MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

M W Rohaan; R Gomez-Eerland; J H van den Berg; M H Geukes Foppen; M van Zon; B Raud; I Jedema; S Scheij; R de Boer; N A M Bakker; D van den Broek; L M Pronk; L G Grijpink-Ongering; A Sari; R Kessels; M van den Haak; H A Mallo; M Karger; B A van de Wiel; C L Zuur; C W Duinkerken; F Lalezari; J V van Thienen; S Wilgenhof; C U Blank; J H Beijnen; B Nuijen; T N Schumacher; J B A G Haanen

doi:10.1016/j.iotech.2022.100089

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

M W Rohaan, R Gomez-Eerland, J H van den Berg, M H Geukes Foppen, M van Zon, B Raud, I Jedema, S Scheij, R de Boer, N A M Bakker, D van den Broek, L M Pronk, L G Grijpink-Ongering, A Sari, R Kessels, M van den Haak, H A Mallo, M Karger, B A van de Wiel, C L ZuurC W Duinkerken, F Lalezari, J V van Thienen, S Wilgenhof, C U Blank, J H Beijnen, B Nuijen, T N Schumacher, J B A G Haanen

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

Abstract

BACKGROUND: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma.

MATERIALS AND METHODS: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed.

RESULTS: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose.

CONCLUSIONS: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

Original language	English
Article number	100089
Journal	Immuno-Oncology and Technology
Volume	15
DOIs	https://doi.org/10.1016/j.iotech.2022.100089
Publication status	Published - Sept 2022
Externally published	Yes

Access to Document

10.1016/j.iotech.2022.100089

Cite this

Rohaan, M. W., Gomez-Eerland, R., van den Berg, J. H., Geukes Foppen, M. H., van Zon, M., Raud, B., Jedema, I., Scheij, S., de Boer, R., Bakker, N. A. M., van den Broek, D., Pronk, L. M., Grijpink-Ongering, L. G., Sari, A., Kessels, R., van den Haak, M., Mallo, H. A., Karger, M., van de Wiel, B. A., ... Haanen, J. B. A. G. (2022). MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial. Immuno-Oncology and Technology, 15, Article 100089. https://doi.org/10.1016/j.iotech.2022.100089

@article{b9e6bca2c31e414e907ec77b53886edb,

title = "MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial",

abstract = "BACKGROUND: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma.MATERIALS AND METHODS: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed.RESULTS: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose.CONCLUSIONS: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.",

author = "Rohaan, {M W} and R Gomez-Eerland and {van den Berg}, {J H} and {Geukes Foppen}, {M H} and {van Zon}, M and B Raud and I Jedema and S Scheij and {de Boer}, R and Bakker, {N A M} and {van den Broek}, D and Pronk, {L M} and Grijpink-Ongering, {L G} and A Sari and R Kessels and {van den Haak}, M and Mallo, {H A} and M Karger and {van de Wiel}, {B A} and Zuur, {C L} and Duinkerken, {C W} and F Lalezari and {van Thienen}, {J V} and S Wilgenhof and Blank, {C U} and Beijnen, {J H} and B Nuijen and Schumacher, {T N} and Haanen, {J B A G}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = sep,

doi = "10.1016/j.iotech.2022.100089",

language = "English",

volume = "15",

}

Rohaan, MW, Gomez-Eerland, R, van den Berg, JH, Geukes Foppen, MH, van Zon, M, Raud, B, Jedema, I, Scheij, S, de Boer, R, Bakker, NAM, van den Broek, D, Pronk, LM, Grijpink-Ongering, LG, Sari, A, Kessels, R, van den Haak, M, Mallo, HA, Karger, M, van de Wiel, BA, Zuur, CL, Duinkerken, CW, Lalezari, F, van Thienen, JV, Wilgenhof, S, Blank, CU, Beijnen, JH, Nuijen, B, Schumacher, TN & Haanen, JBAG 2022, 'MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial', Immuno-Oncology and Technology, vol. 15, 100089. https://doi.org/10.1016/j.iotech.2022.100089

TY - JOUR

T1 - MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma

T2 - a phase I/IIa clinical trial

AU - Rohaan, M W

AU - Gomez-Eerland, R

AU - van den Berg, J H

AU - Geukes Foppen, M H

AU - van Zon, M

AU - Raud, B

AU - Jedema, I

AU - Scheij, S

AU - de Boer, R

AU - Bakker, N A M

AU - van den Broek, D

AU - Pronk, L M

AU - Grijpink-Ongering, L G

AU - Sari, A

AU - Kessels, R

AU - van den Haak, M

AU - Mallo, H A

AU - Karger, M

AU - van de Wiel, B A

AU - Zuur, C L

AU - Duinkerken, C W

AU - Lalezari, F

AU - van Thienen, J V

AU - Wilgenhof, S

AU - Blank, C U

AU - Beijnen, J H

AU - Nuijen, B

AU - Schumacher, T N

AU - Haanen, J B A G

PY - 2022/9

Y1 - 2022/9

N2 - BACKGROUND: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma.MATERIALS AND METHODS: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed.RESULTS: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose.CONCLUSIONS: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

AB - BACKGROUND: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma.MATERIALS AND METHODS: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed.RESULTS: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose.CONCLUSIONS: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

UR - http://www.scopus.com/inward/record.url?scp=85134187755&partnerID=8YFLogxK

U2 - 10.1016/j.iotech.2022.100089

DO - 10.1016/j.iotech.2022.100089

M3 - Article

C2 - 35865122

VL - 15

JO - Immuno-Oncology and Technology

JF - Immuno-Oncology and Technology

M1 - 100089

ER -

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial

Abstract

Access to Document

Other files and links

Fingerprint

Cite this