EBV-specific CTLs for Neuroblastoma

(NESTLES Trial)

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: EBV-specific CTLs

Must not be taking: Investigational agents

Disqualifiers: Pregnancy, Cardiomegaly, Hypersensitivity, others

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

Compensation: Varies

Number of Visits: 1

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating high-risk neuroblastoma, a type of cancer often found in children. It combines two methods: antibodies (proteins that help fight infections) and T cells (blood cells that can destroy tumor cells). The trial tests a modified antibody, 14g2a, attached to T cells to help them remain in the body longer and target cancer cells more effectively. One treatment being tested is EBV-specific CTLs (cytotoxic T lymphocytes), designed to target and destroy cancer cells. Participants include those whose neuroblastoma has worsened despite previous treatments and who have enough of these special immune cells available for another dose. 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 new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be receiving any investigational agents or have received any tumor vaccines within the previous 6 weeks.

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

Research shows that the treatments tested in this study have shown promise in earlier research. EBV-specific cytotoxic T lymphocytes (CTLs), a type of immune cell, have been safely and effectively used in other studies. Patients have tolerated these cells well, with no major safety concerns reported.

For GD2-specific chimeric T cell receptors, studies have found these cells to be generally safe for patients. They target a substance on neuroblastoma cells called GD2, aiding in cancer treatment. In past studies, GD2-targeting CAR-T cells were well-tolerated and did not cause severe side effects.

Overall, both EBV-specific CTLs and GD2-specific T cells have demonstrated positive safety results in research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for neuroblastoma involve chemotherapy, radiation, and surgery. But EBV-specific CTLs offer a different approach by harnessing the body's immune system to attack cancer cells. This treatment uses genetically modified T-cells, specifically engineered to target Epstein-Barr virus (EBV) antigens and GD-2, a molecule found on neuroblastoma cells. Researchers are excited about this approach because it taps into the power of precision immunotherapy, potentially leading to more effective and targeted cancer elimination with fewer side effects compared to traditional methods.

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

Research has shown that a specific type of immune cell, called EBV-specific CTLs, can help treat certain cancers by targeting and killing tumor cells. Studies have found that these cells can be safely administered to patients and might offer a promising way to attack tumors. In this trial, participants will receive escalating doses of 14g2a.zeta chimeric receptor transduced autologous EBV-specific cytotoxic T-lymphocytes (EBV-CTL) and 14g2a.zeta transduced autologous peripheral blood T-cells. The 14g2a antibody attaches to neuroblastoma cells, making it easier for the immune cells to locate and destroy them. By combining the 14g2a antibody with EBV-specific CTLs, researchers aim for these cells to remain active in the body longer and be more effective at killing cancer cells. Early results suggest that this method could enhance the fight against neuroblastoma by maintaining a strong immune response over time. ^{1 2 3 4 6}

Who Is on the Research Team?

Andras A Heczey, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for children with high-risk neuroblastoma who have relapsed or persistent disease after initial therapy. They must not require oxygen (>90% on room air), expect to live at least 12 weeks, and recovered from previous chemotherapy effects. No investigational agents or tumor vaccines should have been received in the last 6 weeks. Participants need normal blood counts, liver and kidney function, no severe heart/lung issues, a decent performance score (Karnofsky/Lansky >60%), and specific immune cells from a prior study.

Inclusion Criteria

My neuroblastoma is high risk and has either come back or didn't fully respond to initial treatment.

Patients must have AST less than 5 times the upper limit of normal

Patient may not have an oxygen requirement as defined by pulse oximetry of > 90% on room air

Exclusion Criteria

Patients not meeting eligibility criteria

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive escalating doses of 14g2a.zeta chimeric receptor transduced autologous EBV specific cytotoxic T-lymphocytes and 14g2a.zeta transduced autologous peripheral blood T-cells

6 weeks

Weekly visits for infusions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including long-term monitoring for gene transfer side effects

15 years

Regular visits, frequency decreasing over time

Optional Additional Dose

Participants may receive an additional dose of cells if desired due to neuroblastoma recurrence

What Are the Treatments Tested in This Trial?

Interventions

• EBV Specific CTLs
• GD-2 Specific Chimeric T Cell Receptors

Trial Overview The trial tests modified immune cells (CTLs) that are trained to fight both neuroblastoma cancer cells and EBV virus by using an antibody called 14g2a attached to them. These 'chimeric receptor-T cells' aim to last longer in the body and effectively target cancer cells. Patients may receive an additional dose of these CTLs if their cancer has returned.

How Is the Trial Designed?

Group I: EBV specific CTLs w/out lymphodepletion Experimental Treatment 1 Intervention

Escalating doses of 14g2a.zeta chimeric receptor transduced autologous EBV specific cytotoxic T-lymphocytes (EBV-CTL) and 14g2a.zeta transduced autologous peripheral blood T-cells administered to patients with Neuroblastoma.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Published Research Related to This Trial

In a study involving 19 patients with high-risk neuroblastoma, GD2 chimeric antigen receptor (CAR) T cells were able to induce complete remission in 3 out of 11 patients with active disease, demonstrating their efficacy in treating this aggressive cancer.

The persistence of CAR T cells in the patients was linked to better clinical outcomes, with some CAR-ATCs lasting up to 192 weeks, suggesting that longer-lasting CAR T cells may contribute to improved survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Louis, CU., Savoldo, B., Dotti, G., et al.[2023]

A 3rd generation CAR T-cell construct targeting GD2 showed improved anti-tumor efficacy in neuroblastoma compared to other constructs, highlighting the importance of the 4-1BB costimulatory domain in enhancing T-cell characteristics like persistence and tumor control.

The inclusion of an inducible safety switch (iC9) in the CAR construct allows for the controlled elimination of CAR T cells if necessary, without compromising their anti-tumor activity, making it a safer option for treating pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. Quintarelli, C., Orlando, D., Boffa, I., et al.[2021]

Despite the integration of anti-GD2 monoclonal antibody therapy, the 5-year overall survival rate for high-risk neuroblastoma patients remains around 50%, highlighting the need for improved treatment options.

CAR T cell therapy has shown promise in early clinical trials for neuroblastoma, demonstrating safety and feasibility, but challenges such as T cell persistence and an immunosuppressive tumor environment need to be addressed to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. Richards, RM., Sotillo, E., Majzner, RG.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC1988944/

Epstein Barr virus–specific cytotoxic T lymphocytes expressing ... EBV-CTLs can express the CD30CAR while retaining their phenotype and native receptor function. The transduction efficiency of CD30CAR was 26% (± 11%; Figure 1A) ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT00085930

NCT00085930 | Blood T-Cells and EBV Specific CTLs ... Both antibodies and T cells have been used to treat patients with cancers and while they have shown promise, they have not been strong enough to cure most ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3234664/

Antitumor activity and long-term fate of chimeric antigen ... Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1465324923000993

Epstein‒Barr virus–associated cellular immunotherapy Currently, many clinical studies have demonstrated that EBV-specific cytotoxic T lymphocytes and other cell therapies can be safely and effectively transfused ...

5. ashpublications.org ashpublications.org/blood/article/110/4/1123/23130/Allogeneic-cytotoxic-T-cell-therapy-for-EBV

Allogeneic cytotoxic T-cell therapy for EBV-positive ... Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for individual patients.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01430390

In Vitro Expanded Allogeneic Epstein-Barr Virus Specific ... The purpose of this study is to test the safety of giving the patient special cells from a donor called "Modified T-cells".