GD2-targeted CAR T-Cells for Neuroblastoma

Recruiting at 1 trial location

Overseen By David Allen

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Immunotherapies, Checkpoint inhibitors, Corticosteroids, others

Disqualifiers: Autoimmune, Brain metastases, Cardiomegaly, others

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

Compensation: Varies

Number of Visits: 15

94 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is for patients with certain cancers that have returned or didn't respond to treatment. It uses the patient's own T cells, modified to better fight cancer and survive longer. The goal is to find the safest dose and see how well these modified cells work against cancer. This approach has changed how doctors treat certain types of cancer by using modified T cells to find and destroy cancer cells.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot be on immunosuppressive drugs or investigational drugs. Maintenance therapy with certain non-investigational oral cancer drugs is allowed up to 48 hours before the infusion.

What data supports the effectiveness of the treatment C7R-GD2.CART cells for neuroblastoma?

Research shows that GD2-targeted CAR T cells can shrink tumors in children with neuroblastoma, and some patients have experienced complete remission. These CAR T cells have shown the ability to persist in the body, which is linked to better outcomes. ^{1 2 3 4 5}

Is GD2-targeted CAR T-cell therapy safe for humans?

GD2-targeted CAR T-cell therapy has shown to be generally safe in early clinical trials for neuroblastoma, with some patients experiencing mild to moderate side effects like cytokine release syndrome (a condition where the immune system is overly activated). However, preclinical studies have shown potential for serious side effects, such as fatal brain inflammation, indicating that more research is needed to ensure safety. ^{1 2 3 6 7}

What makes the C7R-GD2.CART cell treatment unique for neuroblastoma?

The C7R-GD2.CART cell treatment is unique because it uses genetically modified immune cells (CAR T-cells) to specifically target and attack neuroblastoma cells by recognizing the GD2 antigen on their surface. This approach is designed to improve the immune system's ability to fight the cancer, potentially leading to tumor shrinkage without the severe side effects often associated with traditional treatments. ^{1 3 4 7 8}

Research Team

Bilal Omer, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for people aged 1-75 with certain types of cancer (like neuroblastoma, sarcoma, uveal melanoma, breast cancer) that have a substance called GD2 on their cells. The cancers should be resistant to standard treatments or have come back after treatment. Participants need to be relatively healthy otherwise, with a life expectancy of at least 12 weeks and stable organ function.

Inclusion Criteria

You are expected to live for at least 12 weeks.

Informed consent and assent (as applicable) obtained from parent/guardian and child

Your liver function tests are within a certain range.

Exclusion Criteria

You have had an allergic reaction to products containing murine protein, unless you have successfully undergone a desensitization process and re-challenge without another allergic reaction.

I have an autoimmune disease and have been on immunosuppressants in the last 6 months.

I have a primary brain tumor or brain metastases.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Lymphodepletion Chemotherapy

Patients may receive cyclophosphamide and fludarabine to prepare the body for T cell infusion

3 days

3 visits (in-person)

T Cell Infusion

Patients receive GD2-C7R T cells infusion, potentially followed by a second infusion one week later

1-2 weeks

2 visits (in-person)

Initial Follow-up

Patients are monitored for safety and effectiveness with follow-up visits at weeks 1, 2, 4, 6, and 8

8 weeks

5 visits (in-person)

Long-term Follow-up

Patients are monitored for long-term side effects and effectiveness of the gene transfer for up to 15 years

15 years

Bi-annual visits for 4 years, then annual visits

Treatment Details

Interventions

• C7R-GD2.CART cells

Trial Overview The trial tests genetically modified T cells designed to last longer and fight cancer more effectively. These T cells are engineered to recognize and attack GD2 positive cancer cells. Before the T cell infusion, patients may receive chemotherapy to help these special immune cells work better.

Participant Groups

Group I: Arm B: Standard risk group of all other patients Experimental Treatment 1 Intervention

Patients will be treated at 2 dose levels without lymphodepletion chemotherapy. Three patients will be evaluated and if safety is confirmed patients will be treated at the next dose level with C7R.GD2.CART cell infusion without lymphodepletion chemotherapy. The protocol is divided into two arms, a high-risk group of patients with lung metastases (Arm B) and a standard risk group of all other patients (Arm A). The standard risk Arm A includes osteosarcoma patients without pulmonary disease. Each arm will undergo separate dose escalation.

Group II: Arm A: High-risk group of patients with lung metastases Experimental Treatment 1 Intervention

Patients will be treated at 2 dose levels without lymphodepletion chemotherapy. Three patients will be evaluated and if safety is confirmed patients will be treated at the next dose level with C7R.GD2.CART cell infusion without lymphodepletion chemotherapy. The protocol is divided into two arms, a high-risk group of patients with lung metastases (Arm B) and a standard risk group of all other patients (Arm A). The standard risk Arm A includes osteosarcoma patients without pulmonary disease. Each arm will undergo separate dose escalation.

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+

Cancer Prevention Research Institute of Texas

Collaborator

Trials

55

Recruited

98,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

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]

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]

In a phase 1 study involving 12 children with relapsed/refractory neuroblastoma, treatment with GD2-directed CAR-T cells showed some clinical activity, with three patients experiencing regression of their disease despite no objective clinical responses at the 28-day evaluation point.

The study reported that while two patients experienced significant cytokine release syndrome, there was no on-target off-tumor toxicity, indicating that targeting neuroblastoma with CAR-T cells is a safe approach, although further modifications are needed to enhance the effectiveness and longevity of the CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Straathof, K., Flutter, B., Wallace, R., 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]

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]

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]

References

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

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. [2023]

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

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. [2021]

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

CAR T Cells Offer Hope for Neuroblastoma. [2023]

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

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

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

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

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

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

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

CAR T Cells Engineered to Target Low-Density Antigens Show Efficacy and Safety. [2022]