RNA-LP Vaccine for Glioblastoma

(PNOC020 Trial)

Overseen By Marcia Hodik

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Florida

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: HIV, Hepatitis, Metastatic disease, others

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

Compensation: Varies

Number of Visits: 20

52 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objective will be to demonstrate the manufacturing feasibility and safety, and to determine the maximum tolerated dose (MTD) of RNA-LP vaccines in (Stratum 1) adult patients with newly diagnosed GBM (MGMT low level or unmethylated in adults only) and (Stratum 2) in pediatric patients with newly diagnosed HGG (pHGG). Funding Source - FDA OOPD

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, participants who require high doses of corticosteroids must reduce them to lower levels within one week before vaccination.

What data supports the effectiveness of the RNA-LP Vaccine for Glioblastoma treatment?

Research shows that similar mRNA-based vaccines can trigger strong immune responses against tumors, as seen in studies where mRNA vaccines protected mice from melanoma and enhanced immune responses in glioblastoma patients. The use of DOTAP liposomes as an adjuvant has also been shown to boost immune responses in mice, suggesting potential effectiveness in cancer immunotherapy. ^{1 2 3 4 5}

Is the RNA-LP Vaccine for Glioblastoma safe for humans?

The RNA-LP vaccine has been shown to be safe in both animal studies and an early human trial for glioblastoma, with no significant safety concerns reported. ^{1 4 6 7 8}

What makes the RNA-LP Vaccine for Glioblastoma unique compared to other treatments?

The RNA-LP Vaccine for Glioblastoma is unique because it uses a novel delivery system that enhances the immune response by forming 'onion-like' multi-lamellar RNA-lipid particle aggregates, which mimic infectious particles and activate immune cells to target the tumor. This approach differs from traditional mRNA vaccines by stimulating specific intracellular receptors and reprogramming the tumor environment to boost therapeutic T cell activity. ^{1 2 9 10 11}

Research Team

Elias Sayour, MD, PhD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for adults over 21 with newly diagnosed GBM (a type of brain tumor) that hasn't spread, and whose tumors are not responsive to certain DNA repair mechanisms (MGMT unmethylated). Participants must be in good health post-surgery, have adequate organ function, and agree to use contraception. Those with prior treatments for head/neck cancer or other invasive malignancies within the last 3 years, active infections or immune diseases, severe medical conditions, or who are pregnant/breastfeeding cannot join.

Inclusion Criteria

I have given or my legal representative has given consent for me to participate.

For women of childbearing potential (WOCBP), negative serum/urine pregnancy test at enrollment (test will be repeated within 72 hours prior to starting TMZ in Stratum 1 patients)

WOCBP must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug

Exclusion Criteria

Known HIV, Hepatitis B, or Hepatitis C seropositive

My cancer has spread to the brain or beyond.

My cancer has spread to other parts of my body or the lining of my brain and spinal cord.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Surgery

Surgical resection for collection of tumor material for RNA extraction

1 week

1 visit (in-person)

Radiation

Standard of care radiation therapy following surgery

4 weeks

Multiple visits (in-person)

Immunotherapy

Participants receive RNA-LP vaccines, starting with 3 vaccines every 2 weeks, followed by 12 monthly vaccines

14 months

15 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 30 months

Every 3 months for the first year, then every 6-12 months

Treatment Details

Interventions

• Autologous total tumor mRNA and pp65 full length (fl) lysosomal associated membrane protein (LAMP) mRNA loaded DOTAP liposome vaccine

Trial Overview The study tests RNA-LP vaccines made from a patient's own tumor mRNA against GBM. It aims to find the highest dose patients can tolerate without serious side effects (MTD), ensure it's safe to make and give these vaccines intravenously. The vaccine is designed to teach the body’s immune system to recognize and attack the tumor.

Participant Groups

Group I: Phase I pediatric (Stratum 2) Experimental Treatment 1 Intervention

A maximum of 24 adult patients will be enrolled in dose-escalation study using 3+3 study design.

Group II: Phase I adult (Stratum 1) Experimental Treatment 1 Intervention

A maximum of 28 adult patients will be enrolled in dose-escalation study using the BOIN design with an initial embedded accelerated titration design (ATD).

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Team Jack Foundation

Collaborator

Trials

2

Recruited

100+

Florida Department of Health

Collaborator

Trials

30

Recruited

13,000+

University of California, San Francisco

Collaborator

Trials

2,636

Recruited

19,080,000+

CureSearch

Collaborator

Trials

3

Recruited

130+

Pacific Pediatric Neuro-Oncology Consortium

Collaborator

Trials

16

Recruited

840+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

Findings from Research

A new method using lipid-particle delivery systems to enhance the immunogenicity of tumor-derived mRNA has shown promise in mobilizing immune cells and rejecting tumors in murine models, indicating its potential for cancer immunotherapy.

In a first-in-human trial for glioblastoma patients, RNA-LPAs successfully induced pro-inflammatory responses and expanded T cell immunity, suggesting they could be effective in treating poorly immunogenic tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mRNA aggregates harness danger response for potent cancer immunotherapy. Mendez-Gomez, HR., DeVries, A., Castillo, P., et al.[2023]

The novel α-GC-LPR vaccine delivery system effectively protects mRNA and enhances dendritic cell maturation, leading to improved immune responses in tumor immunotherapy.

In combination with PD-1 inhibitors, α-GC-LPR significantly activates natural killer and T cells, reducing immune suppression and promoting strong antigen-specific immunity in a breast cancer model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of a cationic complexes loaded with mRNA and α-Galactose ceramide enhances antitumor immunity and affects the tumor immune microenvironment. Guo, J., Ma, S., Mai, Y., et al.[2023]

Fusogenic liposomes (FLs) effectively deliver tumor cell-lysate (TCL) for both ex vivo dendritic cell-based vaccination and in vivo direct immunization, showing promise in targeting a broader range of tumor-associated antigens (TAAs).

In a murine model of melanoma, ex vivo dendritic cell-mediated vaccination demonstrated a more potent anti-tumor effect compared to direct immunization, indicating that this method may enhance the efficacy of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccine efficacy of fusogenic liposomes containing tumor cell-lysate against murine B16BL6 melanoma. Yoshikawa, T., Okada, N., Tsujino, M., et al.[2019]

The cationic liposome DOTAP effectively enhances immune responses when used as an adjuvant in mice, particularly with the carcinoembryonic antigen (bV-CEA), showing significant differences in antibody production and T-cell responses based on the route of administration.

Subcutaneous (s.c.) immunization with 25 microg of bV-CEA/DOTAP resulted in higher antibody titers and protective immunity against tumor cells, suggesting DOTAP's potential as a valuable immunoadjuvant for anti-tumor therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of a cationic liposome formulation (DOTAP) mixed with a recombinant tumor-associated antigen to induce immune responses and protective immunity in mice. Bei, R., Guptill, V., Masuelli, L., et al.[2021]

Mice immunized with a novel mRNA vaccine formulation targeting the MART1 tumor antigen showed significant protection against aggressive B16F10 melanoma, indicating its potential efficacy as a cancer vaccine.

The vaccine induced a strong immune response, including the production of interferon-gamma and activation of cytotoxic T lymphocytes, suggesting a robust mechanism of action for combating tumor growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes. Mockey, M., Bourseau, E., Chandrashekhar, V., et al.[2013]

Cellular vaccines for gliomas, including those using engineered T cells and autologous dendritic cells, have shown safety and feasibility in clinical trials, indicating they could be a promising approach for treating aggressive brain tumors like glioblastomas.

While these therapies have demonstrated some immune response activation, their overall therapeutic effects have been limited, highlighting the need for larger studies and improved guidelines to enhance their effectiveness in glioma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical implication of cellular vaccine in glioma: current advances and future prospects. Yan, Y., Zeng, S., Gong, Z., et al.[2021]

The LS1 vaccine, made from aberrant gangliosides linked to a protein, was found to be safe with no side effects observed in experimental animals, indicating its potential for further development.

Given the promising safety profile, the LS1 vaccine is recommended for clinical testing in patients with malignant gliomas to evaluate its efficacy in treating this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conjugates of aberrant gangliosides in antiglioma vaccine: toxicological assay. Lombardi, V., Shnaar, R., Minev, B., et al.[2019]

The IMA950 multipeptide vaccine, combined with the adjuvant poly-ICLC, was found to be safe and well tolerated in a study involving 19 glioma patients, with only four cases of temporary cerebral edema.

The vaccine successfully elicited CD8 T-cell responses in 63.2% of patients, with median overall survival for glioblastoma patients reaching 19 months, indicating promising immunogenicity and potential effectiveness in treating glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Migliorini, D., Dutoit, V., Allard, M., et al.[2020]

Patients with advanced non-small-cell lung cancer (NSCLC) receiving the BLP25 liposome vaccine (L-BLP25) showed a median survival time that was 4.4 months longer compared to those receiving best supportive care alone, although this difference was not statistically significant.

The L-BLP25 treatment was associated with minimal toxicity and maintained health-related quality of life longer than best supportive care, suggesting it is a feasible option for patients with stage IIIB and IV NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. Butts, C., Murray, N., Maksymiuk, A., et al.[2021]

A prototype glioma cancer vaccine using a mix of antigens from both patient and donor tumor tissues showed promise in stopping tumor growth in a rat model of malignant glioma.

The vaccine was particularly effective when combined with immunostimulants like Bacille Calmette Guerin (BCG) and interleukin-2, or the TLR 7/8 activator resiquimod, indicating that these combinations enhance the immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the Therapeutic Efficacy of Glioma Vaccines Based on Allo- and Syngeneic Antigens and Distinct Immunological Costimulation Activators. Stathopoulos, A., Pretto, C., Devillers, L., et al.[2021]

The Mannose-PEG1000-lipoplex (MP1000-LPX) mRNA vaccine showed significant accumulation in the liver, lung, and spleen after intravenous injection, but it only successfully expressed luciferase in the lung, indicating a targeted delivery issue.

Serum presence dramatically decreased the transfection efficacy of MP1000-LPX in DC2.4 cells, suggesting that while serum enhances cellular uptake, it hinders the mRNA's ability to effectively transfect cells, highlighting the need for strategies to improve serum resistance in cationic liposome-based mRNA vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Fate of MP1000-LPX In Vivo by Adding Serum to Transfection Medium. He, S., Xia, S., Song, X., et al.[2021]

References

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

mRNA aggregates harness danger response for potent cancer immunotherapy. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Combination of a cationic complexes loaded with mRNA and α-Galactose ceramide enhances antitumor immunity and affects the tumor immune microenvironment. [2023]

3. Japan pubmed.ncbi.nlm.nih.gov

Vaccine efficacy of fusogenic liposomes containing tumor cell-lysate against murine B16BL6 melanoma. [2019]

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

The use of a cationic liposome formulation (DOTAP) mixed with a recombinant tumor-associated antigen to induce immune responses and protective immunity in mice. [2021]

5. England pubmed.ncbi.nlm.nih.gov

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Clinical implication of cellular vaccine in glioma: current advances and future prospects. [2021]

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

Conjugates of aberrant gangliosides in antiglioma vaccine: toxicological assay. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. [2020]

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

Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. [2021]

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

Exploring the Therapeutic Efficacy of Glioma Vaccines Based on Allo- and Syngeneic Antigens and Distinct Immunological Costimulation Activators. [2021]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Investigating the Fate of MP1000-LPX In Vivo by Adding Serum to Transfection Medium. [2021]