Synergistic antitumor activity of tumor-infiltrating lymphocytes, interleukin 2, and local tumor irradiation. Studies on the mechanism of action.

Abstract

IL-2 given either alone or in combination with the administration oflymphokineactivated killer (LAK)' cells has been shown to mediate the regression of established metastatic tumor both in mice and man (1-3). Furthermore, adoptive transfer of tumor-infiltrating lymphocytes (TIL) concomitant with the administration of IL-2 can mediate antitumor effects that are 50-100 times more potent in murine metastatic tumor models than those observed with LAK cells (4, 5). In early human trials using TIL, regression of established metastatic disease has been observed in selected patients (6, 7).In 6-and 14-d murine metastatic models, however, successful TIL therapy is dependent on the use ofeither cyclophosphamide (CP) or whole body irradiation (WBX) (4). The reason for this requirement remains unclear, but reports have demonstrated that mice bearing immunogenic tumors develop suppressor cells capable of inhibiting the antitumor activity of adoptively transferred Lyt-2 + cytotoxic lymphocytes (8, 9).To assess the possible role of immunosuppression, suppressor cells, and direct antitumor activity of CP and WBX in the augmentation ofthe antitumor activity mediated by Lyt-2+ TIL and IL-2, we first compared WBX with local tumor radiation (LTX) in the treatment of established 7-d liver metastases . We also assessed the requirement for CP in B mice that were devoid of mature T cells and, therefore, any Ts cell activity. When taken together, our results strongly suggest that the effects of CP and WBX that combine with Lyt-2+ TIL to mediate antitumor activity against established 7-d hepatic metastases do not involve immunosuppression or the elimination of suppressor cells, but rather a direct antitumor activity. Materials and MethodsMice. Female C57BL/6 mice were used in all experiments. Mice were 8 wk of age when undergoing thymectomy. All other mice were at least 12 wk of age when used in experiments, and were obtained from the Small

Adoptive Immunotherapy of Advanced Tumors with CD62 L-Selectinlow Tumor-Sensitized T Lymphocytes Following Ex Vivo Hyperexpansion

“…Typically, adjunct IL-2 has been an integral component of T cell adoptive immunotherapy, particularly for strategies such as tumor-infiltrating lymphocytes that incorporate high concentrations of IL-2 for ex vivo propagation (39,40). However, our previous studies have demonstrated an inhibitory effect of IL-2 on the efficacy of T cell immunotherapy for tumors in certain anatomic locations, including the brain and s.c. tumors (27,41).…”

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

“…The complexity of TIL production and severe treatment-associated toxicity are obvious boundaries for a more widespread application. The preparative lymphodepleting chemotherapy contributes markedly to treatment-related toxicity but is necessary for achievement of durable clinical responses (5)(6)(7)(8)(9)(10). Previous studies showed that high persistence of the infused cells was achieved only after implementation of lymphodepletion prior to TIL transfer.…”

Intratumoral coinjection of adenoviral vectors expressing IL-2 and IL-12 results in enhanced frequency of regression of injected and untreated distal tumors

“…8,12 The antitumor activity of IL-2 and IL-12 has been shown to be mediated through their ability to induce the cytotoxic activity of lymphokine-activated killer (LAK) cells, cyto-toxic T-lymphocytes (CTLs) and tumor infiltrating lymphocytes (TILs). [15][16][17][18][19][20][21][22][23][24] We and others have demonstrated that intratumoral injection of Ad vectors expressing IL-2 was effective in inducing potent antitumor immune responses leading to regression of established tumors in murine models of carcinoma. [8][9][10] This approach, however, was also associated with severe toxicities resulting in mortality in a large percentage of animals.…”