Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial

Meenakshi Hegde; Shoba Navai; Christopher DeRenzo; Sujith K. Joseph; Khaled Sanber; Mengfen Wu; Ahmed Z. Gad; Katherine A. Janeway; Matthew Campbell; Dolores Mullikin; Zeid Nawas; Catherine Robertson; Pretty R. Mathew; Huimin Zhang; Birju Mehta; Raksha R. Bhat; Angela Major; Ankita Shree; Claudia Gerken; Mamta Kalra; Rikhia Chakraborty; Sachin G. Thakkar; Olga Dakhova; Vita S. Salsman; Bambi Grilley; Natalia Lapteva; Adrian Gee; Gianpietro Dotti; Riyue Bao; Ahmed Hamed Salem; Tao Wang; Malcolm K. Brenner; Helen E. Heslop; Winfried S. Wels; M. John Hicks; Stephen Gottschalk; Nabil Ahmed

doi:10.1038/s43018-024-00749-6

Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial

Meenakshi Hegde, Shoba Navai, Christopher DeRenzo, Sujith K. Joseph, Khaled Sanber, Mengfen Wu, Ahmed Z. Gad, Katherine A. Janeway, Matthew Campbell, Dolores Mullikin, Zeid Nawas, Catherine Robertson, Pretty R. Mathew, Huimin Zhang, Birju Mehta, Raksha R. Bhat, Angela Major, Ankita Shree, Claudia Gerken, Mamta KalraRikhia Chakraborty, Sachin G. Thakkar, Olga Dakhova, Vita S. Salsman, Bambi Grilley, Natalia Lapteva, Adrian Gee, Gianpietro Dotti, Riyue Bao, Ahmed Hamed Salem, Tao Wang, Malcolm K. Brenner, Helen E. Heslop, Winfried S. Wels, M. John Hicks, Stephen Gottschalk, Nabil Ahmed

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

3 Scopus citations

Abstract

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 10⁸ T cells per m² after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 10⁸ CAR⁺ T cells per m² after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044.

Original language	English (US)
Pages (from-to)	880-894
Number of pages	15
Journal	Nature Cancer
Volume	5
Issue number	6
DOIs	https://doi.org/10.1038/s43018-024-00749-6
State	Published - Jun 2024

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1038/s43018-024-00749-6

Cite this

Hegde, M., Navai, S., DeRenzo, C., Joseph, S. K., Sanber, K., Wu, M., Gad, A. Z., Janeway, K. A., Campbell, M., Mullikin, D., Nawas, Z., Robertson, C., Mathew, P. R., Zhang, H., Mehta, B., Bhat, R. R., Major, A., Shree, A., Gerken, C., ... Ahmed, N. (2024). Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial. Nature Cancer, 5(6), 880-894. https://doi.org/10.1038/s43018-024-00749-6

Hegde, M, Navai, S, DeRenzo, C, Joseph, SK, Sanber, K, Wu, M, Gad, AZ, Janeway, KA, Campbell, M, Mullikin, D, Nawas, Z, Robertson, C, Mathew, PR, Zhang, H, Mehta, B, Bhat, RR, Major, A, Shree, A, Gerken, C, Kalra, M, Chakraborty, R, Thakkar, SG, Dakhova, O, Salsman, VS, Grilley, B, Lapteva, N, Gee, A, Dotti, G, Bao, R, Salem, AH, Wang, T, Brenner, MK , Heslop, HE, Wels, WS, Hicks, MJ, Gottschalk, S & Ahmed, N 2024, 'Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial', Nature Cancer, vol. 5, no. 6, pp. 880-894. https://doi.org/10.1038/s43018-024-00749-6

@article{7df35b0cec4d400f8599ab93ddd6934d,

title = "Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial",

abstract = "In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044.",

author = "Meenakshi Hegde and Shoba Navai and Christopher DeRenzo and Joseph, {Sujith K.} and Khaled Sanber and Mengfen Wu and Gad, {Ahmed Z.} and Janeway, {Katherine A.} and Matthew Campbell and Dolores Mullikin and Zeid Nawas and Catherine Robertson and Mathew, {Pretty R.} and Huimin Zhang and Birju Mehta and Bhat, {Raksha R.} and Angela Major and Ankita Shree and Claudia Gerken and Mamta Kalra and Rikhia Chakraborty and Thakkar, {Sachin G.} and Olga Dakhova and Salsman, {Vita S.} and Bambi Grilley and Natalia Lapteva and Adrian Gee and Gianpietro Dotti and Riyue Bao and Salem, {Ahmed Hamed} and Tao Wang and Brenner, {Malcolm K.} and Heslop, {Helen E.} and Wels, {Winfried S.} and Hicks, {M. John} and Stephen Gottschalk and Nabil Ahmed",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = jun,

doi = "10.1038/s43018-024-00749-6",

language = "English (US)",

volume = "5",

pages = "880--894",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "6",

}

TY - JOUR

T1 - Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma

T2 - a phase 1 trial

AU - Hegde, Meenakshi

AU - Navai, Shoba

AU - DeRenzo, Christopher

AU - Joseph, Sujith K.

AU - Sanber, Khaled

AU - Wu, Mengfen

AU - Gad, Ahmed Z.

AU - Janeway, Katherine A.

AU - Campbell, Matthew

AU - Mullikin, Dolores

AU - Nawas, Zeid

AU - Robertson, Catherine

AU - Mathew, Pretty R.

AU - Zhang, Huimin

AU - Mehta, Birju

AU - Bhat, Raksha R.

AU - Major, Angela

AU - Shree, Ankita

AU - Gerken, Claudia

AU - Kalra, Mamta

AU - Chakraborty, Rikhia

AU - Thakkar, Sachin G.

AU - Dakhova, Olga

AU - Salsman, Vita S.

AU - Grilley, Bambi

AU - Lapteva, Natalia

AU - Gee, Adrian

AU - Dotti, Gianpietro

AU - Bao, Riyue

AU - Salem, Ahmed Hamed

AU - Wang, Tao

AU - Brenner, Malcolm K.

AU - Heslop, Helen E.

AU - Wels, Winfried S.

AU - Hicks, M. John

AU - Gottschalk, Stephen

AU - Ahmed, Nabil

PY - 2024/6

Y1 - 2024/6

N2 - In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044.

AB - In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1–2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3–4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044.

UR - http://www.scopus.com/inward/record.url?scp=85191179993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85191179993&partnerID=8YFLogxK

U2 - 10.1038/s43018-024-00749-6

DO - 10.1038/s43018-024-00749-6

M3 - Article

C2 - 38658775

AN - SCOPUS:85191179993

SN - 2662-1347

VL - 5

SP - 880

EP - 894

JO - Nature Cancer

JF - Nature Cancer

IS - 6

ER -

Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this