Personalized DNA Vaccine + PD-1 Blockade for Glioblastoma

Overseen By Tanner M Johanns, M.D., Ph.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: Immunotherapy, Live vaccines

Disqualifiers: Immunodeficiency, Autoimmune conditions, Cancer, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 12 months

12 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 2 6 7 8}

What 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. ^{1 3 4 9 10}

Research Team

Tanner M Johanns, M.D., Ph.D.

Principal Investigator

Washington University School of Medicine

Eligibility 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 have had brain surgery for a tumor, including biopsy or removal.

Ability to understand and willingness to sign an IRB approved written informed consent document

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.

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

Treatment Details

Interventions

• Personalized Neoantigen DNA vaccine
• Retifanlimab

Trial Overview 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.

Participant Groups

Group I: Cohort B: Personalized neoantigen DNA vaccine + retifanlimab Experimental Treatment 3 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 + retifanlimab Experimental Treatment 3 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

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Ichor Medical Systems Incorporated

Industry Sponsor

Trials

11

Recruited

440+

The Foundation for Barnes-Jewish Hospital

Collaborator

Trials

43

Recruited

6,600+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

PapiVax Biotech, Inc.

Collaborator

Trials

6

Recruited

120+

Findings from Research

In a phase I/II trial involving patients with advanced hepatocellular carcinoma, the personalized DNA vaccine GNOS-PV02, when combined with pembrolizumab and plasmid-encoded IL12, achieved a response rate of 25%.

The vaccine was designed to target up to 40 unique neoantigens specific to each patient and demonstrated a manageable safety profile, indicating it could be a promising treatment option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized DNA Vaccine Tamps Down HCC. [2022]

The personalized neoantigen vaccine EVX-02 demonstrated strong and durable T-cell responses in melanoma patients following surgery, indicating its potential effectiveness in cancer immunotherapy.

The promising results from EVX-02 have led to the development of a next-generation vaccine, EVX-03, which features an enhanced antigen-selection process and an additional payload to potentially improve its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized DNA Vaccine Immunogenic Against Melanoma. [2023]

A personalized synthetic long peptide vaccine targeting neoantigens was successfully developed and tested in a patient with glioblastoma (GBM), showing the ability to elicit specific T cell responses post-vaccination.

The study indicates that neoantigen-based vaccines can be a feasible and promising therapeutic strategy for treating lower mutational burden tumors like GBM, as evidenced by the detection of immune responses in both peripheral blood and tumor-infiltrating lymphocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. Johanns, TM., Miller, CA., Liu, CJ., et al.[2021]

Personalized neoantigen vaccination is a feasible strategy for treating glioblastoma, even in tumors with low mutation loads and an immunologically 'cold' environment, as demonstrated in a phase I/Ib study.

Patients who did not receive dexamethasone showed enhanced immune responses, including increased neoantigen-specific T cells that can migrate into glioblastoma tumors, suggesting that this vaccination approach could improve the immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Keskin, DB., Anandappa, AJ., Sun, J., et al.[2023]

Malignant gliomas, particularly glioblastoma, currently lack FDA-approved immunotherapies, but neoantigen vaccines are emerging as a promising approach due to advances in technology and personalized medicine.

Neoantigen vaccines utilize tumor-specific mutations to stimulate T-cell responses, and several platforms are being tested in clinical trials for glioblastoma and other cancers, highlighting a shift towards targeted immunotherapy strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Considerations for personalized neoantigen vaccination in Malignant glioma. Dunn, GP., Sherpa, N., Manyanga, J., et al.[2022]

The personalized neoantigen-based vaccine NEO-PV-01, combined with PD-1 blockade, was found to be safe in a phase Ib trial involving 82 patients with advanced melanoma, lung, or bladder cancer, with no serious treatment-related adverse events reported.

The vaccine successfully induced strong CD4+ and CD8+ T cell responses, which not only targeted the specific neoantigens but also led to an immune response against additional neoantigens, indicating a broadening of the immune attack on the tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Ott, PA., Hu-Lieskovan, S., Chmielowski, B., et al.[2023]

A synthetic DNA vaccine targeting multiple neoepitopes from mouse colorectal tumors was developed, successfully eliciting T cell responses and preventing melanoma growth in mice.

The combination of this DNA vaccine with anti-PD-1 therapy showed a synergistic effect in controlling tumor growth, suggesting that using both strategies together could enhance cancer immunotherapy effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. Tondini, E., Arakelian, T., Oosterhuis, K., et al.[2021]

A personalized DNA-based neoantigen vaccine was developed using whole-exome sequencing and RNA-seq to identify individual mutations, leading to effective immune responses against melanoma in mice.

The vaccine significantly inhibited tumor growth and reduced lung metastasis, demonstrating its potential as a personalized immunotherapy approach, with evidence of strong CD8+ T-cell infiltration targeting melanoma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic multiepitope neoantigen DNA vaccine for personalized cancer immunotherapy. Yang, X., Fan, J., Wu, Y., et al.[2022]

Rindopepimut, an immunotherapy targeting the EGFRvIII mutation, is the first of its kind to enter Phase III clinical trials for treating recurrent glioblastoma, a highly aggressive brain tumor.

The ReACT Phase II trial evaluated the combination of rindopepimut and bevacizumab in patients with EGFRvIII-positive recurrent glioblastoma, highlighting the potential of this approach to activate the immune response against tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. Gatson, NT., Weathers, SP., de Groot, JF.[2018]

Rindopepimut, a peptide vaccine targeting the EGFRvIII variant of the EGF receptor, has shown high efficacy in preclinical models and is specifically designed to avoid affecting normal tissues, making it a promising treatment for glioblastoma multiforme (GBM).

In recent Phase II clinical trials, patients with newly diagnosed GBM who received rindopepimut exhibited significant immune responses and improved time to progression and overall survival compared to standard treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Del Vecchio, CA., Li, G., Wong, AJ.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Personalized DNA Vaccine Tamps Down HCC. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Personalized DNA Vaccine Immunogenic Against Melanoma. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Considerations for personalized neoantigen vaccination in Malignant glioma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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]

7. United States pubmed.ncbi.nlm.nih.gov

A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Synthetic multiepitope neoantigen DNA vaccine for personalized cancer immunotherapy. [2022]

9. England pubmed.ncbi.nlm.nih.gov

ReACT Phase II trial: a critical evaluation of the use of rindopepimut plus bevacizumab to treat EGFRvIII-positive recurrent glioblastoma. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. [2022]