Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma.

Abstract

Lymphoid cells infiltrating into human tumors can be expanded in vitro in medium containing interleukin-2 (IL-2). Adoptive transfer of these tumor-infiltrating lymphocytes (TIL) mediates potent antitumor effects in murine tumor models. Clinical trials to evaluate the efficacy of these cells in patients with advanced cancer are underway. We have investigated whether infused TIL labeled with indium 111 (111In) oxine can traffic and localize to metastatic deposits of tumor. Six patients with metastatic malignant melanoma who had multiple sites of subcutaneous, nodal, and/or visceral disease were the subjects of the study. The patients received cyclophosphamide 36 hours before receiving the intravenous (IV) infusion of TIL followed by IL-2 IV every eight hours. The distribution and localization of the TIL were evaluated using serial whole body gamma camera imaging, serial blood and urine samplings, and serial biopsies of tumor and normal tissue. 111In-labeled TIL localized to lung, liver, and spleen within two hours after the infusion of activity. Activity in the lung diminished within 24 hours. As early as 24 hours after injection of 111In-labeled TIL, localization of TIL to sites of metastatic deposits was demonstrated in all six patients using either imaging studies or biopsy specimens or both. 111In activity in tumor tissue biopsies ranged from three to 40 times greater than activity in normal tissue. A progressive increase in the radioactive counts at sites of tumor deposit was seen. This study shows that labeled TIL can localize preferentially to tumor, and provides information concerning the possible mechanism of the therapeutic effects of TIL.

Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model

“…administration. 14 , 15 This limitation may be a result of sub-optimal expression of appropriate chemokine receptors after in vitro expansion.…”

Optogenetic control of chemokine receptor signal and T-cell migration

“…For example, monitoring of transferred CTLs after ACT has shown that most infused CD8 + T cells localize to the lung, liver, or spleen, whereas only ∼1% of the total transferred T cells migrate to the tumor (3,20). In addition, the majority of adoptively transferred CD8 + T cells are preferentially found in the tumor periphery allowing time for escape mechanisms to be enacted in the central regions of the tumor (21,22).…”

“…The efficacy of adoptive cell transfer (ACT) in cancer immunotherapy and clinical response rates are strongly correlated to the number of adoptively transferred T cells that infiltrate the tumor microenvironment (2), but the trafficking efficiency of transferred T cells is extremely low (3,4). Although the intratumoral delivery of a chemokine-encoding system has been proposed to enhance cytotoxic T cell (CTL) homing to the tumor site (5), chemokines directly contribute to tumor growth, metastasis, and angiogenesis (6).…”

Imaging pattern of radiolabelled lymphokine-activated killer cells in patients with metastatic malignant melanoma

“…More recently, Fisher et al (1989) demonstrated the ability of TILs to traffic and localize in tumour sites. Six patients with malignant melanoma received cyclophosphamide 36 h before intravenous TIL infusion followed by IL-2 injection every 8 h. In all patients positive tumour imaging was achieved.…”

“…It is questionable whether this effect is mediated by indirect mechanisms such as the induction of other cytokines or direct cell-mediated cytotoxicity. More recently, the ability of TILs to traffic and localise at tumour sites was demonstrated after pretreatment with cyclophosphamide and IL-2 infusion (Fisher et al 1989). Previous efforts to traffic radiolabelled LAK cells in patients with cancer of various origins failed (Lotze et al 1980;Mukherji et al 1988), or they showed poor enrichment at the tumour site in comparison with specifically tumour antigen-sensitised killer cells (Mazumber et al 1984).…”