Adoptive Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With Refractory Metastatic Melanoma

Abstract

PurposeWe investigated the combination of lymphodepleting chemotherapy followed by the adoptive transfer of autologous tumor reactive lymphocytes for the treatment of patients with refractory metastatic melanoma. Patients and MethodsThirty-five patients with metastatic melanoma, all but one with disease refractory to treatment with high-dose interleukin (IL)-2 and many with progressive disease after chemotherapy, underwent lymphodepleting conditioning with two days of cyclophosphamide (60 mg/kg) followed by five days of fludarabine (25 mg/m 2 ). On the day following the final dose of fludarabine, all patients received cell infusion with autologous tumor-reactive, rapidly expanded tumor infiltrating lymphocyte cultures and high-dose IL-2 therapy. ResultsEighteen (51%) of 35 treated patients experienced objective clinical responses including three ongoing complete responses and 15 partial responses with a mean duration of 11.5 ± 2.2 months. Sites of regression included metastases to lung, liver, lymph nodes, brain, and cutaneous and subcutaneous tissues. Toxicities of treatment included the expected hematologic toxicities of chemotherapy including neutropenia, thrombocytopenia, and lymphopenia, the transient toxicities of high-dose IL-2 therapy, two patients who developed Pneumocystis pneumonia and one patient who developed an Epstein-Barr virus-related lymphoproliferation. ConclusionLymphodepleting chemotherapy followed by the transfer of highly avid antitumor lymphocytes can mediate significant tumor regression in heavily pretreated patients with IL-2 refractory metastatic melanoma.Address reprint requests to

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

“…42 A pre-transfer conditioning regimen results in enhanced levels of transferred cells in the circulation, and their increased persistence for many months. There are several hypotheses as to why this happens, including the increased availability of cytokines, which can act as growth factors, and the removal of regulatory cells that would otherwise inhibit engraftment of large numbers.…”

Antitumor activity of dual-specific T cells and influenza virus

“…5,6 Nonmyeloablative conditioning before adoptive transfer has been demonstrated to dramatically increase the persistence of adoptively transferred T cells, and preliminary results suggest that this is associated with an increased frequency of patient responses. 7 However, this form of conditioning induces a concerning immunodeficiency and, while producing an apparent homeostatic expansion of transferred lymphocytes, does not specifically activate them.…”

Obstacles to effective Toll-like receptor agonist therapy for hematologic malignancies

“…However, promotion of anti-tumor T-cell immunity alone may not have a meaningful impact on the outcome of hematologic cancers. Even when tumor-reactive T-cell lines are injected into lymphodepleted cancer patients so that more than 90% of the T-cell repertoire is capable of killing cancer cells, very few significant responses are seen (Dudley et al, 2005). Accordingly, it seems more likely that the therapeutic effects of BCG or Coley's toxins resulted from the direct effects of TLR agonists on tumor cells.…”

“…If the patient has a strong NK system, or high numbers of tumor-specific CTLs, then TLR agonists may be active as single agents. Otherwise, the TLR agonists would need to be given following infusions of cytokines such as IL-15 (Waldmann, 2006) to enhance NK activity or vaccines (Spaner and Masellis, 2007) (with or without infusions of T cells; Dudley et al, 2005), to enhance tumor-specific CTL activity. Alternatively, TLR agonists could be used to 'sensitize' tumor cells to conventional chemotherapeutic agents or monoclonal antibodies, such as Rituximab (Spaner and Masellis, 2007).…”