Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients

Abstract

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.

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…4,5 , 35 Recent studies of adoptive transfer with autologous T cells generated from patients have focused on generation of genetically modified memory CD8 C T cells with chimeric antigen receptors or T-cell receptors with a particular focus on improving the proliferation and persistence of T cells after transfer. [36][37][38][39][40] Traditionally, IL-2 has been a central component of T-cell expansion protocols. [41][42][43] However, IL-2-expanded T cells have significant limitations in adoptive therapy, including susceptibility to T-cell activation-induced cell death (AICD), Treg proliferation, and T-cell differentiation.…”

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

“…ACT using tumor infiltrating lymphocytes (TIL) has shown promise for patients with metastatic melanoma, cervical cancer and ovarian cancer. 11–15 We have previously demonstrated efficacy of TIL therapy for patients with metastatic melanoma. 16 The goal of this study was to assess the feasibility of isolation and expansion, and assessment of in vitro efficacy of the tumor infiltrating lymphocytes from bladder tumor specimens obtained from chemotherapy-naive and exposed cases for future use in adoptive cell therapy.…”

Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

“…Another approach that has been used recently is to perform adoptive T-cell therapy (ACT), in which tumor-infiltrating lymphocytes (TIL) are isolated from metastases in patients, massively expanded in vitro, and transferred back into patients. Clinical trials have revealed great efficacy of ACT with an objective response rate of about 40% to 50% and a complete response rate of about 10% to 20% (18)(19)(20)(21)(22). However, the process for generating a large number of TILs can be complex and time consuming; as a result, a high percentage of patients have to drop out during TIL preparation.…”