CAR T-Cell Therapy for Neuroblastoma and Osteosarcoma

Overseen By Lauren Higgins

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Antiepileptics

Disqualifiers: Pregnancy, Breastfeeding, Active malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new cancer treatment that combines antibodies and T-cells to combat neuroblastoma and osteosarcoma. The goal is to determine if this combined approach can more effectively target and kill cancer cells. Participants with neuroblastoma or osteosarcoma that has not responded to other treatments or has recurred may be suitable candidates. The study aims to identify the safest dose of the treatment, with careful monitoring for any side effects. As a Phase 1 trial, this 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 information does not specify whether you need to stop taking your current medications. However, if you have a seizure disorder requiring antiepileptic drug therapy, you may not be eligible to participate.

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

A previous study showed that iC9.GD2.CAR.IL-15 T-cells target a specific protein called GD2, often found on cancer cells in neuroblastoma and osteosarcoma. Research indicates these cells offer a new way to treat these challenging cancers. Safety remains a primary focus for this treatment, with the study closely monitoring how well participants tolerate different doses.

The treatment includes a safety switch, called iCaspase9, to manage any serious side effects. This switch can deactivate the cells if needed, potentially enhancing safety. Evidence suggests the treatment is tested in small groups to determine the safest dose. Each group must complete a set period without major safety issues before the next group begins. This careful approach ensures the treatment remains as safe as possible for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional treatments for neuroblastoma and osteosarcoma, which often involve chemotherapy, radiation, or surgery, the iC9.GD2.CAR.IL-15 T-cell therapy offers a novel approach by utilizing genetically engineered T-cells. These T-cells are designed to specifically target and destroy cancer cells expressing the GD2 protein, which is commonly found on these tumors. Additionally, the inclusion of IL-15 enhances the persistence and effectiveness of the T-cells, potentially leading to a more sustained immune response. Researchers are excited about this therapy because it represents a shift towards personalized medicine that could offer more precise and potent cancer-fighting capabilities with potentially fewer side effects.

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

Research has shown that GD2 is an important target for treating neuroblastoma, a type of cancer. Studies have found that CAR T-cells targeting GD2 can be a promising treatment for difficult cases. In this trial, participants will receive iC9.GD2.CAR.IL-15 T-cells, which include Interleukin-15 (IL-15) to enhance the cells' ability to work together to fight tumors. This method combines the strengths of antibodies and T-cells to potentially improve results for patients with neuroblastoma or osteosarcoma. Early findings suggest that using IL-15 might boost these cells' ability to attack cancer. ^{1 2 3 5 6}

Who Is on the Research Team?

George Hucks, MD

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for people with specific cancers: relapsed/refractory neuroblastoma or osteosarcoma. Participants need a life expectancy of at least 12 weeks, have had previous aggressive treatment, and must not be pregnant or breastfeeding. They should not have hypersensitivity to the drugs used in the study or any other active malignancy requiring treatment.

Inclusion Criteria

I can do most activities but may need help.

My neuroblastoma has returned after completing initial intense treatment.

Written HIPAA authorization signed by legal guardian

Exclusion Criteria

I have another cancer that is growing and needs treatment.

Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)

You have had a bad reaction to cyclophosphamide or fludarabine in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion Chemotherapy

Participants undergo lymphodepletion chemotherapy prior to the cell infusion

1-2 weeks

Treatment

Participants receive iC9.GD2.CAR.IL-15 T cells in dose escalation cohorts

4 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

15 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• iC9.GD2.CAR.IL-15 T-cells

Trial Overview The trial tests a new therapy combining T cells (immune cells) and antibodies targeting GD2, a cancer cell marker, enhanced with IL-15 to boost effectiveness and an iCaspase9 safety switch. It's given after pre-treatment with Cyclophosphamide and Fludarabine to prepare the body.

How Is the Trial Designed?

Group I: iC9.GD2.CAR.IL-15 T-cells Experimental Treatment 3 Interventions

The continuous reassessment method (CRM) will be used to estimate the maximum-tolerated dose (MTD) of cells that to be given in dose escalation cohorts comprised of 2-6 subjects. The final MTD will be the dose with estimated probability of dose limiting toxicity (DLT) closest to the target toxicity rate of 20%. Three cell doses will be evaluated: 0.5 x 10\^6 cells/kg, 1.0 x 10\^6 cells/kg, 1.5 x 10\^6 cells/kg. Cohort enrollment will be staggered and each subject must complete at least 2 weeks of the cell treatment without incident of DLT before another subject can be enrolled at that dose level. A minimum of two subjects must complete the 4-week post-infusion DLT period before enrollment at the next higher dose level will be considered. If dose level 1 is determined to be above a tolerable dose, de-escalation would occur to dose level -1 where subjects would receive 0.25 x 10\^6 cells/kg.

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

Bellicum Pharmaceuticals

Industry Sponsor

Trials

28

Recruited

1,400+

University Cancer Research Fund at Lineberger Comprehensive Cancer Center

Collaborator

Trials

5

Recruited

150+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1 trial involving 12 children with neuroblastoma, GD2-CAR.15 NKTs were found to be safe, with no dose-limiting toxicities and only one case of mild cytokine release syndrome that was manageable with treatment.

The treatment showed an objective response rate of 25%, including one complete response, suggesting that GD2-CAR.15 NKTs can effectively target neuroblastoma, and their anti-tumor activity may be further improved by targeting the BTG1 protein.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Heczey, A., Xu, X., Courtney, AN., et al.[2023]

CAR T cells targeting the GD2 ganglioside show promising antitumor activity against neuroblastoma, but modifications to enhance their efficacy can lead to severe central nervous system (CNS) toxicity, including neuronal destruction.

The observed CNS toxicity highlights the risks of targeting antigens like GD2 that are also present in critical normal tissues, indicating a need for strategies to manage CAR T-cell activity in the brain to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model. Richman, SA., Nunez-Cruz, S., Moghimi, B., et al.[2021]

The newly developed CAR T cells targeting the GD2 molecule showed strong anti-tumor activity against neuroblastoma in both in vitro assays and a xenograft model, indicating their potential effectiveness in treating this type of cancer.

The anti-GD2 CAR T cells not only infiltrated tumors but also induced significant apoptosis in neuroblastoma cells, suggesting a robust mechanism of action that could lead to complete tumor growth inhibition, warranting further clinical testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. Prapa, M., Caldrer, S., Spano, C., et al.[2018]

A new GD2-targeting CAR T-cell therapy has been developed to improve treatment for neuroblastoma, a common childhood cancer, by enhancing T-cell persistence and efficacy.

This therapy specifically targets GD2, a molecule found in high levels on neuroblastoma tumors but mostly absent in healthy tissues, potentially increasing safety while effectively attacking cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Optimized GD2-Targeting Retroviral Cassette for More Potent and Safer Cellular Therapy of Neuroblastoma and Other Cancers. Thomas, S., Straathof, K., Himoudi, N., et al.[2019]

Engineered NK-92 cells expressing a chimeric antigen receptor (CAR) targeting GD2 showed strong and stable cytotoxicity against neuroblastoma cells, indicating their potential as effective cancer immunotherapy.

The addition of an IL-15 superagonist to these CAR NK cells not only enhanced their direct tumor-killing ability but also boosted the activity of surrounding immune cells, suggesting a promising strategy for improving cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-Expression of an IL-15 Superagonist Facilitates Self-Enrichment of GD2-Targeted CAR-NK Cells and Mediates Potent Cell Killing in the Absence of IL-2. Bodden, M., Häcker, A., Röder, J., 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]

IL15-activated NK cells showed significantly higher antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma cells compared to IL2-activated NK cells, indicating a more effective immune response.

In an animal model, using IL15 in combination with chemotherapy and an anti-GD2 antibody resulted in greater tumor regression than traditional treatments, suggesting that IL15 could enhance the effectiveness of immunotherapy for pediatric neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin-15 Enhances Anti-GD2 Antibody-Mediated Cytotoxicity in an Orthotopic PDX Model of Neuroblastoma. Nguyen, R., Moustaki, A., Norrie, JL., et al.[2023]

Murine GD2 CAR-T cells can cause severe neurotoxicity, which is influenced by the costimulatory domain used, highlighting the need for careful evaluation of CAR designs in preclinical models.

The newly developed SynNotch gated CAR-T, GD2-B7H3, shows improved efficacy and specificity against neuroblastoma in mouse models, benefiting from enhanced metabolic fitness and reduced exhaustion compared to traditional CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. Moghimi, B., Muthugounder, S., Jambon, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03721068

NCT03721068 | Study of CAR T-Cells Targeting the GD2 ... The IL-15 gene was added so that the GD2-CAR-T cells can attack tumor cells more effectively. Interleukin-15 (IL-15) is a chemical that cells use to communicate ...

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03721068/

Clinical Trial: NCT03721068 The primary purpose of this study is to determine whether receiving iC9.GD2.IL-15 T cells is safe and tolerable in patients with relapsed/refractory ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2772610X24000382

GD2 targeting CAR T cells for neuroblastoma GD2 is a well-recognised and validated target antigen for neuroblastoma. •. CAR-T cells targeting GD2 are a tractable novel therapeutic approach for refractory ...

4. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/186895

Study of CAR T-Cells Targeting the GD2 With IL-15+ ... Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma or Relapsed/Refractory Osteosarcoma ; Condition. Neuroblastoma; ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7768386/

Strategies to Improve Chimeric Antigen Receptor Therapies ... This review summarizes the crucial features of CARs and their design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic ...

6. clinicaltrial.be clinicaltrial.be/fr/details/66673?per_page=100&only_recruiting=1&only_eligible=0&only_active=0

Study of CAR T-Cells Targeting the GD2 With IL-15 ... A Phase I Study of Autologous Activated T-Cells Expressing a 2nd Generation GD2 Chimeric Antigen Receptor, IL-15, and iCaspase9 Safety Switch Administered ...