Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

Laszlo G. Radvanyi, Chantale Bernatchez, Minying Zhang, Patricia S. Fox, Priscilla Miller, Jessica Chacon, Richard Wu, Gregory Lizee, Sandy Mahoney, Gladys Alvarado, Michelle Glass, Valen E. Johnson, John D. McMannis, Elizabeth Shpall, Victor Prieto, Nicholas Papadopoulos, Kevin Kim, Jade Homsi, Agop Bedikian, Wen Jen HwuSapna Patel, Merrick I. Ross, Jeffrey E. Lee, Jeffrey E. Gershenwald, Anthony Lucci, Richard Royal, Janice N. Cormier, Michael A. Davies, Rahmatu Mansaray, Orenthial J. Fulbright, Christopher Toth, Renjith Ramachandran, Seth Wardell, Audrey Gonzalez, Patrick Hwu

Research output: Contribution to journalArticle

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Abstract

Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.

Original languageEnglish (US)
Pages (from-to)6758-6770
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number24
DOIs
StatePublished - Dec 15 2012

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Tumor-Infiltrating Lymphocytes
Lymphocyte Subsets
Cell- and Tissue-Based Therapy
Melanoma
T-Lymphocytes
Phenotype
Phase II Clinical Trials
Telomere
Immunotherapy
Disease-Free Survival
Interleukin-2
Neoplasms
Research Design
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. / Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick.

In: Clinical Cancer Research, Vol. 18, No. 24, 15.12.2012, p. 6758-6770.

Research output: Contribution to journalArticle

Radvanyi, LG, Bernatchez, C, Zhang, M, Fox, PS, Miller, P, Chacon, J, Wu, R, Lizee, G, Mahoney, S, Alvarado, G, Glass, M, Johnson, VE, McMannis, JD, Shpall, E, Prieto, V, Papadopoulos, N, Kim, K, Homsi, J, Bedikian, A, Hwu, WJ, Patel, S, Ross, MI, Lee, JE, Gershenwald, JE, Lucci, A, Royal, R, Cormier, JN, Davies, MA, Mansaray, R, Fulbright, OJ, Toth, C, Ramachandran, R, Wardell, S, Gonzalez, A & Hwu, P 2012, 'Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients', Clinical Cancer Research, vol. 18, no. 24, pp. 6758-6770. https://doi.org/10.1158/1078-0432.CCR-12-1177
Radvanyi, Laszlo G. ; Bernatchez, Chantale ; Zhang, Minying ; Fox, Patricia S. ; Miller, Priscilla ; Chacon, Jessica ; Wu, Richard ; Lizee, Gregory ; Mahoney, Sandy ; Alvarado, Gladys ; Glass, Michelle ; Johnson, Valen E. ; McMannis, John D. ; Shpall, Elizabeth ; Prieto, Victor ; Papadopoulos, Nicholas ; Kim, Kevin ; Homsi, Jade ; Bedikian, Agop ; Hwu, Wen Jen ; Patel, Sapna ; Ross, Merrick I. ; Lee, Jeffrey E. ; Gershenwald, Jeffrey E. ; Lucci, Anthony ; Royal, Richard ; Cormier, Janice N. ; Davies, Michael A. ; Mansaray, Rahmatu ; Fulbright, Orenthial J. ; Toth, Christopher ; Ramachandran, Renjith ; Wardell, Seth ; Gonzalez, Audrey ; Hwu, Patrick. / Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 24. pp. 6758-6770.
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abstract = "Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4{\%}) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5{\%}) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60{\%}) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule {"}B- and T-lymphocyte attenuator{"} (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.",
author = "Radvanyi, {Laszlo G.} and Chantale Bernatchez and Minying Zhang and Fox, {Patricia S.} and Priscilla Miller and Jessica Chacon and Richard Wu and Gregory Lizee and Sandy Mahoney and Gladys Alvarado and Michelle Glass and Johnson, {Valen E.} and McMannis, {John D.} and Elizabeth Shpall and Victor Prieto and Nicholas Papadopoulos and Kevin Kim and Jade Homsi and Agop Bedikian and Hwu, {Wen Jen} and Sapna Patel and Ross, {Merrick I.} and Lee, {Jeffrey E.} and Gershenwald, {Jeffrey E.} and Anthony Lucci and Richard Royal and Cormier, {Janice N.} and Davies, {Michael A.} and Rahmatu Mansaray and Fulbright, {Orenthial J.} and Christopher Toth and Renjith Ramachandran and Seth Wardell and Audrey Gonzalez and Patrick Hwu",
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T1 - Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

AU - Radvanyi, Laszlo G.

AU - Bernatchez, Chantale

AU - Zhang, Minying

AU - Fox, Patricia S.

AU - Miller, Priscilla

AU - Chacon, Jessica

AU - Wu, Richard

AU - Lizee, Gregory

AU - Mahoney, Sandy

AU - Alvarado, Gladys

AU - Glass, Michelle

AU - Johnson, Valen E.

AU - McMannis, John D.

AU - Shpall, Elizabeth

AU - Prieto, Victor

AU - Papadopoulos, Nicholas

AU - Kim, Kevin

AU - Homsi, Jade

AU - Bedikian, Agop

AU - Hwu, Wen Jen

AU - Patel, Sapna

AU - Ross, Merrick I.

AU - Lee, Jeffrey E.

AU - Gershenwald, Jeffrey E.

AU - Lucci, Anthony

AU - Royal, Richard

AU - Cormier, Janice N.

AU - Davies, Michael A.

AU - Mansaray, Rahmatu

AU - Fulbright, Orenthial J.

AU - Toth, Christopher

AU - Ramachandran, Renjith

AU - Wardell, Seth

AU - Gonzalez, Audrey

AU - Hwu, Patrick

PY - 2012/12/15

Y1 - 2012/12/15

N2 - Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.

AB - Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression.

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