Trial of Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccine

Immunotherapy for Brain Tumors:

Although it is usually ineffective alone, it has long been recognized that the immune system of tumor bearing hosts (human and animal models) does, indeed, mount an endogenous immune-mediated response to tumor. Unfortunately, this immune response alone is not sufficient in combating tumor. The balance of immune response and immune regulation often mitigates this anti-tumor response. Several mechanisms within tumor-bearing hosts compromise the efficacy of this anti-tumor immune response, including low levels of expression of co-stimulatory molecules such as the B7 family of immune-regulatory ligands, the tumor's local production of immunosuppressive factors and the tumor's ability to over-express pro-survival factors thus escaping destruction by the host immune system. However, many have hypothesized that if this immune response can be better harnessed and/or magnified, there is potential for heightened tumor responses.

A number of specific observations support the use of immunotherapy to treat brain tumors. Data published supports a possible correlation between HIV mediated immunosuppression and the development of intracranial glial tumors. Immunosuppression in transplant recipients has also been implicated in the development of intracranial glioma. Further supporting this hypothesis are documented rare cases of long-term remission of malignant brain tumors following significant post-operative infection. These observations have fueled the idea that a heightened immune system may confer some protection against intracranial tumors. With this in mind, one hypothesis is that successful active immunotherapy for patients with brain tumors will require development of a specific peptide or polyvalent vaccines in an effort to further stimulate the host's immune system against specific tumor-associated antigens.

It has been well established that mice can be immunized against syngeneic tumors. Heat shock protein-peptide complexes isolated from a specific tumor can been utilized to elicit both prophylactic and therapeutic immunity against the specific cancer from which the preparations have been isolated. Overexpression of heat shock protein-chaperone complexes (HSPPC) in brain tumor cells suggests that HSPPC are a meaningful target antigen for a brain tumor vaccine. Moreover, in addition to generating tumor-specific immunity, vaccination with heat shock protein peptide complexes in animal models generates therapeutic responses. Since an immune response has not been widely evaluated for pediatric brain tumors, this study will test the safety and feasibility of producing and administering a vaccine capable of generating an autologous, anti-tumor immune response.

HSPPC-96:

Heat shock proteins are up-regulated along with tissue-specific chaperone peptides in the setting of cellular stress to prevent damage and aggregation of the proteome. Therefore, heat shock protein peptide complexes (HSPPC) provide a cytoprotective effect. Overexpression of heat shock proteins has been described in malignant glioma and medulloblastoma cells. HSPPC-96 is an autologous tumor-derived vaccine that has been under clinical investigation for the treatment of a variety of cancer types, including adult high-grade glioma (HGG). It is composed of the 96-kilodalton (KDa) heat shock protein, glycoprotein 96 (gp96), attached to autologous tumor-derived peptides. The gp96 glycoprotein in HSPPC-96 is a highly conserved, abundant, non-polymorphic stress protein found in every cell type of the body. Gp96 isolated from normal or tumor tissues is found in complex with peptides that are specific to the original tissue. Mouse models have shown that HSPPC-96 confers protective immunity only to the tumor from which it is derived and not to genetically distinct tumors or normal tissue.

When injected into the host, HSPPC-96 interacts with antigen presenting cells (APCs) via specific receptors. Once internalized by the APCs, the peptides chaperoned by the HSP are transferred to major histocompatibility complex (MHC) class I and class II molecules in intracellular compartments and eventually expressed at the cell surface. T-cells then recognize the MHC-peptide complexes and are stimulated. HSP-peptide complexes are unique in their ability to elicit an antigen-specific cytotoxic T-cell response. Additionally, cluster of differentiation 4 (CD4+) T cells and natural killer (NK) cells are also recruited adding to the tumor-associated immunity.

Some advantages of heat shock protein-peptide vaccines for immunotherapy are that it elicits a cluster of differentiation (CD8+) T cell response in spite of exogenous administration, it circumvents the need for identification of T-cell epitopes of individual cancers, and it minimizes the possibility of generating epitope variants. Furthermore, heat shock protein-peptide complexes have elicited tumor rejection and CD8+ T cell response without adjuvant therapies. Heat shock protein-peptide complexes, such as HSPPC-96, can be isolated from human tumors, and when injected back into the patient from whom they were isolated, may present a unique opportunity to deliver a vaccine specific to that patient.