Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha

Abstract

A phase I/II study was conducted to test the feasibility and safety of the adoptive transfer of tumor-reactive T cells and daily injections of interferon-alpha (IFNα) in metastatic melanoma patients with progressive disease. Autologous melanoma cell lines were established to generate tumor-specific T cells by autologous mixed lymphocyte tumor cell cultures using peripheral blood lymphocytes. Ten patients were treated with on average 259 (range 38–474) million T cells per infusion to a maximum of six infusions, and clinical response was evaluated according to the response evaluation criteria in solid tumors (RECIST). Five patients showed clinical benefit from this treatment, including one complete regression, one partial response, and three patients with stable disease. No treatment-related serious adverse events were observed, except for the appearance of necrotic-like fingertips in one patient. An IFNα-related transient leucopenia was detected in 6 patients, including all responders. One responding patient displayed vitiligo. The infused T-cell batches consisted of tumor-reactive polyclonal CD8+ and/or CD4+ T cells. Clinical reactivity correlated with the functional properties of the infused tumor-specific T cells, including their in vitro expansion rate and the secretion of mainly Th1 cytokines as opposed to Th2 cytokines. Our study shows that relatively low doses of T cells and low-dose IFNα can lead to successful treatment of metastatic melanoma and reveals a number of parameters potentially associated with this success.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-011-1004-8) contains supplementary material, which is available to authorized users.

Achievements and challenges of adoptive T cell therapy with tumor-infiltrating or blood-derived lymphocytes for metastatic melanoma: what is needed to achieve standard of care?

“…Overall, only a very small percentage of responding TIL populations displayed specificity for any of the tested previously identified melanoma antigens. These data correspond with our own observations that T cells obtained after repeated in vitro stimulations of PBMC with autologous irradiated tumor cells prior to ACT resulting in durable partial or complete responses or disease stabilization [43] contain only very few T cells with specificity for any of the tested large panel of known melanoma antigens (unpublished data from the LUMC), whereas they consist of up-to 85 % of tumor-reactive CD8+ T cells. These data suggest that the majority of the tumor-specific T cells are targeted against mutated antigens that are highly variable between patients and therefore considered 'personal.'…”

“…Another approach to reduce toxicity is to use an IFN-based cytokine support regimen as has been demonstrated at the LUMC using autologous tumor cell-stimulated PBMC-derived T cells for ACT. Interestingly, the use of low-dose IFN-α during 1 week prior to T cell infusion resulted in a transient leukopenia and neutropenia that correlated with response to treatment [43]. These data deserve further exploration since they suggest that the ACT-supportive features of the harsh high-dose IL-2 and lymphodepleting conditioning regimen might be equally well addressed by this far less toxic approach.…”

Therapeutic cancer vaccines

“…Effective adoptive T cell transfer therapy requires drastic lymphopenia, implemented by heavy pretreatment with chemotherapeutics and/or total body x-ray irradiation or IFN-α conditioning (163,164). It is unreasonable to demand that cancer vaccines be effective without a similarly profound restructuring of the cancer microenvironment (Figure 3).…”

Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature

“…We hypothesize that the quality of the ACT T-cell product determines whether a patient responds to therapy. Indeed, T-cell batches that were infused into CB patients comprised tumor-specific T cells with predominantly a Th1 cytokine profile, whereas the T-cell batches that were infused into the patients with PD showed a non-Th1 cytokine profile (22). We speculate that even if good-quality ACT is given to patients whose tumor displays a less desirable immune signature, in particular those showing a failure to recruit large numbers of T cells, only a short period of CB can be achieved.…”

“…Within the cohort of 73 patients, 17 patients were included that were treated with ACT. Of these 17 patients, 6 patients received T cells that were generated by mixed lymphocyte tumor cultures of autologous tumor cells and peripheral blood mononuclear cells (22). The other 11 patients received T cells that were generated by rapid expansion of TILs (23).…”