Bec2/BCG Vaccination in SCLC Patients
The median survival for patients with limited or extensive disease is approximately 18 and 10 months, respectively.
BCG versus observation in patients who responded after combined-modality therapy for limited-disease SCLC.
For patients with limited disease, a combination of chemotherapy and chest radiotherapy has become stan- dard. One of the major problems with SCLC is that this disease, although sensitive to chemotherapy and radiother- apy, almost invariably recurs within 2 years and kills most patients. A well-recognized difficulty in the treatment of SCLC is the maintenance of response. Most studies using maintenance chemotherapy in an attempt to sustain re- sponse in responding patients failed to show an improved survival, and they often added substantial toxicity. Pre- vious studies of biologic agents in this setting, including interferons and matrix metalloproteinase inhibitors, have been negative.2
Bec2 is an anti-idiotypic antibody that mimics GD3, a ganglioside antigen. Gangliosides are complex glycolipid constituents of the cellular plasma membrane located in the outer leaflet of the cell surface. They are involved in numer- ous biologic functions including cell-cell recognition, cell matrix attachment, and differentiation.
Compared to normal lung, the concentrations of neu- tral glycosphingolipids were approximately twice as high in SCLC tissues.3 GD3 was shown to be overexpressed in ap- proximately 60% of the SCLC tissues examined,4 similar to fucosyl-GM1. GD3 expression also is upregulated during neoplastic transformation of normal melanocytes to mela- noma cells. Tumors of neuroectodermal differentiation, such as melanoma, SCLC, neuroblastoma, and soft tissue sarcoma, express high levels of GD3.5 SCLC cell lines of the classic type (expressing neuroendocrine properties) express GD3,6 whereas NSCLC cell lines do not. GD3 is also present in normal tissues such as brain, peripheral nerve, skin, thyroid, kidney, and pancreatic islets.5
Although GD3 is poorly immunogenic either alone or mixed with adjuvants,7 the Bec2 anti-idiotypic monoclonal antibody was more effective in inducing anti-GD3 antibody responses in patients. Bec2, when given in combination with bacille Calmette-Guerin (BCG), produced detectable anti-GD3 antibodies in approximately 20% to 33% of patients.8-10 Studies have been performed without and with several different adjuvants, and BCG was shown to be one of the best in combination with Bec2 in a number of studies. Bec2/BCG was demonstrated to be safe and to stimulate anti-GD3 responses in patients with melanoma.11,12 A small pilot study in patients with SCLC was performed at Memo- rial Sloan-Kettering, where prolonged survival was ob- served in 15 patients vaccinated after induction therapy.10 The median disease-free progression was not reached at over 5 years in seven patients with limited disease. These impressive results, together with the poor prognosis of SCLC patients, stimulated the start of this randomized phase III study, which compared vaccination with Bec2/
PATIENTS AND METHODS
To be eligible for the study, patients had to have limited disease (Veteran Administration classification13), histologically or cytologically proven SCLC, a major response (partial or complete) to adequate induction chemoradiotherapy, a Karnofsky perfor- mance status of 60% or more, adequate bone marrow, liver, renal, and heart functions, age over 18 years, and no known HIV or other active viral infections. Patients had to sign an informed consent form. Originally, patients with a positive purified protein deriva- tive (PPD) test were excluded. This criterion then was relaxed in the fourth study amendment to exclude only patients with a his- tory of tuberculosis or with a grade 3 skin toxicity to a PPD test of 5 U. No surgical or second-line treatment given for SCLC was allowed, and no splenectomy or splenic radiotherapy or prior therapy with proteins of murine origin was permitted. Further- more, patients with active infections or any prior active malignan- cies within 5 years or who were pregnant were excluded, as were patients requiring the chronic use of systemic antihistamines, nonsteroidal anti-inflammatory drugs, or corticosteroids.
Patients must have received adequate induction therapy, consisting of at least a two-drug regimen for four to six cycles and chest radiotherapy. Radiotherapy was given according to institu- tional policy. The timing of chest radiotherapy was left to the investigator, because at the time of the initiation of this study, it was unclear whether concomitant early chest radiotherapy was superior to sequential chemotherapy followed by radiotherapy. Prophylactic cranial irradiation (PCI) was recommended but not required for patients who achieved complete remission to induc- tion therapy but had to be completed before vaccination.
In the initial part of the study, patients were registered before receiving induction therapy, but the protocol was later amended to simultaneously register and randomly assign patients after completing induction treatment. Before the start of induction therapy, patients had to have limited-disease SCLC verified by chest, upper abdomen, and brain computed tomography scans and adequate blood cell counts and chemistries and be able to receive induction therapy. At randomization the same tests were repeated and had to confirm a partial or complete response. At that time a PPD test and an ECG were performed.
Five vaccinations, each consisting of eight injections admin- istered in a single limb, were planned, and vaccinations were rotated among upper arms and thighs at weeks 0, 2, 4, 6, and 10. The Bec2 dose was 2.5 mg. BCG was reconstituted in diluent, giving final solutions containing 2.0 107, 5.0 106, 1.0 106, 5.0 105, and 1.0 105 colony-forming units for vaccinations one through five, respectively.
Although initially patients with a positive PPD test were excluded from random assignment, when the accrual to the study was approximately halfway done, it was decided by the study’s steering committee, on advice of an independent data-monitoring committee, that it was safe to vaccinate patients14 with a positive PPD test (skin induration 10 mm but National Cancer Institute of Canada Clinical Trials Group skin reaction grade 3) by using
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