Heat Shock Protein Vaccines Target Tumor Cell’s ‘Antigenic Profile’

ABSTRACT: Experts in cancer immunology and vaccine therapies discussed recent progress in cancer vaccine development at a satellite symposium of the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO). More than 300 clinicians and researchers attended the symposium, sponsored by the University of Connecticut School of Medicine under an unrestricted educational grant from Antigenics Inc. This page includes reports from two presentations.

ORLANDO—Heat shock proteins (HSPs) purified from tumor cells carry the unique "antigenic fingerprint" of that tumor, and vaccination with tumor-derived HSPs induces specific tumor immunity, said Pramod K. Srivastava, PhD, professor of immunology and director of the University of Connecticut Cancer Center, Farmington.

Speaking at a symposium held in conjunction with the 2002 ASCO annual meeting, Dr. Srivastava explained that each tumor has a unique antigenic profile related to the accumulation of random mutations. With each division of a tumor cell, an estimated 6 to 60 random mutational changes occur, and because tumor cells are continually dividing, a vast number of mutations eventually accumulate. This results in a tumor cell population in which each cell has a unique antigenic profile.

Therefore, although several well-described specific tumor antigens exist, the complete characterization of the antigens associated with an individual tumor is not "practically knowable," he said, owing to the randomness of their generation. However, by isolating the HSPs from individual tumors, it is possible to capture the antigenic fingerprint of that specific tumor.

Heat shock proteins are present in every living cell and have been conserved throughout evolution, from bacteria through humans, Dr. Srivastava said. Collectively, HSPs constitute approximately 10% of the total intracellular protein content. Although the expression of HSPs is increased in response to heat shock, glucose deprivation, or other stresses, HSPs are present in abundant levels even under normal conditions.

Each HSP molecule serves as a chaperone for an individual peptide, and together the HSPs collect a heterogeneous assortment of peptides representative of the antigenic profile of each cell. An extraordinarily useful property of the HSPs, Dr. Srivastava said, is that although a given HSP may purify into a single band, there is actually a vast heterogeneity of chaperoned peptide sequences within this single band. "If, for example, you purify HSPs from a mouse leukemia, you will find leukemia antigens associated with the HSPs. In human melanomas, you’ll find antigenic peptides derived from the melanoma cells. So essentially, when you purify HSPs, you have an antigenic fingerprint," he said.

The HSPs also have immunogenic functions. They can chaperone peptides to antigen-presenting cells (APCs) in the lymph nodes. The APCs bind the HSPs and then re-present the HSP-chaperoned peptides on their MHC class I and II molecules. Interaction with HSPs also stimulates APCs to release cytokines.

Vaccines derived from HSPs can provide specific immunity against individual tumors, Dr. Srivastava said. He described an animal study in which, following surgery to remove pre-existing tumors, mice were vaccinated with HSPs derived from their individual tumors. The majority of vaccinated animals had long-term disease-free survival, whereas nonvaccinated mice died within a short time after surgery due to the persistence of micrometastatic disease.

Clinical trials of HSP-based cancer vaccines, specifically HSPPC-96 (Onco-phage, Antigenics LLC, New York, NY) are underway, and Dr. Srivastava commented that several phase I and phase II trials have already been completed.

At M.D. Anderson Cancer Center, Robert Amato, MD, and his colleagues treated patients with advanced renal cell carcinoma with HSPPC-96 vaccines derived from their individual tumors. Vaccination consisted of four weekly injections starting 4 to 6 weeks after surgery to obtain tumor samples. Patients with disease regression or stabilization could receive additional vaccinations.

At the time of the preliminary report, 29 patients had completed the initial series of four vaccinations. At the 1-year follow-up, one complete response and three partial responses were observed, with an additional 18 patients having stable disease or slight progression. Seventeen patients continued to receive vaccinations, and no significant toxicities were reported.

Based on these data, a randomized multicenter phase III trial has been initiated of autologous vaccination with HSPPC-96 in patients with resected high-risk, nonmetastatic renal cell cancer.

Dr. Srivastava was involved in a study of autologous HSPPC-96 vaccines in patients with metastatic melanoma, conducted by Giorgio Parmiani and his colleagues at several institutions in Italy (ASCO 2002 abstract 49). Among 39 evaluable patients, clinical responses were observed in 7 (18%), and 48% of patients had specific T-cell responses against melanoma antigens.

A study by Christian Hertkorn and his colleagues, conducted at several institutions in Germany, evaluated autologous HSPPC-96 vaccination following surgery in patients with gastric cancer (ASCO 2002 abstract 117). Among 15 patients receiving therapy, 3 (20%) remained disease-free after a median follow-up period of 32 months.

In another ASCO 2002 abstract (2290), researchers from the National Cancer Institute, Milan, Italy, presented findings from a phase II trial of HSPPC-96 in 29 colorectal cancer patients with completely resected liver metastases. Two years after surgery, overall survival and disease-free survival were 79% and 32%, respectively. Almost 60% of patients had a significant tumor-specific T-cell immune response. These patients had a significantly lower recurrence rate (41%) than nonre-sponding patients (92%).

Trials of autologous HSPPC-96 vaccines in patients with B-cell lymphoma, gastric cancer, sarcoma, and other tumor types are ongoing, he said.

Optimal Timing

Dr. Srivastava commented on the lessons learned from mice with respect to the optimal timing of vaccine immunotherapy. Animals with residual disease or bulky disease left untreated will die of their tumors. Such animals treated with HSP-derived vaccines have occasional tumor regressions but most often have disease stabilization leading to improved survival. In contrast, in the adjuvant setting, in which animals have been rendered clinically disease free through surgery, treatment with HSP-derived vaccines results in dramatic improvements in long-term survival.

These observations suggest that optimal results with these vaccines may be obtained in the setting of minimal residual or micrometastatic disease. Although still early, similar observations have been suggested by the results of a limited number of clinical trials, Dr. Srivastava said.

The FDA granted orphan drug status to Oncophage (HSPPC-96) for the treatment of renal cancer in 2001, and in July 2002 for the treatment of metastatic melanoma.