Cellular Therapy for Brain Tumors

(ADAGiO Trial)

Overseen By Phuong Deleyrolle, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Florida

Must not be taking: Corticosteroids, Immunosuppressants, others

Disqualifiers: HIV, Hepatitis B, Hepatitis C, others

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

Compensation: Varies

Number of Visits: 10

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will enroll 6 DLT evaluable subjects (up to 12 patients total) where we will evaluate feasibility and safety of adoptive cellular therapy combined with IDH1/2 inhibitors in patients with recurrent or progressive oligodendroglioma WHO grade 2 and WHO grade 3.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on corticosteroids equivalent to 4mg or more of dexamethasone daily or if you have taken another investigational drug within 30 days before the study treatment.

What data supports the effectiveness of the treatment Cellular Therapy for Brain Tumors?

Research shows that using dendritic cells (a type of immune cell) pulsed with tumor RNA can stimulate the body's immune response against tumors. In a study with children having brain tumors, this approach was safe and led to stable disease in some patients. Additionally, using mRNA-transfected dendritic cells has shown promise in generating strong immune responses in cancer patients, suggesting potential effectiveness for brain tumors. ^{1 2 3 4 5}

Is cellular therapy for brain tumors generally safe in humans?

Research shows that dendritic cell-based vaccines, including those using tumor RNA, have been proven safe in clinical trials for various cancers, including brain tumors, with no significant short or long-term side effects reported. ^{1 2 3 5 6}

How is the TTRNA-DC vaccine treatment for brain tumors different from other treatments?

The TTRNA-DC vaccine treatment is unique because it uses a patient's own dendritic cells (a type of immune cell) that are 'pulsed' with RNA from the patient's tumor to create a personalized vaccine. This approach aims to stimulate the immune system to specifically target and attack the tumor, which is different from traditional treatments that may not be as targeted. ^{1 2 3 7 8}

Research Team

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Duane Mitchell, MD, PhD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for adults with a type of brain tumor called oligodendroglioma that has come back or gotten worse. They must be able to undergo certain medical procedures and treatments.

Inclusion Criteria

Adequate bone marrow and organ function: ANC ≥ 1,000/mcL, Platelets ≥ 100,000/mcL, Hemoglobin ≥ 9 g/dL (can be transfused), Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN, Serum total bilirubin ≤ 1.5 x IULN OR Direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN, AST (SGOT) and ALT (SGPT) ≤ 3 x IULN, Negative serum pregnancy test at enrollment for females of childbearing potential, Willingness to use acceptable contraceptive methods for women and men of childbearing potential

I am eligible for surgery or a biopsy.

My tumor tissue is available for screening.

Exclusion Criteria

I am taking a steroid dose equal to or more than 4mg of dexamethasone daily.

My cancer is present in multiple locations.

Pregnancy or lactation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Surgery and Biopsy

Subjects undergo standard of care resection or biopsy for confirmatory diagnosis and collection of tumor material for DNA and RNA extraction

1-2 weeks

1 visit (in-person)

Chemotherapy and Vaccine Priming

Patients initiate salvage chemotherapy with IDH1/2 inhibitor and receive 3 priming TTRNA-DCs vaccines every 2 weeks

6-8 weeks

3 visits (in-person)

T Cell Expansion and Vaccination

Patients undergo non-mobilized leukapheresis for T cell expansion and receive monthly TTRNA-DC vaccines for 2-3 cycles

2-3 months

2-3 visits (in-person)

Adoptive Cellular Therapy

Patients receive a single i.v. infusion of ex vivo expanded tumor-reactive T cells and autologous HSCs

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose-limiting toxicity

6 weeks

2 visits (in-person)

Treatment Details

Interventions

• Autologous Hematopoietic Stem cells (HSCs)
• TTRNA-DC vaccines with GM-CSF
• TTRNA-xALT

Trial Overview The study tests adoptive cellular therapy, which includes TTRNA-DC vaccines with GM-CSF, autologous hematopoietic stem cells (HSCs), TTRNA-xALT, and the Td vaccine to see if they are safe and workable for these patients.

Participant Groups

Group I: Adoptive Cellular Therapy Experimental Treatment 4 Interventions

All participants will receive 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment), a single i.v. infusion of ex vivo expanded tumor-reactive T cells, and a i.v. single infusion of autologous HSCs.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Oligo Nation, Inc

Collaborator

Trials

1

Recruited

10+

Findings from Research

A new method using total tumor RNA to prime dendritic cells for generating anti-tumor T cells shows promise in creating effective treatments for cancers, including brain tumors.

The study found that using a specific cytokine cocktail, rather than IL-2, enhanced the generation of T cells with high CD62L levels, which are better at recognizing and attacking tumor cells, leading to improved anti-tumor efficacy in mouse models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. Yang, S., Archer, GE., Flores, CE., et al.[2021]

The phase 1 study involving 9 pediatric patients demonstrated that the DCRNA vaccine, made from monocyte-derived dendritic cells pulsed with tumor RNA, is both safe and feasible for treating recurrent brain tumors.

After receiving the DCRNA vaccine, 2 out of 7 patients showed stable disease, and 1 patient had a partial response, indicating potential effectiveness in eliciting tumor-specific immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Caruso, DA., Orme, LM., Neale, AM., et al.[2020]

Dendritic cells (DC) transfected with tumor RNA can effectively serve as a cancer vaccine, showing significant cytotoxic activity against regrowing tumors in mice, especially when co-transfected with GM-CSF mRNA.

The combination of DC transfected with recrudescent tumor RNA and GM-CSF mRNA not only enhances the immune response but also effectively suppresses the growth of tumors that have returned after previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA. Naka, T., Iwahashi, M., Nakamura, M., et al.[2017]

Loading dendritic cells (DCs) with mRNA-encoded tumor antigens is a simple and effective method that enhances their ability to activate T cells, leading to strong antitumor immunity, as shown in clinical trials for urological cancers.

In two phase I clinical trials, most patients with prostate and renal cancers who received mRNA-transfected DC vaccinations demonstrated a T-cell response, indicating that this approach could be a promising strategy for developing effective cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer immunotherapy with mRNA-transfected dendritic cells. Gilboa, E., Vieweg, J.[2022]

The study outlines a method for preparing dendritic cell-based vaccines by delivering synthetic FOXP3 mRNA into human dendritic cells, which is crucial for generating mature dendritic cells that can stimulate specific immune responses against cancer.

This approach successfully generated FOXP3-specific cytotoxic T lymphocytes, which demonstrated the ability to target and kill inflammatory breast cancer cells, highlighting the potential efficacy of this vaccine strategy in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of Synthetic mRNA Encoding FOXP3 Antigen into Dendritic Cells for Inflammatory Breast Cancer Immunotherapy. Devi, GR., Nath, S.[2018]

Dendritic cell (DC) vaccination has been proven safe in clinical trials involving 781 patients with various cancers and HIV, showing no significant short or long-term side effects.

Using mRNA to load DCs with tumor antigens enhances their ability to stimulate the immune system, and this method allows for targeted treatment across a wide range of tumor types, including melanoma and pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells-An Update. Dörrie, J., Schaft, N., Schuler, G., et al.[2020]

Dendritic cells (DC) derived from human UC blood CD34+ cells, when transfected with influenza virus matrix protein M1 mRNA, effectively stimulated antigen-specific cytotoxic T lymphocyte (CTL) responses, demonstrating their potential in tumor immunotherapy.

The study found that CTLs primed with M1 mRNA-transfected DC showed significant cytotoxic activity against autologous DC loaded with M1 mRNA, while showing minimal activity against unloaded DC, indicating the specificity and effectiveness of the immune response generated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Ag-specific cytotoxic T lymphocytes by DC transfected with in vitro transcribed influenza virus matrix protein (M1) mRNA. Osman, Y., Narita, M., Ayres, F., et al.[2015]

Dendritic cell (DC) vaccination using G422 glioblastoma RNA significantly increased the survival duration of mice with glioblastomas, indicating its potential as an effective anti-tumor treatment.

The treatment led to increased levels of the cytokine IFN-gamma and decreased levels of IL-10, suggesting an enhanced immune response against the tumor, along with evidence of tumor necrosis in treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dendritic cells pulsed with glioma RNA induce immunity against intracranial gliomas]. Yu, JB., Feng, ZX., Zhan, RY.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Tumor vaccine therapy against recrudescent tumor using dendritic cells simultaneously transfected with tumor RNA and granulocyte macrophage colony-stimulating factor RNA. [2017]

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

Cancer immunotherapy with mRNA-transfected dendritic cells. [2022]

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

Delivery of Synthetic mRNA Encoding FOXP3 Antigen into Dendritic Cells for Inflammatory Breast Cancer Immunotherapy. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Therapeutic Cancer Vaccination with Ex Vivo RNA-Transfected Dendritic Cells-An Update. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Generation of Ag-specific cytotoxic T lymphocytes by DC transfected with in vitro transcribed influenza virus matrix protein (M1) mRNA. [2015]

8. China pubmed.ncbi.nlm.nih.gov

[Dendritic cells pulsed with glioma RNA induce immunity against intracranial gliomas]. [2022]