Although many systemic treatments for patients with metastatic solid cancers can mediate modest improvements in survival, the long-term cure of patients requires the induction of durable complete regressions. With few exceptions (such as men with germ cell tumors or women with choriocarcinoma) durable complete regressions of metastatic solid cancers are very rare. In patients with metastatic melanoma the administration of high dose IL-2 can mediate durable complete apparently curative responses in 4 to 5% of patients and this led to the FDA approval of IL-2 for patients with melanoma in 19983, 26, 27
. Durable complete regressions using dacarbazine, the only other FDA approved treatment for melanoma, is seen in less than 1% of patients1, 2
. Recent reports of the use of ipilimumab, a molecule reactive with CTLA4 on the cell surface in 540 patients4
and PLX4032, a mutated BRAF inhibitor in 48 patients5
have demonstrated complete responses in 0.6% and 6% of patients with metastatic melanoma respectively, though both treatments appear capable of prolonging the survival of patients.
In the current report, durable complete responses were seen in 22% of patients who received this cell transfer therapy and 95% of these complete responses are ongoing beyond three years. It thus appears to be an effective and possibly curative treatment for many patients with metastatic melanoma capable of receiving it.
Patients with melanoma have been the subject of many attempts at immunotherapy6
. Early reports of a low level of objective responses of melanoma to immunologic modulation with IL-228
and the demonstration that lymphocytes infiltrating into melanomas (TIL) specifically recognized tumor-associated antigens29
suggested that this disease stimulated an endogenous immune response that could be further manipulated to improve anti-tumor effects. Although the immunization of patients with cancer antigens (cancer vaccines) has thus far yielded only modest results30
, early studies of the isolation, growth in IL-2 and infusion of autologous TIL demonstrated that this adoptive immunotherapy approach could mediate transient tumor regression in patients though the lack of persistence of the transferred cells may have hampered their effectiveness31, 32
. An improvement of this treatment reported in 2002 demonstrated that chemotherapy-induced lymphodepletion prior to adoptive cell infusion could lead to the dramatic enhancement of the persistence of the transferred cells and improved anti-cancer effects16
. Studies in tumor-bearing mice demonstrated that the anti-tumor effects of adoptive cell transfer were a direct function of the magnitude of lymphodepletion33
and these findings led to studies of the addition of total body irradiation to the nonmyleoablative chemotherapy preparative regimen that had been used in earlier trials. Earlier reports of these pilot trials showed that 10 of 93 patients achieved a complete regression though follow-up in the trials using maximum lymphodepletion at the time of that report was only 10 months17
. We now report the definitive long-term follow-up of these trials utilizing adoptive transfer of autologous TIL following preparative lymphodepleting treatment with an overall median potential follow-up of 62 months and a median potential follow-up of 42 months in the latest cohort adding 12 Gy irradiation. Ten of the partial responders have now converted to complete durable regressions without any further treatment. This is likely due to the resolution of scarring after tumor destruction or to the ongoing anti-tumor impact of persisting T lymphocytes for months after cell transfer. Of the 93 patients, 20 (22%) have achieved a complete regression of metastatic disease and 19 of these 20 patients have ongoing complete responses beyond three years. Regressions have been seen at all visceral sites. The average patient had a median of three different metastatic anatomic sites.
Of particular importance is the induction of durable complete responses in patients who have received and progressed through multiple prior treatment regimens. Seventy percent of the complete responders had progressed through IL-2, 35% through chemotherapy and 30% had both IL-2 and chemotherapy. Of the 11 patients that had previously progressed after receiving anti-CTLA4 monoclonal antibody, five experienced a complete regression in addition to two partial regressions. There was no influence of any prior therapy on the likelihood of achieving a complete regression or on overall survival in these 93 patients suggesting that this treatment approach can be useful as an upfront treatment or as a salvage regimen for patients with progression after other therapies.
Although complete regressions were seen in patients receiving each of the preparative regimens there is a strong suggestion that increasing the lymphodepletion by adding TBI enhanced the anti-tumor effects. Studies in murine models suggested that lymphodepletion prior to adoptive cell transfer reduced the competition for homeostatic cytokines such as IL-7 and IL-1534
that promote lymphocyte growth and indeed we measured an increase in serum IL-15 in all patients on the day after the lymphodepleting regimen was completed17
. Other impacts of the lymphodepletion are likely due to transient elimination of regulatory T cells and enhancement of the activity of antigen presenting cells35, 36
. In preliminary studies we have seen an inverse correlation between the likelihood of response and the return of CD4+
cells in the circulation after treatment and this is now being further studied. In concert with results from murine models indicating that infused cells that were less differentiated and with a higher proliferative potential had increased anti-tumor activity37
we noted a highly significant association between the likelihood of having a complete response and the infusion of TIL with longer telomeres, TIL with more CD8+
cells and increased persistence in the circulation of the infused cells at one month after transfer. There is an inverse correlation of telomere length with time in culture38
though there was no maximum time in culture that precluded administration of cells. These findings point the way towards increasing the therapeutic effectiveness of TIL by choosing cultures with higher average telomere lengths or cultures containing cells with a higher absolute number of CD27+
cells, a marker of less differentiated cells37
. Generation of less-differentiated cells might also be accomplished by minimizing time in culture and use of alternative cytokines.
It should be emphasized that not all patients with metastatic melanoma can receive this treatment approach. A metastatic nodule of at least 2 cm diameter must be present and suitable for resection. Most resections have been from soft tissue lesions but peripheral lung and liver lesions have also been used24
. Metastatic lesions resected for symptomatic relief in the course of disease progression or lymph nodes resected for Stage III disease can be cryopreserved and are a suitable source for later growth of TIL. Since about 85% of patients have lesions capable of being resected and about 55% grow cells suitable for infusion we estimate that about 45% of all patients with metastatic melanoma can receive this treatment. About 5% of patients develop complications of tumor growth during the 4 to 6 weeks of cell preparation that preclude treatment. An important advantage of this cell transfer approach is its ability to mediate complete regressions regardless of the failure of prior treatments.
Current efforts are devoted to developing simpler and faster methods to grow TIL with increased anti-tumor efficacy and to develop alternative preparative regimens. TIL grown by a simplified method that eliminates in vitro testing for anti-tumor activity38
have mediated tumor regressions in patients with melanoma, though followup in these patients is short39, 40
. The ability to transduce genes encoding anti-tumor T cell receptors into normal circulating lymphocytes and the use of these genetically engineered autologous cells for adoptive transfer is being explored in ongoing clinical trials41, 42