The concept of adoptive cell transfer (ACT) hasopened an exciting and promising avenue ofresearch in the field of melanoma therapy. Theprocess of ACT differs technically from that ofvaccination, although the therapeutic objective ofinducing anti-tumor immune response is similar.Still in early-stage trials, ACT has provided initialpromising results, and efforts are ongoing to finetunethe process, enhance efficacy, and identify idealcandidates for treatment.
ACT: A Snapshot Overview
ACT has been tested in several solid tumors, includingmelanoma and colorectal cancer. In simpleterms, the process consists primarily of three steps:First, antigen-specific cells are isolated from thehost; the cells are then cultured and activated exvivo, and finally these antigen-specific cells areadministered back to the original host. Prior to introductionof the activated antigen-specific cells, therecipient must undergo chemo-depletion of lymphocytes.Typically, an immunomodulatory anticancertherapy, such as IL-2, is administered along with theantigen-specific cells. As Dudley and Rosenbergexplain, “When anti-tumor lymphocyte cultures areadministered to autologous patients with high doseinterleukin-2 following a lymphodepleting conditioningregimen, the cells can expand in vivo, traffic totumor, and mediate tumor regression and durableobjective clinical responses.”1 Targeted immunotherapyhas shown greater safety and better results thanchemotherapy or radiotherapy.2
A benefit of ACT over vaccine is the fact that thelymphoablated host lacks suppressive and competing cells.3 A recent analysis of data from multiple ACTtreatedpatients concluded that patient conditioningis “crucial to clinical success,” noting that use oftumor-infiltrating lymphocytes (TILs) in conjunctionwith non-myeloablative condition offered betterresults than treatment with TILs alone.4
Three consecutive clinical trials of ACT formelanoma have reported objective response ratesbetween 49 percent and 72 percent. When patientsrespond, that response tends to be durable: amongresponding patients in these three trials, many hadongoing response beyond three years; of 12 patientsin the three trials who achieved a complete response,11 are ongoing between 18 and 75 months.5
In one melanoma patient who experienced a completeregression of all metastatic lesions in lungs andsoft tissues following ACT therapy, analysis detectedhigher levels of persistent tumor-reactive T-cellclones in tumor cell samples one month followingtransfer than in the peripheral blood obtained at thesame time.6
Despite these promising findings, theinvestigational ACT process remains an imperfecttreatment, though it is not clear why some patientsfail to respond. Non-response or minimal responsehas been blamed on immuno-selection of antigennegativetumor cells and silencing of melanomaassociatedantigens (MAAs).2
One team of researchers had compared the efficacy ofTIL plus IL-2 to IL-2 alone following complete tumorresection in 88 patients with stage III melanoma. Theyfound that TIL prevented further development ofmelanoma and increased overall survival. However, this investigation found no correlation between overallor disease-free survival and the amount of infusedtumor-specific TIL. This lack of correlation promptedthe researchers to investigate the ability of the protocolTIL to recognize 38 tumor-associated antigens(TAA). Results indicated that the infusion of Melan-A/MART-1 reactive TIL appeared to be associated witha longer relapse-free survival for HLA-A2 patients.7HLA-A2 had been shown to be important for tumorcell recognition by autologous T-lymphocytes.8
In light of their findings suggesting that Melan-A/MART-1 antigen may be a prime target forimmunotherapy protocols in melanoma, the teamundertook a new study. This most recent investigationof ACT involved 14 patients with metastaticmelanoma who were treated with clones of autologousMelan-A-specific T-cells. While clones werebeing developed and activated, each patient underwent underwenttherapy with dacarbazine. Following deliveryof the T-cell clones, each patient received subcutaneousinjection of interleukin 2 and interferon-α. Sixpatients (43 percent) experienced either complete orpartial remission, and two patients achieved longtermcomplete remission (five years for one and 28months for the other). Of note, in vivo expression ofMelan-A-specific T-cells was found to be significantlyassociated with clinical responses. The authors proposethat patients can be monitored for melanomaspecificT-cell expansion in order to predict clinicalefficacy.9
Immunotherapy remains one of the most promisingareas of investigation for the treatment of melanoma.With better safety than chemotherapy and impressiveresults to date, it may prove to be an important managementtool within a few years. Vaccines are currentlyin clinical trials, and research on ACT is ongoing.As research continues to elucidate ideal TIL targetsand their effects, efforts to fine tune ACT will hopefullyyield success and improve outcomes.
Dr. Wolfe has no relevant disclosures.