Extended Tumor Control after Dendritic Cell Vaccination with Low- Dose Cyclophosphamide as Adjuvant Treatment in Patients with Malignant Pleural Mesothelioma

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Summary

Malignant pleural mesothelioma (MPM) normally has limited treatment options, it is almost inevitably accompanied with recurrences. Ten patients with MPM received metronomic cyclophosphamide and dendritic cell–based immunotherapy. The result of the treatment showed that it is well-tolerated and overall survival was promising for the MPM patients.

Patients Characteristics

10 patients with a suspicion of malignant pleural mesothelioma (MPM) and treatment-naive patients who had already been diagnosed with MPM. Patients underwent standard treatment consisting of four to six courses of chemotherapy with either pemetrexed- cisplatin or pemetrexed-carboplatin. Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and acceptable vital organ functions. Patients had to be negative for autoimmune disease and were tested for antinuclear antibodies, extractable nuclear antigens, and rheumatoid factors.

Methodology

Patients received at least three immunizations with mature DC loaded with autologous tumor lysate and keyhole limpet hemocyanin (KLH) with a 2-week interval.

Treatment

Six and 12 months after the third DC vaccination, a revaccination was given to boost the immune system if enough DCs were available (fourth/fifth vaccination). Each immunization, consisting of 50 3×106 DCs, was administered intradermally and intravenously. Dosage was divided into one-third administered intradermally (ID) in the forearm and two-thirds administered intravenously (IV).

Results

Clinical response

Of the five nonsurgical patients, four had stable disease (SD) and one had complete response (CR) after DC therapy. In three of the surgically treated patients, the disease could not be evaluated, because surgery led to a macroscopic CR. Two surgical patients presented with new lesions after DC therapy and therefore had progressive disease (PD). Therefore, in total, disease control (no remaining evaluable disease, CR, partial response [PR], and SD) was achieved in 8 out of 10 patients. Seven of the 10 patients had a survival of greater than or equal to 24 months. Nearly 4 years, two patients were still alive, one of whom was in complete remission 66 months after diagnosis, and in the other the disease was very slowly progressive 50 months after diagnosis.

Safety and Toxicity

The safety and toxicity of the combination of a low-dose CTX (orally) and tumor lysate–pulsed DCs injected intradermally and intravenously in patients with MPM were assessed. No related greater than grade 3 toxicities were found in any of the patients. Injection of DCs was well tolerated without systemic toxicity, except for transient fatigue and low-grade fever on the day of the DC injection. These symptoms normalized after 1 day. After DC injection, a local skin reaction in the form of erythema without induration was seen in more than half of the subjects. Subsequent vaccinations (second and third) gave a quicker and increased induration and erythema in all patients, suggesting that some form of immunity was induced. None of the study participants developed any clinical evidence of autoimmunity. One patient developed a cardiomyopathy 18 months after DC vaccination. This was deemed to be related to the previous cisplatin treatment.

Immune Responses

In all patients, a comparison of pre–first- vaccine and post–third-vaccine serum samples showed a significant increase of antibodies reactive to the model antigen KLH, both of the IgG and IgM isotype. Responses to KLH increased after the initial three vaccinations were completed. Three months after the third vaccination, KLH responses were evidently present in the six patients in whom it could be determined. This proves that a successful immune reaction was induced by the DC vaccinations.

Conclusion

Consolidation therapy with autologous tumor lysate– pulsed dendritic cell–based therapy and simultaneously reducing the tumor-induced immune suppression is well-tolerated and shows signs of clinical activity in patients with mesothelioma. DC vaccination therapy in combination with low-dose metronomic Cyclophosphamide is safe and feasible in patients with mesothelioma and no significant adverse effects were observed.

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Scientific article publishing date : 1/5/2016

Immucura identifier : BSC21_046EN

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