Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens

By M. Dudley, Jie Yang, R. Sherry, M. Hughes, R. Royal, U. Kammula, P. Robbins, Jianping Huang, D. Citrin, S. Leitman and 10 more. Journal of Clinical Oncology, 2008

1,357 citations recorded by the source corpus.

Purpose The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens. Patients and Methods We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied. Results Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells. Conclusion Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.

View Paper: https://www.semanticscholar.org/paper/22b0d7134e1f675222552551ac23876f132fb355

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

Citations in the corpus

Phase 2 Trial of Single Agent Ipilimumab (Anti-CTLA-4) for Locally Advanced or Metastatic Pancreatic Adenocarcinoma (2010, background): “Adoptive T-cell therapy mediates objective tumor regressions in 49% to 72% of patients with melanoma.(21) These examples validate the further development of more effective immunotherapy for melanoma and kidney cancer, and justify extending the application of this modality to other forms of cancer.”
A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: Long term follow up and correlates with response (2014, background): “The durable complete cancer regressions observed using cell transfer immunotherapy for melanoma in multiple clinical trials (1, 13, 16) have stimulated efforts to genetically modify lymphocytes to improve their antitumor efficacy and to extend the range of tumors types that can be treated.”
Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T Cell Transfer Immunotherapy (2011, methodology): “The toxicities of treatment have been previously reported and were largely due to the lymphodepleting preparative regimen or IL-2 (17, 25).”
Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts (2010, background): “…numbers of tumor-reactive CD8+ CTLs expanded and differentiated in vitro has shown significant clinical promise after lymphoablative conditioning, where responses occur in up to 70% of patients from whom tumor-reactive lymphocytes can be isolated (Dudley et al., 2008; Muranski and Restifo, 2009).”
Adoptive cell transfer: a clinical path to effective cancer immunotherapy (2008, background): “007), but this should be interpreted with caution as this was not a randomized compariso”
IL-2: The First Effective Immunotherapy for Human Cancer (2014, background): “cells was seen in most responding patients (65, 66).”
Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. (2011, background): “Clinical trials in patients with metastatic melanoma have demonstrated the ability of adoptively transferred T cells to mediate durable complete cancer regression.(1,15,16) These results have stimulated efforts to genetically modify lymphocytes to improve their antitumor efficacy and to extend the r”