Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

Indu Ramachandran, Daniel E. Lowther, Rebecca Dryer-Minnerly, Ruoxi Wang, Svetlana Fayngerts, Daniel Nunez, Gareth Betts, Natalie Bath, Alex J. Tipping, Luca Melchiori, Jean Marc Navenot, John Glod, Crystal L. MacKall, Sandra P. D'Angelo, Dejka M. Araujo, Warren A. Chow, George D. Demetri, Mihaela Druta, Brian A. Van Tine, Stephan A. GruppAlbiruni R. Abdul Razak, Breelyn Wilky, Malini Iyengar, Trupti Trivedi, Erin Van Winkle, Karen Chagin, Rafael Amado, Gwendolyn K. Binder, Samik Basu

Research output: Contribution to journalArticle

Abstract

Background: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.

Original languageEnglish (US)
Article number276
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
StatePublished - Oct 24 2019
Externally publishedYes

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Synovial Sarcoma
Adoptive Transfer
Immunity
T-Lymphocytes
Tumor Microenvironment
Leukocytes
Neoplasms
Genes
Macrophages
Interleukin-15
Interleukin-7
HLA-A Antigens
Antigen Presentation
Neoplasm Antigens
Cell- and Tissue-Based Therapy
T-Cell Antigen Receptor
Serum
Immunoassay
Immunotherapy
Cyclophosphamide

Keywords

  • Adoptive immunotherapy
  • Antigen loss
  • Checkpoint therapy
  • Cyclophosphamide
  • Cytokine
  • Engineered cell therapy
  • Fludarabine
  • IL-15
  • NY-ESO-1
  • Synovial sarcoma
  • T cell
  • TCR

ASJC Scopus subject areas

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

Cite this

Ramachandran, I., Lowther, D. E., Dryer-Minnerly, R., Wang, R., Fayngerts, S., Nunez, D., ... Basu, S. (2019). Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. Journal for ImmunoTherapy of Cancer, 7(1), [276]. https://doi.org/10.1186/s40425-019-0762-2

Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. / Ramachandran, Indu; Lowther, Daniel E.; Dryer-Minnerly, Rebecca; Wang, Ruoxi; Fayngerts, Svetlana; Nunez, Daniel; Betts, Gareth; Bath, Natalie; Tipping, Alex J.; Melchiori, Luca; Navenot, Jean Marc; Glod, John; MacKall, Crystal L.; D'Angelo, Sandra P.; Araujo, Dejka M.; Chow, Warren A.; Demetri, George D.; Druta, Mihaela; Van Tine, Brian A.; Grupp, Stephan A.; Abdul Razak, Albiruni R.; Wilky, Breelyn; Iyengar, Malini; Trivedi, Trupti; Winkle, Erin Van; Chagin, Karen; Amado, Rafael; Binder, Gwendolyn K.; Basu, Samik.

In: Journal for ImmunoTherapy of Cancer, Vol. 7, No. 1, 276, 24.10.2019.

Research output: Contribution to journalArticle

Ramachandran, I, Lowther, DE, Dryer-Minnerly, R, Wang, R, Fayngerts, S, Nunez, D, Betts, G, Bath, N, Tipping, AJ, Melchiori, L, Navenot, JM, Glod, J, MacKall, CL, D'Angelo, SP, Araujo, DM, Chow, WA, Demetri, GD, Druta, M, Van Tine, BA, Grupp, SA, Abdul Razak, AR, Wilky, B, Iyengar, M, Trivedi, T, Winkle, EV, Chagin, K, Amado, R, Binder, GK & Basu, S 2019, 'Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma', Journal for ImmunoTherapy of Cancer, vol. 7, no. 1, 276. https://doi.org/10.1186/s40425-019-0762-2
Ramachandran, Indu ; Lowther, Daniel E. ; Dryer-Minnerly, Rebecca ; Wang, Ruoxi ; Fayngerts, Svetlana ; Nunez, Daniel ; Betts, Gareth ; Bath, Natalie ; Tipping, Alex J. ; Melchiori, Luca ; Navenot, Jean Marc ; Glod, John ; MacKall, Crystal L. ; D'Angelo, Sandra P. ; Araujo, Dejka M. ; Chow, Warren A. ; Demetri, George D. ; Druta, Mihaela ; Van Tine, Brian A. ; Grupp, Stephan A. ; Abdul Razak, Albiruni R. ; Wilky, Breelyn ; Iyengar, Malini ; Trivedi, Trupti ; Winkle, Erin Van ; Chagin, Karen ; Amado, Rafael ; Binder, Gwendolyn K. ; Basu, Samik. / Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. In: Journal for ImmunoTherapy of Cancer. 2019 ; Vol. 7, No. 1.
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abstract = "Background: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5{\%}) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.",
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TY - JOUR

T1 - Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma

AU - Ramachandran, Indu

AU - Lowther, Daniel E.

AU - Dryer-Minnerly, Rebecca

AU - Wang, Ruoxi

AU - Fayngerts, Svetlana

AU - Nunez, Daniel

AU - Betts, Gareth

AU - Bath, Natalie

AU - Tipping, Alex J.

AU - Melchiori, Luca

AU - Navenot, Jean Marc

AU - Glod, John

AU - MacKall, Crystal L.

AU - D'Angelo, Sandra P.

AU - Araujo, Dejka M.

AU - Chow, Warren A.

AU - Demetri, George D.

AU - Druta, Mihaela

AU - Van Tine, Brian A.

AU - Grupp, Stephan A.

AU - Abdul Razak, Albiruni R.

AU - Wilky, Breelyn

AU - Iyengar, Malini

AU - Trivedi, Trupti

AU - Winkle, Erin Van

AU - Chagin, Karen

AU - Amado, Rafael

AU - Binder, Gwendolyn K.

AU - Basu, Samik

PY - 2019/10/24

Y1 - 2019/10/24

N2 - Background: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.

AB - Background: Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.

KW - Adoptive immunotherapy

KW - Antigen loss

KW - Checkpoint therapy

KW - Cyclophosphamide

KW - Cytokine

KW - Engineered cell therapy

KW - Fludarabine

KW - IL-15

KW - NY-ESO-1

KW - Synovial sarcoma

KW - T cell

KW - TCR

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U2 - 10.1186/s40425-019-0762-2

DO - 10.1186/s40425-019-0762-2

M3 - Article

C2 - 31651363

AN - SCOPUS:85074080761

VL - 7

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

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