Purpose: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability.Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients.The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy.Experimental Design: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients.Results: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable.Conclusion: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer. Clin Cancer Res; 16(9); 2646-55. ©2010 AACR.

Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) and high-dose interleukin-2 (IL-2), after nonmyeloablative chemotherapy, has been shown to result in tumor regression in half of refractory metastatic melanoma patients. In the present study, we describe 2 separate clinical protocols. Twelve patients were treated with "Selected"-TIL, as previously reported and 8 patients with the modified version of "Young"-TIL. Selected-TIL protocol required the establishment of multiple T-cell cultures from 1 patient and in vitro selection of cultures secreting interferon-gamma upon antigenic stimulation. In contrast, Young-TIL are minimally cultured T cells with superior in vitro features that do not require further selection. Two of 12 Selected-TIL patients experienced objective clinical responses (1 complete response, 1 partial response). Out of 8 treated Young-TIL patients, 1 experienced complete response, 2 partial response, and 4 patients had disease stabilization. Twenty-one of 33 enrolled Selected-TIL patients were excluded from the protocol, mainly as cultures failed the interferon-gamma selection criteria or due to clinical deterioration, compared with only 3 Young-TIL patients. Expected bone marrow suppression and high-dose IL-2 toxicity were transient. There was no treatment-related mortality. This study vindicates the feasibility and effectiveness of TIL technology and calls for further efforts to implement and enhance this modality. The use of minimally cultured, unselected Young-TIL enables the treatment of most enrolled patients. Although the cohort of Young-TIL patients treated so far is rather small and the follow-up short, the response rate is encouraging.

BackgroundThere is a paucity of literature about the benefits of bone-targeted agents for breast cancer patients with bone metastases treated in the non-trial setting. We explored the incidence, consequences, and treatment of bone metastases at a single cancer centre.MethodsElectronic records of metastatic breast cancer patients were reviewed and pertinent information was extracted.ResultsOf 264 metastatic breast cancer patients, 195 (73%) developed bone metastases. Of these patients, 176 were eligible for analysis. Median age at bone metastases diagnosis was 56.9 years (IQR 48–67) and initial presentation of bone metastases included asymptomatic radiological findings (58%), bone pain (40%), or a SRE (12.5%). Most patients (88%) received a bone-targeted agent, starting a median of 1.5 months (IQR 0.8–3.30) after bone metastasis diagnosis. 62% of patients had ≥1 SRE. The median time from bone metastasis diagnosis to first SRE was 1.8 months (IQR 0.20–8.43 months). Median number of SREs per patient was 1.5 (IQR 0–3). Overall, 26.8% of all SREs were clinically asymptomatic. Within the entire cohort, 51% required opioids and 20% were hospitalized due to either an SRE or bone pain.ConclusionsDespite extensive use of bone-targeted agents, the incidence of SREs remains high. Nearly half of SREs occur prior to starting a bone-targeted agent. Use of opioids and hospitalizations secondary to bone metastases remain common. More effective treatment options are clearly needed.