Preliminary Mesothelioma Vaccine Appears Safe and Promising

Roxanne Nelson

March 09, 2010

March 9, 2010 — New data suggest that immunotherapy has potential in the treatment of malignant pleural mesothelioma. Dutch researchers have found that the use of an investigational antigen-pulsed dendritic cell vaccine is safe and feasible when administered to mesothelioma patients after chemotherapy.

Although the data are preliminary, antitumor immune responses were detected in several of the patients after receiving dendritic cell–based immunotherapy.

“To our knowledge, this is the first study assessing autologous monocyte-derived dendritic cells loaded with autologous tumor cell lysate in patients with mesothelioma,” the study authors write, adding that further studies will be needed to see if the vaccine improves survival.

The results of the study appear online in the March 4 issue of the American Journal of Respiratory and Critical Care Medicine.

Malignant pleural mesothelioma is an invariably lethal disease, with death generally occurring within 12 months after the onset of signs and symptoms, note the study authors. The incidence of the disease is closely linked with exposure to airborne asbestos fibers, and even though asbestos use has been banned or strictly curtailed in most developed nations, the incidence of mesothelioma is increasing because of the lengthy incubation period from initial exposure to asbestos to the onset of disease.

In the Netherlands and most other European countries, write the study authors, mesothelioma-related mortality is expected to continue increasing until 2020. In addition, asbestos is still used in many parts of the world, and thus, the global incidence of mesothelioma will further increase. According to the study authors, this anticipated increase in mesothelioma, plus the paucity of currently available treatment options, has spurred considerable interest in developing improved therapies.

Immunotherapy Feasible?

Immunotherapy is one of the new treatment options being evaluated for mesothelioma, and the “possibility to harness the potency and specificity of the immune system underlies the growing interest in cancer immunotherapy,” notes study author Joachim G. Aerts, MD, PhD, a pulmonary physician at Erasmus Medical Center, Rotterdam, the Netherlands.

“Mesothelioma is a very special malignant tumor, especially because of the fact that it metastasizes very late in the disease and, until that point, remains a very local disease,” Dr. Aerts told Medscape Oncology. “We believe that this has to do with the fact that this tumor is immunogenic, and therefore circulating cells are removed until the general condition of the patient has deteriorated — and the immune system is no longer working properly.”

In preclinical studies, Dr. Aerts and his team observed that dendritic cell–based based immunotherapy induced strong tumor-specific cytotoxic T-lymphocyte responses, which led to prolonged survival in mice. On the basis of those results, they moved ahead to evaluate the safety and immunological response of a tumor lysate–pulsed dendritic cell–based vaccine in human mesothelioma patients.

Response Observed

Their study involved 10 male patients, ranging in age from 56 to 78 years (median age, 65 years), who were newly diagnosed as having malignant pleural mesothelioma. Of this group, 9 patients received 4 cycles of chemotherapy consisting of pemetrexed (Alimta), 500 mg/m2, and cisplatin, 75 mg/m2, every 4 weeks. One patient received carboplatin, 80 mg/m2, instead of cisplatin because of a hearing implant.

After chemotherapy, 4 patients had stable disease and 6 patients showed a partial response. All patients then received 3 vaccinations of clinical-grade autologous dendritic cells intradermally and intravenously at 2-week intervals. Each vaccine contained 50 x 106 mature dendritic cells that were pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH) as a surrogate marker.

The study authors assessed delayed-type hypersensitivity activity to tumor antigens. In addition, KLH was assessed, both in vivo and in vitro, and peripheral blood mononuclear cells were analyzed for immunological responses.

Three patients showed partial responses after receiving immunotherapy, whereas 1 had stable disease and 6 patients had no response. Serum samples from all patients showed a significant increase of prevaccine vs postvaccine antibodies to KLH.

In 6 patients whose tumor material was sufficient for cytotoxicity testing, almost no lysis of autologous tumor cells was observed before vaccination. But after the immunotherapy, “clear inductions of cytotoxicity against autologous tumor cells were measurable” in 4 patients, the study authors note. In 1 patient, cytotoxicity increased after each vaccination, whereas in the other 3 cases, all 3 vaccinations were necessary to induce cytotoxicity.

The median survival was 19 months (range, 11-34 months), and 1 patient currently remains alive.

Minimal Adverse Events

The vaccine was well tolerated overall. There were no grade 3 or 4 toxic effects or any clinical signs and/or laboratory data of any autoimmune diseases. None of the patients required dose adjustments or dose discontinuations.

A local rash occurred at the intradermal injection site after the first vaccination in nearly all of the participants, and 8 patients developed mild to severe flulike symptoms. The flulike symptoms subsided in 7 of these patients after 1 day.

Interpret Results With Caution

Although the results are encouraging, the researchers note that these results should be interpreted with caution. The tumor regressions observed on computed tomographic scans cannot solely be attributed to the vaccine therapy because they could be caused by a delayed reaction of the chemotherapy. A proper control group is necessary to draw conclusions about tumor regressions, and it is also difficult to evaluate overall survival in the absence of a randomized trial, they write.

Dr. Aerts explained that they are now working on optimizing the vaccine. “Further optimization will influence the immunosuppressive properties of the tumor,” he said. “This method has been tested in our murine model, and we will now start testing in humans.”

The study was supported by Stichting Asbestkanker Rotterdam. The study authors have disclosed no relevant financial relationships.

Am J Respir Crit Care Med. Published online March 4, 2010.