Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab

Amy K. Erbe, Wei Wang, Lakeesha Carmichael, Anna Hoefges, Bartosz Grzywacz, Patrick K. Reville, Erik A. Ranheim, Jacquelyn A. Hank, Kyung Mann Kim, Songwon Seo, Eneida A. Mendonca, Yiqiang Song, Vaishalee P. Kenkre, Fangxin Hong, Randy D. Gascoyne, Elisabeth M. Paietta, Sandra J. Horning, Jeffrey S. Miller, Brad Kahl, Paul M. Sondel

Research output: Contribution to journalArticle

Abstract

Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage. Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.

Original languageEnglish (US)
Article number70
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Mar 12 2019

Fingerprint

KIR Receptors
Follicular Lymphoma
Ligands
Genotype
Natural Killer Cells
Maintenance
Neoplasms
Rituximab
HLA-Bw4 antigen
Reaction Time
Therapeutics

Keywords

  • ADCC
  • CD20
  • Follicular lymphoma
  • HLA
  • Immunotherapy
  • KIR
  • MHC class I
  • Monoclonal antibody
  • NK cells
  • Rituximab

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Cite this

Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. / Erbe, Amy K.; Wang, Wei; Carmichael, Lakeesha; Hoefges, Anna; Grzywacz, Bartosz; Reville, Patrick K.; Ranheim, Erik A.; Hank, Jacquelyn A.; Kim, Kyung Mann; Seo, Songwon; Mendonca, Eneida A.; Song, Yiqiang; Kenkre, Vaishalee P.; Hong, Fangxin; Gascoyne, Randy D.; Paietta, Elisabeth M.; Horning, Sandra J.; Miller, Jeffrey S.; Kahl, Brad; Sondel, Paul M.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 70, 12.03.2019.

Research output: Contribution to journalArticle

Erbe, AK, Wang, W, Carmichael, L, Hoefges, A, Grzywacz, B, Reville, PK, Ranheim, EA, Hank, JA, Kim, KM, Seo, S, Mendonca, EA, Song, Y, Kenkre, VP, Hong, F, Gascoyne, RD, Paietta, EM, Horning, SJ, Miller, JS, Kahl, B & Sondel, PM 2019, 'Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, 70. https://doi.org/10.1186/s40425-019-0538-8
Erbe, Amy K. ; Wang, Wei ; Carmichael, Lakeesha ; Hoefges, Anna ; Grzywacz, Bartosz ; Reville, Patrick K. ; Ranheim, Erik A. ; Hank, Jacquelyn A. ; Kim, Kyung Mann ; Seo, Songwon ; Mendonca, Eneida A. ; Song, Yiqiang ; Kenkre, Vaishalee P. ; Hong, Fangxin ; Gascoyne, Randy D. ; Paietta, Elisabeth M. ; Horning, Sandra J. ; Miller, Jeffrey S. ; Kahl, Brad ; Sondel, Paul M. / Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1.
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abstract = "Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ({"}maintenance{"}) vs. no additional rituximab until progression ({"}non-maintenance{"}). Based on {"}time-to-rituximab-failure (TTRF){"}, the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and {\%} tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of {\%} tumor shrinkage. Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.",
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author = "Erbe, {Amy K.} and Wei Wang and Lakeesha Carmichael and Anna Hoefges and Bartosz Grzywacz and Reville, {Patrick K.} and Ranheim, {Erik A.} and Hank, {Jacquelyn A.} and Kim, {Kyung Mann} and Songwon Seo and Mendonca, {Eneida A.} and Yiqiang Song and Kenkre, {Vaishalee P.} and Fangxin Hong and Gascoyne, {Randy D.} and Paietta, {Elisabeth M.} and Horning, {Sandra J.} and Miller, {Jeffrey S.} and Brad Kahl and Sondel, {Paul M.}",
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doi = "10.1186/s40425-019-0538-8",
language = "English (US)",
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journal = "Journal for ImmunoTherapy of Cancer",
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TY - JOUR

T1 - Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab

AU - Erbe, Amy K.

AU - Wang, Wei

AU - Carmichael, Lakeesha

AU - Hoefges, Anna

AU - Grzywacz, Bartosz

AU - Reville, Patrick K.

AU - Ranheim, Erik A.

AU - Hank, Jacquelyn A.

AU - Kim, Kyung Mann

AU - Seo, Songwon

AU - Mendonca, Eneida A.

AU - Song, Yiqiang

AU - Kenkre, Vaishalee P.

AU - Hong, Fangxin

AU - Gascoyne, Randy D.

AU - Paietta, Elisabeth M.

AU - Horning, Sandra J.

AU - Miller, Jeffrey S.

AU - Kahl, Brad

AU - Sondel, Paul M.

PY - 2019/3/12

Y1 - 2019/3/12

N2 - Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage. Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.

AB - Background: The ECOG-ACRIN Cancer Research Group evaluated rituximab treatment schedules for patients with newly-diagnosed low-tumor-burden follicular-lymphoma (FL). All patients received 4-weekly rituximab treatments as induction therapy. Clinically-responding patients were randomized to receive rituximab every 13 weeks ("maintenance") vs. no additional rituximab until progression ("non-maintenance"). Based on "time-to-rituximab-failure (TTRF)", the study-committee reported there was no overall-benefit for maintenance rituximab in this setting. Tumor-reactive mAbs, like rituximab, trigger natural killer (NK) cells. NK-cell responses are regulated, in part, by interactions between killer immunoglobulin-like receptors (KIRs) on NK cells and their interactions with KIR-ligands. In a separate study of children with neuroblastoma treated with a different mAb, we found certain KIR/KIR-ligand genotypes associated with improved outcome. Here, we assessed whether a subset of FL patients show improved outcome from the maintenance rituximab based on these same KIR/KIR-ligand genotypes. Methods: Genotypes for KIR/KIR-ligand were determined and assessed for associations with outcome [duration of response, TTRF and % tumor shrinkage] as a post-hoc analysis of this phase III trial. Our primary objective was to assess specific KIR/KIR-ligand genotype associations, followed by separate prespecified KIR/KIR-ligand genotype associations in follow-up analyses. Statistical analyses for association of genotype with clinical outcome included: Log-rank tests and Cox proportional hazards regression models to assess duration of response and TTRF; analysis of variance (ANOVA) was used for assessment of % tumor shrinkage. Results: We found that patients inheriting KIR2DL2 and its ligand (HLA-C1) along with KIR3DL1 and its ligand (HLA-Bw4) had improved outcome over patients without this genotype. In addition, patients with KIR2DL2 and HLA-C1 along with KIR3DL1 and HLA-Bw4 also showed improved duration of response and tumor shrinkage if they received maintenance, while patients without this genotype showed no such improvement when receiving maintenance. Conclusions: The data presented here indicate that a subset of FL patients, identified by certain KIRs/KIR-ligands, have improved outcome and may benefit from additional rituximab treatment. Taken together, this suggests that the efficacy of tumor-reactive mAb treatment for some patients is influenced by KIRs on NK cells. However, prior to considering these genotypes in a clinically-actionable manner, these findings need independent validation in other studies.

KW - ADCC

KW - CD20

KW - Follicular lymphoma

KW - HLA

KW - Immunotherapy

KW - KIR

KW - MHC class I

KW - Monoclonal antibody

KW - NK cells

KW - Rituximab

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U2 - 10.1186/s40425-019-0538-8

DO - 10.1186/s40425-019-0538-8

M3 - Article

VL - 7

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

IS - 1

M1 - 70

ER -