Adoptive Cellular Therapy for Brain Cancer

(PEACH Trial)

Recruiting at 2 trial locations

Overseen By Sharon McKee

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Giselle SaulnierSholler

Must not be taking: Investigational drugs

Disqualifiers: Autoimmune, Immunosuppressive, Organ dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

24 Participants Needed

Trial Summary

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, if you are taking steroids for CNS disease, you must be on a stable dose for at least one week before the biopsy.

What data supports the effectiveness of the treatment TTRNA-xALT for brain cancer?

Research shows that using tumor RNA-pulsed dendritic cells (DCs) can expand tumor-reactive T cells, which are effective in treating brain tumors in animal models. Additionally, these DCs have been shown to generate strong immune responses against tumors, suggesting potential effectiveness in treating brain cancer. ^{1 2 3 4 5}

Is adoptive cellular therapy for brain cancer safe for humans?

Research shows that adoptive cellular therapy, including methods using dendritic cells pulsed with tumor RNA, has been generally safe in clinical trials for various cancers, including brain tumors. A phase 1 study in children with brain cancer found the treatment to be safe and feasible, with no major safety concerns reported. ^{1 2 4 6 7}

How is the treatment TTRNA-xALT different from other treatments for brain cancer?

TTRNA-xALT is unique because it uses a patient's own immune cells, specifically dendritic cells and T cells, that are modified outside the body to recognize and attack brain cancer cells. This approach is different from traditional treatments as it involves a personalized immune response, potentially offering a more targeted and effective treatment for brain tumors. ^{1 3 4 8 9}

What is the purpose of this trial?

A Phase I open-label, multicenter study, to evaluate the safety, feasibility, and maximum tolerated dose (MTD) of treating children with newly diagnosed DIPG or recurrent neuroblastoma with molecular targeted therapy in combination with adoptive cell therapy (Total tumor mRNA-pulsed autologous Dendritic Cells (DCs) (TTRNA-DCs), Tumor-specific ex vivo expanded autologous lymphocyte transfer (TTRNA-xALT) and Autologous G-CSF mobilized Hematopoietic Stem Cells (HSCs)).

Research Team

Giselle Sholler, MD

Principal Investigator

Beat Childhood Cancer at Atrium Health

Duane Mitchell, M.D., Ph.D.

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for children with specific pediatric cancers like high-risk neuroblastoma or brain stem gliomas, who have no known effective curative therapy available. Participants must be aged ≤ 30 years, have a certain level of physical functioning (Lansky/Karnofsky Score ≥ 60), and agree to use effective birth control. They should not have significant organ dysfunction or other serious medical conditions that could affect the study.

Inclusion Criteria

Informed Consent: All subjects and/or legal guardians must sign informed written consent

I am over 12 months old with neuroblastoma.

Women who could become pregnant need to have a negative pregnancy test.

Exclusion Criteria

My biopsy did not show cancer or showed a type other than neuroblastoma or glioma.

Subjects with any other medical condition deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a subject's ability to sign or the legal guardian's ability to sign the informed consent, and subject's ability to cooperate and participate in the study

Subjects receiving any investigational drug concurrently

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive molecular targeted therapy in combination with adoptive cell therapy, including TTRNA-DCs, TTRNA-xALT, and autologous G-CSF mobilized HSCs

2 years

Follow-up

Participants are monitored for safety, effectiveness, and overall survival after treatment

7 years

Dose Escalation

A standard 3+3 dose escalation design to establish the maximum tolerated dose (MTD) with three pre-specified dose levels of xALT

Treatment Details

Interventions

• TTRNA-xALT

Trial Overview The PEACH TRIAL tests a combination of molecular targeted therapy with adoptive cell therapy in children with newly diagnosed DIPG or recurrent neuroblastoma. It aims to find the safest dose for treatments involving autologous dendritic cells, lymphocyte transfer, and hematopoietic stem cells.

Participant Groups

Group I: Arm 2: Relapsed/Refractory Neuroblastoma (NB) Experimental Treatment 1 Intervention

This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT: Dose Level 1: 3 x10\^7 cells/kg Dose Level +1: 3 x10\^8 cells/kg Dose Level -1: 3 x10\^6 cells/kg The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects).

Group II: Arm 1: Subjects with Diffuse Intrinsic Pontine Glioma (DIPG). Experimental Treatment 1 Intervention

This Phase I study is will utilize a standard 3+3 dose escalation design to establish the MTD and will evaluate the following three pre-specified dose levels of xALT: Dose Level 1: 3 x10\^7 cells/kg Dose Level +1: 3 x10\^8 cells/kg Dose Level -1: 3 x10\^6 cells/kg The dose escalation scheme will be evaluated for Arm 1 and Arm 2 separately. For each Study Arm, a minimum of 4 DLT evaluable subjects and a maximum of 12 DLT evaluable subjects will be enrolled (a total of 8 to 24 DLT evaluable subjects).

Who Is Running the Clinical Trial?

Giselle SaulnierSholler

Lead Sponsor

Trials

22

Recruited

2,400+

Giselle Sholler

Lead Sponsor

Trials

23

Recruited

2,500+

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Beat Childhood Cancer Research Consortium

Collaborator

Trials

1

Recruited

20+

Findings from Research

Adoptive cellular therapy (ACT) using tumor RNA-pulsed dendritic cells successfully expanded tumor-reactive T lymphocytes, leading to effective treatment in a model of malignant glioma, which is typically resistant to conventional therapies.

Hematopoietic stem cells (HSCs) not only supported recovery from myeloablative conditioning but also enhanced the immune response against tumors, suggesting a new role for HSCs in improving outcomes for patients with solid tumors like gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas. Flores, C., Pham, C., Snyder, D., et al.[2021]

The study evaluated a novel cancer vaccine using autologous dendritic cells (DCs) transfected with patient-specific tumor mRNA, aiming to present a wide range of unique tumor antigens for each individual, which could enhance the vaccine's effectiveness.

In vitro tests showed that the transfected DCs successfully generated specific T-cell responses in all six patients tested, indicating the potential for this personalized approach to stimulate the immune system against malignant melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Kyte, JA., Kvalheim, G., Aamdal, S., 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]

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 study developed RNA-nanoparticles (NPs) using the cationic lipid DOTAP, which effectively deliver tumor-derived RNA to antigen-presenting cells (APCs), leading to systemic activation of the immune response.

RNA-NPs significantly enhance the expression of key activation markers on APCs and induce a stronger expansion of antigen-specific T-cells compared to traditional peptide vaccines, demonstrating their potential as a more effective immunotherapy for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Sayour, EJ., De Leon, G., Pham, C., 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 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]

Using RNA derived from small tumor cells to generate cytotoxic T lymphocytes (CTLs) is a promising method, as it allows for the creation of effective antigen-presenting cells (APCs) without needing large amounts of tumor cells.

The study demonstrated that amplified tumor RNA can be successfully introduced into dendritic cells and EBV-transformed B cells, leading to the generation of polyclonal polyspecific CTLs, which could enhance the effectiveness of cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tumor RNA introduction into dendritic cells and Epstein-Barr virus transformed B cells]. Minami, K., Yamaguchi, Y., Ohshita, A., et al.[2006]

The study developed an adoptive cellular therapy using dendritic cells loaded with tumor RNA to stimulate T cells that target multiple antigens in brain tumors like medulloblastoma and glioblastoma.

In both preclinical models and a patient case, successful therapy was marked by a significant expansion and long-term presence of tumor-specific T cells in the blood, indicating a strong immune response to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Massive clonal expansion of medulloblastoma-specific T cells during adoptive cellular therapy. Flores, C., Wildes, T., Dean, BD., et al.[2023]

References

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

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas. [2021]

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

Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. [2020]

3. China pubmed.ncbi.nlm.nih.gov

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

4. 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]

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

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. [2021]

6. 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]

7. Switzerland pubmed.ncbi.nlm.nih.gov

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

8. Japan pubmed.ncbi.nlm.nih.gov

[Tumor RNA introduction into dendritic cells and Epstein-Barr virus transformed B cells]. [2006]

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

Massive clonal expansion of medulloblastoma-specific T cells during adoptive cellular therapy. [2023]