CAR T-cell Therapy for Neuroblastoma

Overseen By Navin Pinto, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Anti-epileptics, Corticosteroids

Disqualifiers: CNS pathology, Pregnancy, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

65 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic corticosteroids (unless it's a small replacement dose) at least 7 days before joining. You also need to be off chemotherapy or biologic therapy for at least 7 days before starting the trial. If you're on anti-tumor antibody therapy, you need to wait 3 half-lives or 30 days, whichever is shorter, before enrolling.

What data supports the effectiveness of the treatment for neuroblastoma?

Research shows that CAR T-cell therapy, which uses specially modified immune cells, has been effective in shrinking tumors in children with neuroblastoma. Additionally, CAR T cells targeting low-density antigens have shown activity without causing harm, indicating potential safety and effectiveness. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for humans?

CAR T-cell therapy has been shown to be safe in early clinical trials for neuroblastoma, with no significant toxicities observed in tissues that express the target molecule. The treatment has been tested in children with neuroblastoma and has demonstrated safety and some anti-tumor effects. ^{1 2 3 6 7}

How is CAR T-cell therapy for neuroblastoma different from other treatments?

CAR T-cell therapy for neuroblastoma is unique because it uses genetically engineered T cells to specifically target and attack cancer cells, offering a personalized approach that harnesses the immune system. Unlike traditional treatments, this therapy can potentially provide long-term protection by persisting in the body and targeting tumor-associated antigens that are not widely present on normal tissues, reducing the risk of side effects. ^{1 2 3 4 6}

What is the purpose of this trial?

Patients with recurrent or refractory neuroblastoma are resistance to conventional chemotherapy. For this reason, the investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the neuroblastoma cell through the recognition of CD171, a protein expressed of the surface of the neuroblastoma cell in patients with neuroblastoma. This is a phase 1 study designed to determine the maximum tolerated dose of the CAR+ T cells.

Research Team

Catherine Albert, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for children and young adults up to 26 years old with high-risk neuroblastoma or ganglioneuroblastoma that's resistant to standard treatments. They must have a life expectancy of at least 8 weeks, be in relatively stable health, and not have received certain recent therapies like allogeneic stem cell transplants.

Inclusion Criteria

My organs are functioning well.

My cancer can be measured or seen on tests.

I was diagnosed with high-risk neuroblastoma or it spread after I turned 18 months.

Exclusion Criteria

I have a condition that affects my immune system or bone marrow.

I am currently suffering from a severe infection.

I have a history of or currently have significant brain-related health issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Generation

T cells are isolated, selected, transduced with a lentivirus to express CD171 CAR, and expanded in culture

4-6 weeks

Lymphodepletion and T Cell Infusion

Participants receive lymphodepletion chemotherapy followed by infusion of CAR+ T cells

1 week

Intensive Follow-up

Participants are monitored intensely for 6 weeks with serial blood testing and disease status re-evaluation

6 weeks

Long-term Follow-up

Participants are followed bi-annually for 5 years, then annually for 10 years to monitor long-term health effects

15 years

Treatment Details

Interventions

• Patient Derived CD171 specific CAR T cells

Trial Overview The ENCIT-01 study tests different versions of genetically engineered T cells designed to target CD171 on neuroblastoma cells. It aims to find the highest dose patients can tolerate without severe side effects. These T cells are taken from the patient, modified in the lab, then given back to attack the cancer.

Participant Groups

Group I: C: Long Spacer 2nd Generation CE7R CAR T Cells Experimental Treatment 1 Intervention

Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.

Group II: B: 3rd Generation CE7R CAR T Cells Experimental Treatment 1 Intervention

Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.

Group III: A: 2nd Generation CE7R CAR T Cells Experimental Treatment 1 Intervention

Autologous CD4 and CD8 cells are lentivirally transduced to generate patient-derived CD171 specific CAR T cells also expressing an EGFRt. Patients will receive lymphodepletion chemotherapy prior to T cell infusion. CD171 specific CAR T cells will be administered approximately 2-3 days after lymphodepletion chemotherapy. Cells will be administered approximately 1:1 CD4 and CD8 cells with planned dose level evaluations of total T cell dose of 1x10\^6 cells/kg, 5x10\^6 cells/kg, 1x10\^7 cells/kg, 5x10\^7 cells/kg, and 1x10\^8 cells/kg will be evaluated.

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Ben Towne Center for Childhood Cancer Research

Collaborator

Trials

1

Recruited

70+

The Evan Foundation

Collaborator

Trials

5

Recruited

240+

Findings from Research

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. [2023]

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

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

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

CAR T Cells Offer Hope for Neuroblastoma. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Genetic engineering of cytolytic T lymphocytes for adoptive T-cell therapy of neuroblastoma. [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression. [2021]

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

Advances in chimeric antigen receptor immunotherapy for neuroblastoma. [2021]

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

Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. [2023]