Minimally Cultured or Selected Autologous Tumor-infiltrating Lymphocytes After a Lympho-depleting Chemotherapy Regimen in Metastatic Melanoma Patients

Abstract

Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) and high-dose interleukin-2 (IL-2), after nonmyeloablative chemotherapy, has been shown to result in tumor regression in half of refractory metastatic melanoma patients. In the present study, we describe 2 separate clinical protocols. Twelve patients were treated with "Selected"-TIL, as previously reported and 8 patients with the modified version of "Young"-TIL. Selected-TIL protocol required the establishment of multiple T-cell cultures from 1 patient and in vitro selection of cultures secreting interferon-gamma upon antigenic stimulation. In contrast, Young-TIL are minimally cultured T cells with superior in vitro features that do not require further selection. Two of 12 Selected-TIL patients experienced objective clinical responses (1 complete response, 1 partial response). Out of 8 treated Young-TIL patients, 1 experienced complete response, 2 partial response, and 4 patients had disease stabilization. Twenty-one of 33 enrolled Selected-TIL patients were excluded from the protocol, mainly as cultures failed the interferon-gamma selection criteria or due to clinical deterioration, compared with only 3 Young-TIL patients. Expected bone marrow suppression and high-dose IL-2 toxicity were transient. There was no treatment-related mortality. This study vindicates the feasibility and effectiveness of TIL technology and calls for further efforts to implement and enhance this modality. The use of minimally cultured, unselected Young-TIL enables the treatment of most enrolled patients. Although the cohort of Young-TIL patients treated so far is rather small and the follow-up short, the response rate is encouraging.

Novel Immunotherapy for Malignant Melanoma with a Monoclonal Antibody That Blocks CEACAM1 Homophilic Interactions

“…Primary cultures of melanoma and TILs were established and grown as previously described (25). Cells from the synovial fluids of pediatric patients with acute exacerbation of juvenile rheumatoid arthritis were obtained following Institutional Review Board (IRB) approval no.…”

Ras Oncoproteins Transfer from Melanoma Cells to T Cells and Modulate Their Effector Functions

“…After surgical resection of metastatic melanoma lesions, minimally cultured unselected, short-term cultures of "young" TILs were established, as previously described (18). The cultured TILs were then expanded to clinical-treatment levels in a rapid expansion procedure, using anti-CD3 Abs (Orthoclone OKT-3; Cilag), a medium supplemented with 2000 IU/ml rhIL-2 (Proleukin; Chiron B.V.), and irradiated feeder cells, as previously described (18,19).…”

“…The cultured TILs were then expanded to clinical-treatment levels in a rapid expansion procedure, using anti-CD3 Abs (Orthoclone OKT-3; Cilag), a medium supplemented with 2000 IU/ml rhIL-2 (Proleukin; Chiron B.V.), and irradiated feeder cells, as previously described (18,19). Cells were maintained at 37˚C in a humidified 5% CO 2 incubator.…”

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…11 In contrast, the use of "young" unselected TIL have simplified the production of large-scale numbers of lymphocytes that demonstrate comparable antitumor activity to standard TIL. 12,13 Young TIL also display a favorable differentiation status with higher expression of costimulatory molecules and longer telomeres.…”