Long-term Complete Remission Following Radiosurgery and Immunotherapy in a Melanoma Patient with Brain Metastasis: Immunologic Correlates

Discussion

The combination of radiotherapy with active immunotherapy may restore immunosurveillance in patients with advanced cancers, resulting in long-term tumor control. The effective stimulation of the immune system in the patient presented here is mainly characterized by the induction of high levels of MAGE-A1_p161–169–specific antitumor CD8⁺ T cells. This finding matches with early T-cell data of our historical melanoma patient MZ2, in whom MAGE-A1_p161–169–specific T cells were first identified (13). In both cases, complete tumor eradication and long-term survival correlated with the presence of MAGE-A1–specific T cells, thus highlighting their potential to effectively control tumor growth. Analyzing early immune responses in the patient described herein, we found that T cells responding to tumor-associated antigens MAGE-A1, MAGE-A3, NY-ESO-1, and Melan-A were present in the peripheral blood already in June 2002. However, the T-cell response at the time was ineffective and failed to prevent tumor progression. Upon local radiotherapy and immunotherapy with TL-DC, the patient's immune response shifted toward tumor recognition indicated by the development of NY-ESO-1 antibodies. It turned out that NY-ESO-1 antibody response was directed against two distinct epitopes, each of which was targeted at different time points and different tumor sites. Moreover, the antibody switch observed indicated an important evolution of the patient's antitumor immune response as NY-ESO-1_p161–180–specific antibody appeared independent of radiation, and spontaneously. Of note, subsequent to radiotherapy and vaccination with TL-DC, the patient showed a prolonged time to disease progression of 16 months, which was potentially mediated by the initiation of effective immune responses.

A major goal of active cancer immunotherapy is to induce T-cell–mediated antitumor immune responses with the potential to control tumor growth and to protect against tumor recurrence. To achieve this goal, DC-based vaccines represent a promising treatment approach as DC play a key role in the initiation and regulation of cellular immune responses (14). In our case, immunotherapy with TL-DC was initiated 1 week after gamma-knife surgery of brain metastases. Analysis of the first postvaccination blood sample revealed a strong ex vivo detectable MAGE-A1–specific antitumor CD8⁺ T-cell response that was maintained at a relatively constant high level over time and is still present in the patient, who is alive without any evidence of disease. Therefore, it is likely that the durable expansion of MAGE-A1_p161–169–specific T cells has been maintained and is still being boosted by continued vaccination with TL-DC. However, evidence that the vaccine still enables the patient's immune system to protect against melanoma recurrence would only be provided by cessation of vaccination. Therefore, it remains uncertain whether the induced T-cell immune response still controls the outgrowth of residual tumor cells, thus keeping the patient's disease in a dormant state (15), or whether the strong anti-MAGE-A1 T-cell immune response has led to the complete elimination of residual tumor cells. The clinical efficacy of our treatment approach may be due to several factors. The use of autologous whole tumor cell lysate as the source of antigens to load DC generates a broad immune response covering all relevant antigens of the individual's disease (16). In this regard, the antigenic material obtained from the abdominal metastases in December 2003 was highly effective in stimulating T-cell responses in vivo (Fig. 3D). For the timing of vaccination, it is assumed that patients with large tumor burdens are less likely to clinically respond to therapeutic cancer vaccines because of immunosuppressive mechanisms released by the tumor microenvironment. Furthermore, a minimum time is required to generate a sufficient immune response. Vaccination with TL-DC in our patient was initiated after gamma-knife surgery in a status of minimal residual disease and was even continued beyond tumor recurrence and the subsequent surgery in December 2003. Finally, our data suggest that immunotherapy may synergize well with radiotherapy, especially hypofractionated radiosurgery. Our patient developed tumor antigen–specific antibody and T-cell responses that were not detectable before treatment, suggesting that radiation has led to the release of tumor-associated antigens and DC activation, which in turn may have supported the initiation of a tumor-specific CD8⁺ T-cell response (17, 7). In mice, it has been shown recently that eradication of murine colon adenocarcinoma under immunotherapy was successful only when preceded by radiotherapy (18).

The cancer immunoediting model by Dunn and colleagues describes the interaction between cancer development and a patient's immune response resulting in tumor elimination, equilibrium, or escape (19). It has been established that the immunoediting process can be affected significantly by therapeutic manipulations (20). In our patient, it seems probable that after the failure of immunosurveillance, the rapidly growing tumor was locally controlled by surgery and radiotherapy. However, long-term disease-free survival may have resulted from the induction of an antitumor T-cell response triggered by auto-vaccination effects of radiotherapy durably sustained by immunotherapy with TL-DC.

On the basis of the convincing evidence of effective tumor control following surgery, hypofractionated radiotherapy, and immunotherapy with TL-DC, we suggest considering conventional cancer treatments to be combined with active immunotherapy as a means to improve patient survival.