Specific Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-Infiltrating Lymphocytes in Metastatic Melanoma Patients

• Published in: Clinical cancer research Vol. 18; no. 24; pp. 6758 - 6770
• Main Authors: RADVANYI, Laszlo G, BERNATCHEZ, Chantale, GLASS, Michelle, JOHNSON, Valen E, MCMANNIS, John D, SHPALL, Elizabeth, PRIETO, Victor, PAPADOPOULOS, Nicholas, KIM, Kevin, HOMSI, Jade, BEDIKIAN, Agop, HWU, Wen-Jen, MINYING ZHANG, 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, FOX, Patricia S, TOTH, Christopher, RAMACHANDRAN, Renjith, WARDELL, Seth, GONZALEZ, Audrey, HWU, Patrick, MILLER, Priscilla, CHACON, Jessica, WU, Richard, LIZEE, Gregory, MAHONEY, Sandy, ALVARADO, Gladys
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2012
• Subjects: Antineoplastic agents; Biological and medical sciences; Cells, Cultured; Combined Modality Therapy; Dermatology; Disease-Free Survival; Female; Humans; Immunotherapy, Adoptive; Interleukin-2 - therapeutic use; Lymphocyte Subsets - transplantation; Male; Medical sciences; Melanoma - immunology; Melanoma - mortality; Melanoma - secondary; Melanoma - therapy; Middle Aged; Pharmacology. Drug treatments; Remission Induction; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Survival Analysis; T-Lymphocytes, Cytotoxic - transplantation; Telomere - metabolism; Transplantation, Autologous; Treatment Outcome; Tumor Burden - immunology; Tumors of the skin and soft tissue. Premalignant lesions; Human; Prognosis; Tumor infiltrating lymphocyte; Autologous system; Malignant tumor; Metastasis; Cell subpopulation; Phenotype; Treatment; Phase II trial; T-Lymphocyte; Malignant melanoma; Adoptive cell immunotherapy; Predictive factor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-1177

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. 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. 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. 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.