SBIR-STTR Award

Recently, temozolomide (TMZ), a myelosuppressive alkylating chemotherapy, has shown a benefit in patients with glioblastoma multiformes (GBM), but median survival is still less than 15 months. Moreover, these conventional chemotherapies lack specificity and result in incapacitating damage to surrounding normal brain and systemic tissues. Immunotherapy may provide an opportunity to eliminate altered neoplastic cells without adding additional toxicity to multi-modality therapy, but the lymphopenia induced by cycles of adjuvant TMZ, now the standard-of-care in patients with GBM, would be predicted to curtail the induction of productive immune responses. However, when given to patients with newly diagnosed glioblastoma multiforme during the recovery from TMZ-induced lymphopenia, the investigators demonstrated that a vaccine targeting a EGFRvIII mutation on GBM induced strong immunologic responses in all vaccinated patients that were accompanied by complete radiographic responses in patients with residual disease and prolonged survival compared to matched historical controls. However, the EGFRvIII mutation is expressed in only about a third of GBMs, limiting the number of patients who may benefit from this therapy and highlighting the need to target more ubiquitously expressed antigens. The recent discovery that greater than 90% of GBMs are associated with tumor-restricted reactivation of human cytomegalovirus (CMV) provides an opportunity to leverage the well characterized viral antigens of CMV as tumor-specific targets. Following a developmental pathway used successfully to advance EGFRvIII specific vaccines to large scale efficacy trials and commercialization, the investigators propose to evaluate the preclinical and clinical advancement of peptide vaccines targeting the immunodominant antigens of CMV. The objectives of this phase I STTR proposal are to finalize the composition of a multi-component peptide vaccine targeting CMV antigens through investigation of the impact of peptide length, hapten conjugation, and the inclusion of class II-restricted helper T cell epitopes on immunologic responses in HLA transgenic mice, and to determine the impact of vaccine dose and timing with respect to administration of TMZ in order to define variables worthy of investigation within the context of early phase clinical trials.

Public Health Relevance:
The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.

Public Health Relevance Statement:
The significance of this research is that it may advance a new therapy for malignant brain tumors as well as provide a strategy for treatment that can be applied to many other cancers. Improved therapy for cancer has significant potential to improve public health and quality of life for patients affected by malignant disease.

NIH Spending Category:
Biotechnology; Brain Cancer; Brain Disorders; Cancer; Immunization; Neurosciences; Orphan Drug; Prevention; Rare Diseases; Vaccine Related

Project Terms:
Address; Adjuvant; Adjuvant Therapy; Affect; Alabama; Animals; Antibodies; Antigens; base; Blinded; Brain; cancer immunotherapy; cancer therapy; Caring; CD4 Positive T Lymphocytes; cell mediated immune response; chemotherapy; Clinical; Clinical Trials; commercialization; Complement; Comprehensive Cancer Center; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Development; Disease; Dose; Drug Formulations; efficacy trial; Epidermal Growth Factor; epidermal growth factor receptor VIII; Epitopes; Evaluation; Glioblastoma; Glioma; Haplotypes; Haptens; Helper-Inducer T-Lymphocyte; Hematopoietic; Homeostasis; Immune response; Immunity; Immunodominant Antigens; immunogenic; Immunologics; Immunotherapy; improved; Institutes; Institution; Investigation; Keyhole Limpet Hemocyanin; Laboratories; Lead; Length; Licensing; Lymphocyte; Lymphopenia; Malignant - descriptor; Malignant Glioma; Malignant neoplasm of brain; Malignant neoplasm of prostate; Malignant Neoplasms; meetings; Metastatic Melanoma; Modality; Modeling; Mus; Mutation; neoplastic cell; Newly Diagnosed; novel strategies; Pathway interactions; Patients; Peptide Vaccines; Peptides; Phase; pre-clinical; Preparation; public health medicine (field); Quality of life; Randomized; Recovery; Refractory; Regimen; Research; Research Personnel; Residual Tumors; response; Small Business Technology Transfer Research; Specificity; success; Sweden; T-Lymphocyte; T-Lymphocyte Epitopes; temozolomide; Therapeutic; therapeutic vaccine; Time; Tissues; Toxic effect; Transgenic Mice; Treatment Protocols; treatment strategy; tumor; Tumor Antigens; Universities; Vaccinated; Vaccination; Vaccines; Viral Antigens

Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapeutic approaches are exquisitely precise and can eradicate large, well-established tumors in mice and humans even when tumors reside within the "immunologically privileged" brain. However, immunotherapy is limited by the lack of frequent and homogeneously-expressed tumor-specific antigens. We have previously demonstrated that a peptide vaccine targeting the tumor-specific EGFRvIII mutation (PEPvIII) induces immune responses sufficient to eliminate all EGFRvIII-expressing tumor cells in mice and humans without toxicity. Unfortunately, EGFRvIII is heterogeneously expressed and tumors recur as a result of outgrowth of the EGFRvIII negative tumor cells. However, the nearly universal presence and homogeneous expression of cytomegalovirus (CMV) antigens in GBM, but not normal brain, has now been well-established and provides an unparalleled opportunity to subvert these immunogenic viral proteins as tumor-specific targets. In two consecutive clinical trials from our laboratory using dendritic cells (DCs) targeting CMV pp65 in patients with GBM, specific immunologic responses were induced along with remarkably enhanced progression free survival and overall survival. However, DC vaccination is expensive, time-consuming, and commercialization is challenging. In contrast, peptide vaccines are cost-effective, easier to produce, and easier to commercialize. Leveraging our experience with PEPvIII, we have developed a CMV-specific multi-epitope peptide cocktail (PEP-CMV). PEP-CMV vaccination is immunogenic in HLA-A2 transgenic mice and peripheral blood mononuclear cells from CMV seropositive patients with GBM respond to stimulation with PEP-CMV, indicating PEP-CMV is broadly immunogenic in our patient population. We have already shown with PEPvIII that lymphopenia induced by both standard of care temozolomide (TMZ) and dose intensified TMZ can be leveraged to augment immunogenicity and the impact these regimens have on PEP-CMV immunogenicity will be compared in our proposed trial. Additionally, we will examine a novel immunostimulant, tetanus (Td), as an adjuvant to PEP-CMV. In a recent pilot trial from our laboratory, patients randomized to receive Td as vaccine- site pre-conditioning prior to CMV pp65-loaded DC immunization, experienced significantly enhanced PFS and OS in comparison to the control arm. A Td booster was included for site pre-conditioning during PEP-CMV immunogenicity analysis and was demonstrated to significantly enhance IFN¿ secretion of CMV targeted T cells in HLA-A2 transgenics. Therefore, in this proposal, we will test the HYPOTHESIS that vaccination with PEP-CMV after Td skin conditioning will be a feasible, safe, and immunogenic tumor-specific therapy in patients with newly-diagnosed GBM during TMZ chemotherapy, without antigen escape or toxicity.

Public Health Relevance Statement:


Public Health Relevance:
Glioblastoma (GBM) is uniformly lethal. It is also the most common malignant primary brain tumor, and these tumors now represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Current therapy is incapacitating and produces a median overall survival of <15 months because of limits defined by non-specific toxicity. We have developed a peptide vaccine that specifically targets patient GBM and redirects patients' own immune cells to recognize and destroy tumors.

Project Terms:
Accounting; Adjuvant; Antigens; arm; Autologous; base; Blinded; Brain; Cancer Etiology; cell motility; Cells; Cessation of life; chemotherapy; Child; Clinical Trials; cohort; commercialization; conditioning; cost effective; cytokine; Cytolysis; Cytomegalovirus; Cytomegalovirus Vaccines; Data; Dendritic Cell Vaccine; Dendritic Cells; design; Dose; Drug Formulations; Epidermal Growth Factor Receptor; epidermal growth factor receptor VIII; Epitopes; experience; Glioblastoma; Growth; HLA-A2 Antigen; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; immunogenic; immunogenicity; Immunologic Adjuvants; Immunologics; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Inflammatory; Inguinal lymph node group; Interferons; International; Laboratories; Licensing; Lymphopenia; Malignant - descriptor; Malignant neoplasm of brain; melanoma; migration; Mus; Mutation; neoplastic cell; Newly Diagnosed; novel; novel vaccines; patient population; Patients; Peptide Vaccines; Peptides; Peripheral Blood Mononuclear Cell; Phase; pilot trial; pre-clinical research; Primary Brain Neoplasms; Progression-Free Survivals; public health relevance; Publishing; Randomized; Regimen; Regulatory T-Lymphocyte; Renal carcinoma; response; Safety; seropositive; Site; Skin; standard of care; T-Lymphocyte; temozolomide; Testing; Tetanus; Therapeutic; therapeutic vaccine; Time; Toxic effect; Training; Transgenic Mice; Transgenic Organisms; tumor; Tumor Antigens; Tumor Specific Peptide; Vaccination; Vaccines; Viral Proteins; young adult