Personalized DNA Vaccine + PD-1 Blockade for Glioblastoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Washington University School of Medicine
Must not be taking: Immunotherapy, Live vaccines
Disqualifiers: Immunodeficiency, Autoimmune conditions, Cancer, others
Stay on Your Current Meds
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a single institution, open-label, multi-arm, phase I study assessing the safety and immunogenicity of a personalized neoantigen-based personalized DNA vaccine combined with PD-1 blockade therapy in subjects with newly diagnosed, MGMT promoter unmethylated glioblastoma (GBM).
Immune checkpoint blockade, specifically those targeting the PD-1/PD-L1 pathways, has shown efficacy in multiple solid and hematologic malignancies. Furthermore, as has been demonstrated in metastatic melanoma, combining PD-1/PD-L1 blockade with other immune checkpoint inhibitors has shown improved objective response rates, though there is a significant increase in serious immune-related adverse events. As such, current trials are exploring different doses, administration schedules, and immune checkpoint agents. One alternative approach, however, is to introduce a tumor-directed therapy such as a personalized neoantigen vaccine combined with these immune modulating agents (i.e. immune checkpoint blocking antibodies) to maximize the tumor-specific response but minimize the toxicity associated with increasing non-specific systemic immune activation by generating a potent and focused neoantigen specific immune response.
This study will test the hypothesis that a personalized neoantigen DNA vaccine in combination with concurrent administration of immune checkpoint blockade therapy will enhance the magnitude and breadth of neoantigen-specific T cell responses while maintaining an acceptable safety profile. The overall goal of this study is to identify the optimal vaccine plus adjuvant platform that can be tested in a subsequent phase II study to determine the efficacy of a personalized neoantigen vaccine approach in patients with GBM.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, systemic corticosteroid therapy is allowed if the dose is no greater than 2 mg per day, and Bevacizumab is permitted for certain conditions. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment Personalized DNA Vaccine + PD-1 Blockade for Glioblastoma?
Research shows that personalized neoantigen vaccines can generate immune responses in glioblastoma patients, with evidence of T cells (a type of immune cell) targeting the tumor. This suggests that such vaccines can potentially improve the immune environment in glioblastoma, making it a promising approach for treatment.
12345Is the personalized DNA vaccine with PD-1 blockade generally safe for humans?
The personalized DNA vaccine combined with PD-1 blockade has been tested in various clinical trials for different cancers, such as melanoma and lung cancer, and has shown a manageable safety profile with no serious treatment-related adverse events reported.
12678What makes the Personalized DNA Vaccine + PD-1 Blockade treatment unique for glioblastoma?
This treatment is unique because it combines a personalized DNA vaccine that targets specific mutations in a patient's tumor with a PD-1 blockade, which helps the immune system attack cancer cells. This approach is novel for glioblastoma, a cancer with few effective treatments, as it aims to generate a strong immune response against the tumor.
134910Eligibility Criteria
This trial is for adults with newly diagnosed, unmethylated glioblastoma who haven't had prior immunotherapy. Participants must have adequate organ function, agree to use contraception, and can consent to genome sequencing. They should not have certain other cancers within the last 3 years or conditions that could interfere with the study.Inclusion Criteria
I agree to have my genes sequenced and shared for research.
I am 18 years old or older.
I have had brain surgery for a tumor, including biopsy or removal.
+2 more
Exclusion Criteria
I have never received immunotherapy.
I haven't had cancer in the past 3 years, except for certain types that were fully treated.
I have not had a live vaccine in the last 4 weeks.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a personalized neoantigen DNA vaccine via electroporation mediated IM injection and retifanlimab, with the vaccine given once every 28 days for up to 6 doses and retifanlimab for up to 12 months
12 months
6 visits (in-person) for vaccine doses, additional visits for retifanlimab administration
DLT Observation
Safety is monitored by assessing treatment-related dose-limiting toxicity (DLT) rate related to vaccination alone or in combination with retifanlimab
87 days
Follow-up
Participants are monitored for progression-free survival and immunogenicity, with assessments continuing through progression
36 months
Participant Groups
The trial tests a personalized neoantigen DNA vaccine combined with Retifanlimab PD-1 blockade therapy in patients with glioblastoma. It aims to enhance T cell responses against cancer while keeping side effects low and will set the stage for future efficacy studies.
2Treatment groups
Experimental Treatment
Group I: Cohort B: Personalized neoantigen DNA vaccine + retifanlimabExperimental Treatment3 Interventions
* Cohort B will receive the personalized neoantigen DNA vaccine via electroporation mediated IM injection plus concurrent retifanlimab beginning with Dose 1 and continuing for a total of 6 doses.
* The personalized neoantigen DNA vaccine will be given once every 28 days for up to 6 doses. Retifanlimab is given at a fixed dose of 500 mg every 28 days.
* Patients may receive up to 6 doses of personalized neoantigen DNA vaccine and up to 12 months total of retifanlimab
Group II: Cohort A: Personalized neoantigen DNA vaccine + retifanlimabExperimental Treatment3 Interventions
* Cohort A will receive the personalized neoantigen DNA vaccine via electroporation mediated IM injection alone during the first two priming doses, then concurrently with retifanlimab during the subsequent boosting doses (Doses 3 through 6)
* The personalized neoantigen DNA vaccine will be given once every 28 days for up to 6 doses. Retifanlimab is given at a fixed dose of 500 mg every 28 days.
* Patients may receive up to 6 doses of personalized neoantigen DNA vaccine and up to 12 months total of retifanlimab
Personalized Neoantigen DNA vaccine is already approved in United States for the following indications:
🇺🇸 Approved in United States as Zynyz for:
- Metastatic or recurrent locally advanced Merkel cell carcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
Ichor Medical Systems IncorporatedIndustry Sponsor
The Foundation for Barnes-Jewish HospitalCollaborator
Incyte CorporationIndustry Sponsor
PapiVax Biotech, Inc.Collaborator
References
Personalized DNA Vaccine Tamps Down HCC. [2022]In a phase I/II trial, the personalized DNA vaccine GNOS-PV02 combined with pembrolizumab and plasmid-encoded IL12 yielded a response rate of 25% in patients with advanced hepatocellular carcinoma. The vaccine encoded up to 40 patient-specific neoantigens and had a manageable safety profile.
Personalized DNA Vaccine Immunogenic Against Melanoma. [2023]A personalized neoantigen vaccine built around a DNA backbone, EVX-02, elicited robust and lasting T-cell responses in patients with melanoma after surgery. The first-in-human data, presented at the Society for Immunotherapy of Cancer Annual Meeting, have inspired a next-generation DNA vaccine candidate, EVX-03, that includes an additional payload and a more sophisticated antigen-selection process.
Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. [2021]Neoantigens represent promising targets for personalized cancer vaccine strategies. However, the feasibility of this approach in lower mutational burden tumors like glioblastoma (GBM) remains unknown. We have previously reported the use of an immunogenomics pipeline to identify candidate neoantigens in preclinical models of GBM. Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I- and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood. A similar pattern of reactivity was observed among isolated post-treatment tumor-infiltrating lymphocytes. Genomic analysis of pre- and post-treatment GBM reflected clonal remodeling. These data demonstrate the feasibility and translational potential of a therapeutic neoantigen-based vaccine approach in patients with primary CNS tumors.
Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. [2023]Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.
Considerations for personalized neoantigen vaccination in Malignant glioma. [2022]Malignant gliomas are the most common primary brain cancer diagnosed and still carry a poor prognosis despite aggressive multimodal management. Despite the continued advances in immunotherapy for other cancer types, however, there remain no FDA approved immunotherapies for cancers such as glioblastoma. OF the many approaches being explored, cancer vaccine programs are undergoing a renaissance due to the technological advances and personalized nature of their contemporary design. Neoantigen vaccines are a form of immunotherapy involving the use of DNA, mRNA, and proteins derived from non-synonymous mutations identified in patient tumor tissue samples to stimulate tumor-specific T-cell reactivity leading to enhance tumor targeting. In the last several years, the study of neoantigens as a therapeutic target has increased, with the routine workflow implementation of comprehensive next generation sequencing and in silico peptide binding prediction algorithms. Several neoantigen vaccine platforms are being evaluated in clinical trials for malignancies including melanoma, pancreatic cancer, breast cancer, lung cancer, and glioblastoma, among others. In this review, we will review the concept of neoantigen discovery using cancer immunogenomics approaches in glioblastoma and explore the disease-specific issues being addressed in the design of effective personalized cancer vaccine strategies.
A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer. [2023]Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. [2021]The combination of immune-stimulating strategies has the potency to improve immunotherapy of cancer. Vaccination against neoepitopes derived from patient tumor material can generate tumor-specific T cell immunity, which could reinforce the efficacy of checkpoint inhibitor therapies such as anti-PD-1 treatment. DNA vaccination is a versatile platform that allows the inclusion of multiple neoantigen-coding sequences in a single formulation and therefore represents an ideal platform for neoantigen vaccination. We developed an anti-tumor vaccine based on a synthetic DNA vector designed to contain multiple cancer-specific epitopes in tandem. The DNA vector encoded a fusion gene consisting of three neoepitopes derived from the mouse colorectal tumor MC38 and their natural flanking sequences as 40 amino acid stretches. In addition, we incorporated as reporter epitopes the helper and CTL epitope sequences of ovalbumin. The poly-neoantigen DNA vaccine elicited T cell responses to all three neoantigens and induced functional CD8 and CD4 T cell responses to the reporter antigen ovalbumin after intradermal injection in mice. The DNA vaccine was effective in preventing outgrowth of B16 melanoma expressing ovalbumin in a prophylactic setting. Moreover, the combination of therapeutic DNA vaccination and anti-PD-1 treatment was synergistic in controlling MC38 tumor growth whereas individual treatments did not succeed. These data demonstrate the potential of DNA vaccination to target multiple neoepitopes in a single formulation and highlight the cooperation between vaccine-based and checkpoint blockade immunotherapies for the successful eradication of established tumors.
Synthetic multiepitope neoantigen DNA vaccine for personalized cancer immunotherapy. [2022]Neoantigen-based personalized vaccination has emerged as a viable method for tumor immunotherapy. Here we set up a DNA-based neoantigen vaccine platform with comprehensive identification of individual somatic mutations using whole-exome sequencing (WES) and RNA-seq, bioinformatic prediction of neo-epitopes, dendritic cell (DC)-based efficacy prevalidation of vaccine candidates, optimization of the DNA vaccine and its nanocarrier and adjuvant, and preparation of a liposome-encapsulated multiepitope DNA vaccine. The DNA vaccine was efficiently uptaken by DCs and induced effective immune response against mouse melanoma cells, leading to significant inhibition of melanoma tumor growth and reduction of lung metastasis in a mouse model. Numerous intratumoral infiltrated CD8+ T-cells with specific in vitro killing ability towards melanoma cells were identified. Our study offers evidence that a multiepitope neoantigen DNA vaccine in a nanocarrier can be exploited for personalized tumor immunotherapy and as a reliable prevalidation approach for rapid enrichment of effective neoantigens.
ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. [2018]Glioblastoma is the most deadly primary brain tumor in adults and has long represented a therapeutic challenge. Disease recurrence is inevitable, and the management of recurrent disease is complicated by spontaneous or induced tumor heterogeneity which confers resistance to therapy and increased oncogenicity. EGFR and the tumor-specific mutation EGFRvIII is commonly altered in glioblastoma making it an appealing therapeutic target. Immunotherapy is an emerging and promising therapeutic approach to glioma and the EGFRvIII vaccine, rindopepimut, is the first immunotherapeutic drug to enter Phase III clinical trials for glioblastoma. Rindopepimut activates a specific immune response against tumor cells harboring the EGFRvIII protein. This review evaluates the recently completed ReACT Phase II trial using rindopepimut plus bevacizumab in the setting of EGFRvIII-positive recurrent glioblastoma (Clinical Trials identifier: NCT01498328).
Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. [2022]Glioblastoma multiforme (GBM) is the most common and deadly of the human brain cancers. The EGF receptor is often amplified in GBM and provides a potential therapeutic target. However, targeting the normal receptor is complicated by its nearly ubiquitous and high level of expression in certain tissues. A naturally occurring deletion mutant of the EGF receptor, EGFRvIII, is a constitutively active variant originally identified in a high percentage of brain cancer cases, and more importantly is rarely found in normal tissue. A peptide vaccine, rindopepimut (CDX-110, Celldex Therapeutics), is directed against the novel exon 1-8 junction produced by the EGFRvIII deletion, and it has shown high efficacy in preclinical models. Recent Phase II clinical trials in patients with newly diagnosed GBM have shown EGFRvIII-specific immune responses and significantly increased time to progression and overall survival in those receiving vaccine therapy, as compared with published results for standard of care. Rindopepimut therefore represents a very promising therapy for patients with GBM.