Personalized DNA Vaccine + PD-1 Blockade for Glioblastoma

Recruiting at 1 trial location

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for aggressive brain cancer known as glioblastoma. It combines a personalized DNA vaccine, designed to target specific tumor markers, with Retifanlimab, a PD-1 blockade drug that enhances the immune system's ability to fight cancer. The researchers aim to determine if this combination can boost the immune response against the tumor while keeping side effects manageable. Individuals recently diagnosed with glioblastoma and possessing specific genetic characteristics might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have found personalized neoantigen DNA vaccines to be safe and generally well-tolerated in patients with glioblastoma, a type of brain cancer. These vaccines have triggered strong immune responses, with patients experiencing few serious side effects. Specifically, one study showed that 87.5% of vaccinated patients did not experience cancer recurrence over three years, and no major safety issues were reported.

Retifanlimab, the other treatment in this trial, has also undergone safety studies. It has been used successfully to treat other cancers, such as advanced squamous cell anal carcinoma, and is considered an effective immunotherapy. While it can cause some side effects, such as immune-related issues, these are usually manageable.

Overall, both the personalized vaccine and retifanlimab have demonstrated promising safety in previous research. This trial will further evaluate their safety when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for glioblastoma because they take a personalized approach to cancer therapy. Unlike standard treatments like surgery, radiation, and chemotherapy, this approach uses a personalized neoantigen DNA vaccine designed to target unique markers on an individual's tumor. This vaccine is combined with retifanlimab, a PD-1 blockade, which helps the immune system recognize and attack cancer cells more effectively. Additionally, the delivery method via electroporation-mediated injection enhances the vaccine's uptake, potentially leading to a more robust immune response. Together, these features offer a promising new direction for treating a notoriously challenging type of brain cancer.

What evidence suggests that this trial's treatments could be effective for glioblastoma?

Studies have shown that personalized neoantigen DNA vaccines can trigger strong immune responses in patients with glioblastoma, a type of brain cancer. Specifically, patients with these vaccine-induced immune responses sometimes lived much longer, with survival times reaching up to 53 months. Research indicates these vaccines are safe and can prevent cancer from returning in most patients. In this trial, participants in both Cohort A and Cohort B will receive a combination of the personalized neoantigen DNA vaccine and retifanlimab. Retifanlimab has shown promise in treating different types of tumors by helping the immune system target cancer cells. This combination could enhance the body's ability to fight glioblastoma, but more research is needed to confirm these early results. ^{1 2 3 5 6}

Who Is on the Research Team?

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

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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.

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

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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 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]

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]

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]

Citations

1. nature.com nature.com/articles/s41467-024-51315-8

A real-world observation of patients with glioblastoma ... Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/ ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8427683/

Efficacy and Safety of Actively Personalized Neoantigen ... Recently, neoantigen-based personalized vaccines have shown tremendous immunogenicity and safety in GBM. We aimed to systematically review the ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05743595

NCT05743595 | Neoantigen-based Personalized DNA ... 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.

4. genomemedicine.biomedcentral.com genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01388-3

Neoantigen DNA vaccines are safe, feasible, and induce ... At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion. Our ...

5. scientificarchives.com scientificarchives.com/article/personalized-neoantigen-dna-cancer-vaccines-current-status-and-future-perspectives

Personalized Neoantigen DNA Cancer Vaccines Interim data from Geneos Therapeutics reported the PCV as safe and well-tolerated, leading to clinical responses in 8 out of 34 HCC patients, and the detection ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04015700

Neoantigen-based Personalized DNA Vaccine in Patients ... Safety and tolerability of a personalized neoantigen DNA vaccine as measured by dose-limiting toxicities (DLTs), A DLT will be defined as any grade 3 toxicity ...