Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system

Cristina Puig-Saus, Giulia Parisi, Angel Garcia-Diaz, Paige E. Krystofinski, Salemiz Sandoval, Ruixue Zhang, Ameya S. Champhekar, James McCabe, Gardenia C. Cheung-Lau, Nhat A. Truong, Agustin Vega-Crespo, Marie Desiles S. Komenan, Jia Pang, Mignonette H. Macabali, Justin D. Saco, Jeffrey L. Goodwin, Brad Bolon, Christopher S. Seet, Amelie Montel-Hagen, Gay M. CrooksRoger P. Hollis, Beatriz Campo-Fernandez, Daniela Bischof, Kenneth Cornetta, Eric H. Gschweng, Celia Adelson, Alexander Nguyen, Lili Yang, Owen N. Witte, David Baltimore, Begonya Comin-Anduix, Donald B. Kohn, Xiaoyan Wang, Paula Cabrera, Paula J. Kaplan-Lefko, Beata Berent-Maoz, Antoni Ribas

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. Experimental Design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/ suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/K b mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. Results: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. Conclusions: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.

Original languageEnglish (US)
Pages (from-to)1000-1011
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number3
DOIs
StatePublished - Feb 1 2019

Fingerprint

T-Cell Antigen Receptor
Immune System
Clinical Trials
Hematopoietic Stem Cells
Neoplasms
T-Lymphocytes
Transgenes
Investigational New Drug Application
Investigational Drugs
HLA-A2 Antigen
Safety
Adoptive Transfer
Hematopoietic Stem Cell Transplantation
Cell Lineage
Clinical Protocols
Reporter Genes
Suicide
Cell Differentiation
Blood Cells
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Puig-Saus, C., Parisi, G., Garcia-Diaz, A., Krystofinski, P. E., Sandoval, S., Zhang, R., ... Ribas, A. (2019). Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. Clinical Cancer Research, 25(3), 1000-1011. https://doi.org/10.1158/1078-0432.CCR-18-0963

Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. / Puig-Saus, Cristina; Parisi, Giulia; Garcia-Diaz, Angel; Krystofinski, Paige E.; Sandoval, Salemiz; Zhang, Ruixue; Champhekar, Ameya S.; McCabe, James; Cheung-Lau, Gardenia C.; Truong, Nhat A.; Vega-Crespo, Agustin; Komenan, Marie Desiles S.; Pang, Jia; Macabali, Mignonette H.; Saco, Justin D.; Goodwin, Jeffrey L.; Bolon, Brad; Seet, Christopher S.; Montel-Hagen, Amelie; Crooks, Gay M.; Hollis, Roger P.; Campo-Fernandez, Beatriz; Bischof, Daniela; Cornetta, Kenneth; Gschweng, Eric H.; Adelson, Celia; Nguyen, Alexander; Yang, Lili; Witte, Owen N.; Baltimore, David; Comin-Anduix, Begonya; Kohn, Donald B.; Wang, Xiaoyan; Cabrera, Paula; Kaplan-Lefko, Paula J.; Berent-Maoz, Beata; Ribas, Antoni.

In: Clinical Cancer Research, Vol. 25, No. 3, 01.02.2019, p. 1000-1011.

Research output: Contribution to journalArticle

Puig-Saus, C, Parisi, G, Garcia-Diaz, A, Krystofinski, PE, Sandoval, S, Zhang, R, Champhekar, AS, McCabe, J, Cheung-Lau, GC, Truong, NA, Vega-Crespo, A, Komenan, MDS, Pang, J, Macabali, MH, Saco, JD, Goodwin, JL, Bolon, B, Seet, CS, Montel-Hagen, A, Crooks, GM, Hollis, RP, Campo-Fernandez, B, Bischof, D, Cornetta, K, Gschweng, EH, Adelson, C, Nguyen, A, Yang, L, Witte, ON, Baltimore, D, Comin-Anduix, B, Kohn, DB, Wang, X, Cabrera, P, Kaplan-Lefko, PJ, Berent-Maoz, B & Ribas, A 2019, 'Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system', Clinical Cancer Research, vol. 25, no. 3, pp. 1000-1011. https://doi.org/10.1158/1078-0432.CCR-18-0963
Puig-Saus, Cristina ; Parisi, Giulia ; Garcia-Diaz, Angel ; Krystofinski, Paige E. ; Sandoval, Salemiz ; Zhang, Ruixue ; Champhekar, Ameya S. ; McCabe, James ; Cheung-Lau, Gardenia C. ; Truong, Nhat A. ; Vega-Crespo, Agustin ; Komenan, Marie Desiles S. ; Pang, Jia ; Macabali, Mignonette H. ; Saco, Justin D. ; Goodwin, Jeffrey L. ; Bolon, Brad ; Seet, Christopher S. ; Montel-Hagen, Amelie ; Crooks, Gay M. ; Hollis, Roger P. ; Campo-Fernandez, Beatriz ; Bischof, Daniela ; Cornetta, Kenneth ; Gschweng, Eric H. ; Adelson, Celia ; Nguyen, Alexander ; Yang, Lili ; Witte, Owen N. ; Baltimore, David ; Comin-Anduix, Begonya ; Kohn, Donald B. ; Wang, Xiaoyan ; Cabrera, Paula ; Kaplan-Lefko, Paula J. ; Berent-Maoz, Beata ; Ribas, Antoni. / Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 3. pp. 1000-1011.
@article{cbd9bff9a28746b8a61ffd44f1b6c36c,
title = "Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system",
abstract = "Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. Experimental Design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/ suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/K b mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. Results: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. Conclusions: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.",
author = "Cristina Puig-Saus and Giulia Parisi and Angel Garcia-Diaz and Krystofinski, {Paige E.} and Salemiz Sandoval and Ruixue Zhang and Champhekar, {Ameya S.} and James McCabe and Cheung-Lau, {Gardenia C.} and Truong, {Nhat A.} and Agustin Vega-Crespo and Komenan, {Marie Desiles S.} and Jia Pang and Macabali, {Mignonette H.} and Saco, {Justin D.} and Goodwin, {Jeffrey L.} and Brad Bolon and Seet, {Christopher S.} and Amelie Montel-Hagen and Crooks, {Gay M.} and Hollis, {Roger P.} and Beatriz Campo-Fernandez and Daniela Bischof and Kenneth Cornetta and Gschweng, {Eric H.} and Celia Adelson and Alexander Nguyen and Lili Yang and Witte, {Owen N.} and David Baltimore and Begonya Comin-Anduix and Kohn, {Donald B.} and Xiaoyan Wang and Paula Cabrera and Kaplan-Lefko, {Paula J.} and Beata Berent-Maoz and Antoni Ribas",
year = "2019",
month = "2",
day = "1",
doi = "10.1158/1078-0432.CCR-18-0963",
language = "English (US)",
volume = "25",
pages = "1000--1011",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

T1 - Ind-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system

AU - Puig-Saus, Cristina

AU - Parisi, Giulia

AU - Garcia-Diaz, Angel

AU - Krystofinski, Paige E.

AU - Sandoval, Salemiz

AU - Zhang, Ruixue

AU - Champhekar, Ameya S.

AU - McCabe, James

AU - Cheung-Lau, Gardenia C.

AU - Truong, Nhat A.

AU - Vega-Crespo, Agustin

AU - Komenan, Marie Desiles S.

AU - Pang, Jia

AU - Macabali, Mignonette H.

AU - Saco, Justin D.

AU - Goodwin, Jeffrey L.

AU - Bolon, Brad

AU - Seet, Christopher S.

AU - Montel-Hagen, Amelie

AU - Crooks, Gay M.

AU - Hollis, Roger P.

AU - Campo-Fernandez, Beatriz

AU - Bischof, Daniela

AU - Cornetta, Kenneth

AU - Gschweng, Eric H.

AU - Adelson, Celia

AU - Nguyen, Alexander

AU - Yang, Lili

AU - Witte, Owen N.

AU - Baltimore, David

AU - Comin-Anduix, Begonya

AU - Kohn, Donald B.

AU - Wang, Xiaoyan

AU - Cabrera, Paula

AU - Kaplan-Lefko, Paula J.

AU - Berent-Maoz, Beata

AU - Ribas, Antoni

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. Experimental Design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/ suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/K b mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. Results: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. Conclusions: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.

AB - Purpose: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. Experimental Design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/ suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/K b mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. Results: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. Conclusions: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.

UR - http://www.scopus.com/inward/record.url?scp=85060911669&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060911669&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-0963

DO - 10.1158/1078-0432.CCR-18-0963

M3 - Article

C2 - 30409823

AN - SCOPUS:85060911669

VL - 25

SP - 1000

EP - 1011

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 3

ER -