Randomized Selection Design Trial Evaluating CD8⁺-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

Abstract

A B S T R A C T PurposeAdoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and MethodsPatients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8 ϩ -enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4ϩ lymphocytes, and 35 patients received CD8ϩ -enriched TILs with a median of 0.3% CD4 ϩ lymphocytes. One month after TIL infusion, patients who received CD8 ϩ -enriched TILs had significantly fewer CD4 ϩ peripheral blood lymphocytes (P ϭ .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8 ϩ -enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P ϭ .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8ϩ -enriched TILs responded. ConclusionA randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8 ϩ -enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation

“…2,3,6,10 This immune reaction is believed to be beneficial, leading to the overall improved survival in these patients, 2,3,6,10 such as seen in some other lymphoid-rich neoplasms of both thymic 2 and nonthymic origin. [11][12][13][14][15] It is not clear what mechanism initially triggers such immune reaction, or why this type of reaction only occurs in a subset of thymic epithelial neoplasms. In addition, it is not certain whether the mechanism is a localized or more of a systemic process.…”

Towards gene therapy for EBV-associated posttransplant lymphoma with genetically modified EBV-specific cytotoxic T cells

“…[21][22][23][24][25] Adoptive transfer of ex vivo-derived EBV-specific CTLs to reconstitute EBV-specific T-cell immunity 3,26 is a logical approach for patients in whom PTLD develops. This disease represents an ideal target for adoptive T-cell therapy because of the high level expression of immunogenic antigens from EBV presented by excellent antigen-presenting cells.…”

PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

“…In the particular case of TIL therapy, persistence of transferred tumor-specific T cell clones is associated with tumor regression (8). Moreover, retrospective clinical studies have shown an association of autologous tumor recognition by TILs and clinical response (9,10), which suggests that enrichment of tumor-reactive cells could enhance clinical efficacy. However, the identification of the diverse repertoire of tumor-reactive cells limits the ability to study these cells, enhance clinical efficacy, and extend this therapy to other malignancies.…”