CAR T Cell Therapy for Pediatric Cancer

Overseen By Navin Pinto, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Immunosuppressants, Radiation therapy

Disqualifiers: Active malignancy, CNS pathology, Severe infection, others

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

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

68 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for children and young adults with hard-to-treat solid tumors. It uses the patient's own immune cells, modified to better attack cancer cells. The study aims to see if this approach is safe and effective. This type of therapy has shown remarkable results in young patients with certain types of blood cancers.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop all current medications, but it does require stopping certain treatments like chemotherapy, biologic therapy, and corticosteroids at least 7 days before enrollment if no apheresis product is available. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment B7H3 CAR T Cell Immunotherapy for pediatric cancer?

Research shows that B7-H3 CAR T cells have shown significant activity against pediatric solid tumors in preclinical models, including neuroblastoma and osteosarcoma, and have demonstrated anti-tumor effects in clinical studies for metastatic neuroblastoma. This suggests potential effectiveness in treating pediatric cancers. ^{1 2 3 4 5}

What safety data exists for CAR T Cell Therapy in pediatric cancer?

CAR T Cell Therapy has shown promise in treating pediatric cancers, but it can cause side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Safety data from various studies indicate that these side effects are more common in certain conditions, and using specific treatments can help manage them. ^{3 6 7 8 9}

How is B7H3 CAR T Cell Immunotherapy different from other treatments for pediatric cancer?

B7H3 CAR T Cell Immunotherapy is unique because it targets the B7-H3 protein, which is found on many pediatric solid tumors and brain tumors, offering a new approach for cancers that have limited treatment options. Unlike traditional treatments like surgery, chemotherapy, and radiotherapy, this therapy uses genetically engineered T cells to specifically attack cancer cells, potentially reducing side effects and improving outcomes. ^{3 10 11 12 13}

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 certain relapsed or refractory solid tumors. They must have a life expectancy of at least 8 weeks, be recovered from previous treatments, have adequate organ function and lab values, and not be pregnant or breastfeeding. Participants over 15 must agree to use effective contraception.

Inclusion Criteria

My condition has not improved or has returned after treatment.

I haven't received any antibody cancer treatment for the last 30 days or 3 half-lives, whichever is shorter.

I stopped all chemotherapy at least 7 days before joining.

Exclusion Criteria

I have a current brain or spinal cord condition.

Unwilling or unable to provide consent/assent for participation in the study and 15 year follow up period

I am currently suffering from a severe infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of genetically modified T cells targeting B7H3 and/or CD19

4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety, efficacy, and persistence of CAR T cells in the body

12 weeks

Multiple visits (in-person and virtual)

Extension

Participants may receive additional monitoring or treatment based on response and safety

Long-term

Treatment Details

Interventions

• B7H3 CAR T Cell Immunotherapy

Trial Overview The study tests genetically modified T cells targeting B7H3 in non-CNS solid tumors. It has two arms: one receives only B7H3-specific CAR T cells; the other also targets CD19+ B cells. The goals are to assess safety, dose tolerance, cell persistence in the body, and anti-tumor effects.

Participant Groups

Group I: SCRI-CARB7H3(s)x19 plus pembrolizumab Experimental Treatment 2 Interventions

Autologous CD4+ and CD8+ T-cells genetically modified to express a bispecific B7H3xCD19 CAR given in combination with pembrolizumab

Group II: SCRI-CARB7H3(s)x19 Experimental Treatment 1 Intervention

Autologous CD4+ and CD8+ T-cells genetically modified to a bispecific B7H3xCD19 CAR

Group III: SCRI-CARB7H3(s) Experimental Treatment 1 Intervention

Autologous CD4+ and CD8+ T-cells genetically modified to express an B7H3-specific CAR

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

B7-H3 CAR T cells have shown significant antitumor activity in various pediatric solid tumor models, including osteosarcoma and medulloblastoma, indicating their potential as a treatment option for relapsed pediatric malignancies.

The effectiveness of B7-H3 CAR T cells is linked to the density of the B7-H3 antigen on tumor cells, suggesting that this therapy could be selectively effective against tumors with high antigen expression while minimizing effects on normal tissues with lower expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Majzner, RG., Theruvath, JL., Nellan, A., et al.[2021]

B7-H3 is a promising target for immunotherapy in pediatric solid tumors, as it is highly expressed in cancers like neuroblastoma and rhabdomyosarcoma but low in normal tissues, making it a safe target for treatment.

Research shows that targeting B7-H3 with antibody-drug conjugates and CAR-T cells can significantly reduce tumor growth and improve anti-tumor immune responses in preclinical models, indicating strong potential for effective therapies in children with these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment. Rasic, P., Jeremic, M., Jeremic, R., et al.[2023]

CAR T-cell therapy has shown high response rates in treating relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) in children, but the effects are often of limited duration, highlighting the need for improved persistence and strategies to prevent relapse.

There are significant challenges in applying CAR T-cell therapy to other pediatric malignancies like acute myeloid leukaemia (AML) and solid tumors, necessitating further research into alternative targets and combination therapies to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. Pearson, AD., Rossig, C., Mackall, C., et al.[2023]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

CAR-modified T-cell therapy targeting CD19 has shown impressive remission rates of 50% to 60% at 1 year for patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), marking a significant advancement in treatment for this challenging condition.

While the therapy is effective, it can lead to side effects such as cytokine release syndrome (CRS) and neurotoxicity shortly after treatment, as well as long-term B-cell aplasia, which are important considerations for patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. DiNofia, AM., Maude, SL.[2020]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR T cell therapy shows promise for pediatric patients with relapsed or refractory malignancies, emphasizing the importance of patient selection and coordination in the treatment process.

Effective management of toxicities following CAR T cell infusion is crucial for the safety and success of this immunotherapy, highlighting the need for nursing staff to be well-informed about these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization of CAR T Cell Therapy in Pediatric Patients. Szenes, V., Curran, KJ.[2020]

An 11-year-old girl with relapsed acute B lymphoblastic leukemia (B-ALL) was treated with fourth generation CD19 CAR-T therapy, which was found to be effective and safe, resulting in a negative minimal residual disease after treatment.

Despite initial success and 10 months of disease-free survival, the patient ultimately relapsed due to increasing TEL-AML1 gene copies, highlighting the need for ongoing monitoring and potential further interventions in CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review]. Zuo, Y., Wang, J., Lu, A., et al.[2020]

Atypical teratoid/rhabdoid tumors (ATRTs) express the B7-H3 protein, which is crucial for their growth and can be targeted for therapy, highlighting its potential as a therapeutic target for this aggressive pediatric cancer.

Using B7-H3-targeted CAR T cells delivered directly into the brain showed faster and more effective tumor suppression in mouse models compared to traditional intravenous delivery, suggesting that localized treatment may reduce systemic side effects and improve outcomes for children with ATRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Theruvath, J., Sotillo, E., Mount, CW., et al.[2022]

Brain tumors are the most common solid tumors in children and the leading cause of cancer-related deaths, highlighting the urgent need for more effective treatments.

Recent advancements in CAR T cell immunotherapy show promise for improving outcomes in pediatric brain cancer, with ongoing research focusing on specific targets and strategies to enhance the effectiveness of this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in CAR T cell immunotherapy for paediatric brain tumours. Rao, P., Furst, L., Meyran, D., et al.[2022]

References

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

Adoptive Cellular Therapy for Pediatric Solid Tumors: Beyond Chimeric Antigen Receptor-T Cell Therapy. [2023]

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

Implications of Immunotherapy for Pediatric Malignancies: A Summary from the APSA Cancer Committee. [2023]

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

CAR T Cells Targeting B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration. [2023]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL. [2020]

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

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

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

Utilization of CAR T Cell Therapy in Pediatric Patients. [2020]

10. China pubmed.ncbi.nlm.nih.gov

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review]. [2020]

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

Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. [2022]

12. China pubmed.ncbi.nlm.nih.gov

[Efficacy of Chimeric Antigen Receptor T Cell in the Treatment of Refractory/Recurrent B Acute Lymphocytic Leukemia in Children]. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Advances in CAR T cell immunotherapy for paediatric brain tumours. [2022]