Localization of111Indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response

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Abstract
Background. The adoptive transfer of interleukin‐2 (IL‐2)‐cultured tumor infiltrating lymphocytes (TIL) can cause tumor regression in patients with metastatic melanoma. Methods. Thirty‐eight patients with metastatic melanoma receiving high dose IL‐2 and TIL were studied for the ability of autologous 111In‐labeled TIL to localize to metastatic tumor deposits by gamma camera imaging and biopsy. Single bolus cyclophosphamide was administered 24–36 hours before TIL infusion in 27 treatment courses. Results. Tumor localization by 111In‐labeled TIL was seen by gamma camera imaging in 26 (68.4%) treatment courses. In a univariate analysis of factors influencing TIL traffic, cyclophosphamide administration was significantly associated with the ability to localize tumor by radionuclide imaging (P2 = 0.026). Twenty‐one of 26 (80.8%) treatment courses given with cyclophosphamide demonstrated tumor localization, compared with only 5 of 12 (41.7%) treatment courses without cyclophosphamide. In addition, patients whose 111In‐labeled TIL imaged their tumor received significantly more TIL than did those that did not (P2 = 0.0052). Biopsies revealed a greater accumulation of 111In in cutaneous tumors than in normal skin biopsy specimens (0.0021 and 0.0004% injectate/gram of tissue, respectively; P2 = ≤0.001). The median tumor‐to‐normal‐skin ratio of simultaneous biopsies was 5.0. Finally, 10 of 26 (38.5%) patients who had tumor localization by scan had a clinical response, whereas no responses were noted in 12 patients whose tumors were not imaged (P2 = 0.022). Conclusions. Localization in tumor may be important in the mechanism of TIL antitumor activity because no clinical responses were seen in patients who did not have their tumors imaged with 111In‐TIL. Cyclophosphamide administration before TIL and IL‐2 therapy and the administration of large numbers of TIL appear to improve the frequency of TIL localization to tumor.