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.