Abstract
BackgroundGlycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma.MethodsPatients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 μg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The γ-interferon (IFNγ) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8.ResultsAmong 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNγ-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years.ConclusionTreatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-μg dose level was shown to be practical for further study.
Highlights
The past two decades have witnessed increasingly sophisticated approaches to incorporating active immunotherapy into the multimodality care of the population of oncology patients for whom there continues to be significant unmet medical need
Immunotherapy of mice with preexisting cancer treated with heat-shock protein (HSP) preparations derived from syngeneic cancer resulted in a delay of progression of the primary cancer, a reduced metastatic load, and prolongation of life span, whereas treatment with HSP preparations derived from cancers other than the syngeneic cancer did not provide such protection [1,2]
Patients undergoing resection of large (>3 cm) histologically confirmed metastatic melanoma as part of their routine clinical management and who agreed to participate in the study signed an Institutional Review Board (IRB)-approved consent form for procurement of tissue for autologous tumorderived HSPPC-96 preparation
Summary
The past two decades have witnessed increasingly sophisticated approaches to incorporating active immunotherapy into the multimodality care of the population of oncology patients for whom there continues to be significant unmet medical need. Gp96 is a non-polymorphic constitutively expressed and inducible heat-shock protein (HSP) which associates with intracellular antigenic peptides Such gp96-peptide complexes have been shown to elicit potent tumor-specific T cell responses and protective immunity in a variety of animal models. Immunotherapy of mice with preexisting cancer (including spontaneously derived B16 melanoma) treated with HSP preparations derived from syngeneic cancer resulted in a delay of progression of the primary cancer, a reduced metastatic load, and prolongation of life span, whereas treatment with HSP preparations derived from cancers other than the syngeneic cancer did not provide such protection [1,2] These studies were especially interesting in that they showed an autologous antitumor response without identifying the specific tumor antigenic epitopes [1]. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma
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