Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients

Abstract

Adoptive therapy for cancer using tumor-infiltrating lymphocytes (TIL) has mainly been investigated in cancer patients with advanced stage disease. The limited clinical success has not been encouraging, although this might be explained by poor TIL specificity and/or high tumor burden. To re-evaluate the effectiveness of adoptive therapy, we analyzed the capacity of tumor-reactive TIL injection in preventing the further development of disease in stage III melanoma patients after complete tumor resection. A phase II/III randomized trial was performed on 88 melanoma patients, who received autologous TIL plus interleukin-2 (IL-2) or IL-2 only. The duration of relapse-free survival was analyzed, taking into account the immunological specificity of injected TIL and the number of metastatic lymph nodes removed before treatment. Kaplan-Meyer analysis revealed that the injection of tumor-reactive TIL was statistically correlated with prolonged relapse-free survival in patients with only one metastatic lymph node. Therefore, improved clinical outcome could be obtained after adoptive therapy by selecting appropriate groups of patients and monitoring the specificity of the injected TIL populations.

Loss of oncostatin M receptor β in metastatic melanoma cells

“…OSM resistance does not strictly correlate with resistance to other cytokines In a first attempt to describe the responsiveness of melanomas to growth-inhibitory cytokines, we analysed the proliferation of metastatic melanoma cell lines obtained from the lymph nodes of 22 patients (stage III) who were enrolled in a previously described phase II/III randomized clinical trial Labarriere et al, 2002). The WM-266-4 metastatic cell line was used as a positive control.…”

“…Metastatic melanoma cell lines were established from tumorinvaded lymph node fragments as described previously (Gervois et al, 1990;Dreno et al, 2002;Labarriere et al, 2002). Melanoma cell lines were established before injection of autologous TILs plus IL-2 or IL-2 only.…”

Tissue Prognostic Factors in Melanoma: Expression of B7 Family Members B7-H3 and B7-H4 and Death Receptors TRAIL-R1 and TRAILR2

“…Metastatic melanoma tumour-invaded LNs from which TIL were obtained, were used [5,24,25]. After lymphadenectomy, the majority of the invaded LN samples was used to produce TIL but a biopsy fragment was collected for immunochemistry, and for the establishment of the autologous tumor cell line.…”

Stratégies vaccinales contre le mélanome

“…Greenberg et ses collaborateurs ont apporté la preuve de principe de la migration préférentielle intratumorale des TIL ré-injectés, et de l'intérêt de modifier génétiquement les lymphocytes T pour allonger leur survie, souvent courte in vivo [7]. Le groupe français de Jotereau et Dreno a également mené un essai clinique de phase II/III sur 88 patients atteints d'un mélanome de stade III en adjuvant, testant l'efficacité d'une thérapie par TIL expandus ex vivo + IL-2, contre un traitement par l'IL-2 seule : cette étude a montré le bénéfice thérapeutique, en survie sans récidive, de la ré-injection de TIL reconnaissant la tumeur autologue chez le sous-groupe de patients n'ayant qu'un seul ganglion envahi [8]. Enfin, l'intérêt de cette thérapeutique a été renouvelé par l'équipe de Rosenberg [9] : des patients ayant résisté à l'IL-2 ont été traités par transfert passif de lymphocytes sélectionnés pour leur capacité à reconnaître les cellules tumorales autologues après un prétraitement lympho-ablatif (cyclophosphamide + fludarabine).…”