CAR T-Cell Therapy for Neuroblastoma and Osteosarcoma

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by George Hucks, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: UNC Lineberger Comprehensive Cancer Center

Must not be taking: Antiepileptics

Disqualifiers: Pregnancy, Breastfeeding, Active malignancy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The body has different ways of fighting infections and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are molecules that fight infections and protect your body from diseases caused by bacteria and toxic substances. Antibodies work by sticking to those bacteria or substances, which stops them from growing and causing bad effects. T cells are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been enough to cure most patients. This multicenter study is designed to combine both T cells and antibodies in order to create a more effective treatment. The treatment that is being researched is called autologous T lymphocyte chimeric antigen receptor cells (CAR) cells targeted against the disialoganglioside (GD2) antigen that express Interleukin (IL)-15, and the inducible caspase 9 safety switch (iC9), also known as iC9.GD2.CAR.IL-15 T cells.

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.

What data supports the effectiveness of this treatment for neuroblastoma and osteosarcoma?

Research shows that CAR T-cell therapy targeting GD2, a molecule found on neuroblastoma cells, has demonstrated strong anti-tumor activity in preclinical models. The inclusion of IL-15 enhances the effectiveness of these CAR T-cells, and the safety switch iC9 allows for controlled cell death if needed, making this a promising approach for treating neuroblastoma. ^{1 2 3 4 5}

Is CAR T-cell therapy for neuroblastoma and osteosarcoma safe in humans?

CAR T-cell therapy targeting GD2 has shown potential safety concerns, including fatal neurotoxicity and encephalitis (brain inflammation) in preclinical models. However, the inclusion of a safety switch, like inducible Caspase-9 (iC9), can help manage these risks by allowing the therapy to be stopped if severe side effects occur. ^{1 2 3 6 7}

What makes the treatment iC9.GD2.CAR.IL-15 T-cells unique for neuroblastoma and osteosarcoma?

This treatment is unique because it uses engineered T-cells that target the GD2 antigen on tumor cells, includes a safety switch to control the therapy, and is enhanced with IL-15 to improve T-cell persistence and anti-tumor activity, which is not common in standard treatments for these cancers. ^{1 3 4 7 8}

Research Team

George Hucks, MD

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)
• iC9.GD2.CAR.IL-15 T-cells (CAR T-cell Therapy)

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.

Participant Groups

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+

Dr. Shelley Earp

UNC Lineberger Comprehensive Cancer Center

Chief Medical Officer since 2018

MD from Johns Hopkins Medical School

Dr. Robert L. Ferris

UNC Lineberger Comprehensive Cancer Center

Chief Executive Officer

PhD in Immunology and MD from Johns Hopkins Medical School; Bachelor's in Chemistry from UNC-Chapel Hill

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+

Pete Hegseth

United States Department of Defense

Chief Executive Officer

Bachelor's degree in Political Science from Princeton University, JD from Harvard Law School

Lisa Hershman

United States Department of Defense

Chief Medical Officer since 2021

MD from Uniformed Services University of the Health Sciences

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Switzerland 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. [2023]

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

Interleukin-15 Enhances Anti-GD2 Antibody-Mediated Cytotoxicity in an Orthotopic PDX Model of Neuroblastoma. [2023]

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

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. [2021]

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

A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. [2018]

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

An Optimized GD2-Targeting Retroviral Cassette for More Potent and Safer Cellular Therapy of Neuroblastoma and Other Cancers. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. [2021]

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

High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model. [2021]

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

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. [2023]