Efficacy of Adoptive Cell Transfer of Tumor-infiltrating Lymphocytes After Lymphopenia Induction for Metastatic Melanoma

Abstract

A single-institution pilot clinical trial was performed combining non-myeloablative chemotherapy and the adoptive transfer of tumor-infiltrating lymphocytes with IL-2 in patients with metastatic melanoma. Nineteen patients were enrolled with 13 patients (68%) successfully completing treatment. An overall response rate (partial and complete responses) of 26% by intention to treat was achieved with a median follow-up time of 10 months. Of the 13 treated patients, there were 2 complete responses and 3 partial responses (38% response rate among treated patients), along with 4 patients with stable disease ranging from 2+ to 24+ months. Three of the four patients with stable disease have had disease control without additional therapy, including one at 24+ months. Adoptive therapy with TIL is labor-intensive but feasible and has a high response rate in treated patients.

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

“…The efficacy of this personalized immunotherapy based on preconditioning chemotherapy followed by infusion of TILs and IL2 has been confirmed by several independent centers. Objective response rates of 40%-50% including complete tumor regression in 10%-20% of treated patients have consistently been reported (1)(2)(3)(4). The major advantage of TIL-ACT over current standard treatments is the relative high frequency and long-term durability of complete responses, highlighting the curative potential of this treatment.…”

“…Accordingly, the HD bolus IL2 regimen was used in the early ACT trials (9,16) where cells were infused without prior lymphodepletion. Since the implementation of lymphodepleting chemotherapy, most ACT-TIL trials have also used the HD bolus IL2 regimen and the efficacy of this three-step treatment has been proven in several phase II trials (1)(2)(3)(4). However, different doses and schedules of IL2 administered in this context have only been sparsely explored.…”

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

“…At progression, TIL numbers would be expanded in a REP and infused into the patient after treatment with a pre-conditioning regime such as cyclophosphamide and fludarabine as previously described for the treatment of metastatic melanoma patients. 16 Alternatively, to potentially avoid radical cystectomy, growth of TIL from transurethral surgical resection or resection of a lymph node metastatic lesion may allow for the expansion of TIL and subsequent neoadjuvant (or primary) administration followed by local delivery of TIL to primary bladder tumors.…”

“…11–15 We have previously demonstrated efficacy of TIL therapy for patients with metastatic melanoma. 16 The goal of this study was to assess the feasibility of isolation and expansion, and assessment of in vitro efficacy of the tumor infiltrating lymphocytes from bladder tumor specimens obtained from chemotherapy-naive and exposed cases for future use in adoptive cell therapy.…”

Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression

“…Recent advances in CTL engineering have allowed the enforced expression of high-affinity and tumor-specific T cell receptors (TCRs) or chimeric antigen receptors, thereby mitigating part of the difficulties in CTL isolation and expansion, and the efficacy of tumor antigen targeting (2)(3)(4). Paradoxically, although these strategies are capable of generating highly cytotoxic tumor-specific CTLs in vitro, the clinical success of ACT using ex vivo IL-2-conditioned and TCR-redirected CTLs has been partial at best -the majority of patients fail to respond with complete tumor regressions (5)(6)(7).…”