteman Cancer Center supported by the National Institutes of Health National Cancer Institute Cancer Center Support Grant (P30CA91842). T.A.F. reports grants from National Institutes of Health National Cancer Institute (R01CA205239), Leukemia and Lymphoma Society, V Foundation for Cancer Research, and Siteman Cancer Center at Washington University School of Medicine and Children's Discovery Institute. M.M.B.-E. was supported by funding from National Institutes of Health National Cancer Institute (K12CA167540). University of Minnesota studies were supported by funding to J.S.M. from National Institutes of Health National Cancer Institute (P01CA111412, P01CA65493, and R35CA197292). M.M.B.-E., T.A.F., and A.F.C. were also funded by National Institutes of Health National Cancer Institute (grant P50CA171063). P. Wong was supported by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute (T32HL007088). Schemas were created using Biorender.com . Publisher Copyright: © 2022 American Society of Hematology

PY - 2022/2/24

Y1 - 2022/2/24

N2 - Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

AB - Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.

KW - Allogeneic Cells/immunology

KW - Antineoplastic Agents/administration & dosage

KW - CD8-Positive T-Lymphocytes/immunology

KW - Female

KW - Hematopoietic Stem Cell Transplantation

KW - Humans

KW - Immunotherapy, Adoptive

KW - Interleukin-15/administration & dosage

KW - Killer Cells, Natural/immunology

KW - Leukemia, Myeloid, Acute/immunology

KW - Male

KW - Recombinant Fusion Proteins/administration & dosage

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U2 - 10.1182/blood.2021011532

DO - 10.1182/blood.2021011532

M3 - Article

C2 - 34797911

AN - SCOPUS:85125114362

SN - 0006-4971

VL - 139

SP - 1177

EP - 1183

JO - Blood

JF - Blood

IS - 8

ER -

Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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