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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treat certain brain tumors called oligodendrogliomas that have returned or are not responding to other treatments. Researchers aim to determine if a combination of cellular therapy (a treatment using the body's own cells) and IDH1/2 inhibitors is safe and feasible. Participants will receive several injections of a special vaccine, specifically TTRNA-DC vaccines with GM-CSF, along with infusions of modified T cells (a type of immune cell) to target the tumor. Individuals with a confirmed diagnosis of certain types of oligodendroglioma who are more than 12 weeks past their radiation treatment may be suitable for this trial. 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 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.

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

Research has shown that adoptive cellular therapy, including treatments like TTRNA-DC vaccines and TTRNA-xALT, is under evaluation for safety in treating brain tumors. Early results suggest these treatments are generally well-tolerated. Specifically, the PEACH trial, which examines TTRNA-xALT, reported manageable side effects for participants.

While detailed information on side effects is still being gathered, the early-phase trials primarily focus on safety. Researchers closely monitor any side effects participants might experience.

Adoptive cellular therapy harnesses the body's immune system to attack cancer cells, potentially leading to fewer severe side effects compared to traditional cancer treatments. However, further studies are necessary to confirm these findings and fully understand the safety of these therapies. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer a new approach to tackling brain tumors. Unlike standard treatments such as surgery, radiation, or chemotherapy, these therapies use the body's immune system to fight cancer. The TTRNA-DC vaccines combined with GM-CSF and the TTRNA-xALT treatment harness tumor-reactive T cells that are expanded outside the body and then infused back to target cancer cells directly. This innovative method aims to improve the precision and effectiveness of treatment, potentially leading to better outcomes and fewer side effects.

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

Research has shown that TTRNA-xALT, a type of cell therapy studied in this trial, may help treat brain tumors. This therapy uses special cells to trigger a strong immune response, activating certain immune cells to attack and destroy brain tumor cells in lab tests. Early results from other studies suggest that this method can increase the number of immune cells targeting tumors, potentially benefiting brain cancer patients.

Additionally, TTRNA-DC vaccines combined with GM-CSF, another treatment option in this trial, have shown promise. These vaccines are designed to help the immune system recognize and attack tumor cells. Recent trials demonstrated that these vaccines can work together to boost the immune response against glioma, a type of brain cancer. Although still in early stages, these findings offer hope for treating brain tumors with these new therapies. ^{4 6 7 8 9}

Who Is on the Research Team?

Ashley Ghiaseddin, MD

Principal Investigator

University of Florida

Duane Mitchell, MD, PhD

Principal Investigator

University of Florida

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8592940/

Dendritic Cell Vaccination of Glioblastoma: Road to Success ... Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies ...

2. oaepublish.com oaepublish.com/articles/2347-8659.2018.44

Total tumor RNA pulsed dendritic cells plus adoptive ... Our lab has expertise in the development of ex vivo “educated” adoptive T-cell transfer along with total tumor RNA (ttRNA) DC vaccines for the treatment of ...

3. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/total-tumor-rna-loaded-dendritic-cell-vaccine?pn=1

Clinical Trials Using Total Tumor RNA-loaded Dendritic ... Review the clinical trials studying total tumor rna-loaded dendritic cell vaccine on this list and use the filters to refine the results by age and location ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1471491424001679

Vaccine-based immunotherapy and related preclinical ... This review discusses tumor vaccines against glioma, preclinical models in immunological research, and the role of CD4 + T cells in vaccine-induced antitumor ...

5. cell.com cell.com/cms/10.1016/j.ymthe.2018.10.007/attachment/1434cacd-52ab-4516-aba1-d07264886a1c/mmc2.pdf

RNA-Modified T Cells Mediate Effective Delivery of ... With the presence of the blood-brain barrier (BBB), successful immunotherapeutic drug delivery to CNS malignancies re- mains a challenge.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12418593/

Translational advancements in tumor vaccine therapies for ... Tumor vaccines aim to harness and stimulate the intrinsic immune response by activating effector immune cells to recognize and infiltrate tumors ...

7. withpower.com withpower.com/trial/phase-1-glioma-8-2021-fb81e

Adoptive Cellular Therapy for Brain Cancer (PEACH Trial) The PEACH medical study, being run by Giselle SaulnierSholler, needs participants to evaluate whether TTRNA-xALT will have tolerable side effects & efficacy ...

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03688178/

Clinical Trial: NCT03688178 The study cycle of TMZ comprises a targeted dose of 150-200mg/m2/day for 5 days every 4 (+2) weeks for up to 12 cycles (patients with ...

9. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-02444

Adoptive Cell Therapy (TTRNA-xALT), Dendritic ... This phase I trial tests the safety, side effects, and effectiveness of adoptive cell therapy (ACT) with total tumor messenger ribonucleic acid (mRNA)-pulsed ...