CAR T-Cell Therapy for Pediatric Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Chris DeRenzo, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: St. Jude Children's Research Hospital

Must not be taking: Systemic steroids

Disqualifiers: Primary immunodeficiency, HIV, Severe infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

3CAR is being done to investigate an immunotherapy for patients with solid tumors. It is a Phase I clinical trial evaluating the use of autologous T cells genetically engineered to express B7-H3-CARs for patients ≤ 21 years old, with relapsed/refractory B7-H3+ solid tumors. This study will evaluate the safety and maximum tolerated dose of B7-H3-CAR T cells.The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give to patients with B7-H3-positive solid tumors. Primary objective To determine the safety of one intravenous infusion of autologous, B7-H3-CAR T cells in patients (≤ 21 years) with recurrent/refractory B7-H3+ solid tumors after lymphodepleting chemotherapy Secondary objective To evaluate the antitumor activity of B7-H3-CAR T cells Exploratory objectives * To evaluate the tumor environment after treatment with B7-H3-CAR T cells * To assess the immunophenotype, clonal structure and endogenous repertoire of B7-H3-CAR T cells and unmodified T cells * To characterize the cytokine profile in the peripheral blood after treatment with B7-H3-CAR T cells

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic steroid therapy exceeding a certain dose 7 days before the infusion and any systemic therapy that might interfere with the CAR T-cell product 14 days before the infusion.

What data supports the effectiveness of the treatment B7-H3 CAR T cells for pediatric cancer?

Research shows that B7-H3 CAR T cells have demonstrated significant activity against models of pediatric solid tumors like neuroblastoma and osteosarcoma, suggesting they could be effective in treating these cancers. ^{1 2 3 4 5}

Is CAR T-cell therapy safe for pediatric cancer patients?

CAR T-cell therapy has shown promise in treating certain pediatric cancers, but it can have serious side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). Safety data from various studies indicate that these risks are higher in some conditions, but treatments like cytokine-directed therapies and corticosteroids can help manage these side effects. ^{3 6 7 8 9}

How is the B7-H3 CAR T-cell treatment different from other treatments for pediatric cancer?

B7-H3 CAR T-cell therapy is unique because it targets the B7-H3 protein, which is highly expressed in many pediatric solid tumors but not in normal tissues, making it a promising target for treatment. Unlike traditional treatments, this therapy can be administered directly into the brain or tumor, potentially offering faster and more effective results with fewer side effects. ^{1 3 4 10 11}

Research Team

Chris DeRenzo, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults (≤21 years old) with certain solid tumors that have come back or didn't respond to treatment. Participants must have a life expectancy of more than 8 weeks, a performance score ≥50, good heart function, adequate kidney and lung function, not be pregnant or breastfeeding, agree to use birth control methods if applicable, and have an available T-cell product made from their own cells.

Inclusion Criteria

I am not pregnant or breastfeeding and can undergo or have had apheresis.

My tumor is B7-H3 positive and can be measured.

I am 21 years old or younger.

Exclusion Criteria

I haven't taken any medication in the last 14 days that could affect my upcoming CAR T-cell therapy.

I do not have any severe, uncontrolled infections.

I haven't taken high doses of steroids in the week before my planned CAR T-cell therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Collection and Manufacturing

Collection of T cells from participants and manufacturing of B7-H3-CAR T cells

4-6 weeks

Treatment

Participants receive lymphodepleting chemotherapy followed by a single infusion of B7-H3-CAR T cells

6 weeks

Multiple visits for chemotherapy and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

Long-term follow-up

Participants enroll in an institutional long-term follow-up protocol

1 year

Treatment Details

Interventions

• B7-H3 CAR T cells (CAR T-cell Therapy)
• Cyclophosphamide (Alkylating agents)
• Fludarabine (Anti-metabolites)
• MESNA (Other)

Trial Overview The trial tests B7-H3-CAR T cell therapy in pediatric patients with relapsed/refractory solid tumors expressing B7-H3. It aims to find the highest safe dose of these genetically modified T cells after chemotherapy that depletes lymphocytes (a type of white blood cell).

Participant Groups

Group I: Treatment Phase Experimental Treatment 4 Interventions

During the treatment phase, the participant receives an infusion of the B7-H3-CAR T cells that were made in the Collection and Manufacturing Phase. Chemotherapy is given for several days prior to the cellular infusion. Patients are then monitored for possible side effects, as well as effects of the treatment on their cancer.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Dr. James R. Downing

St. Jude Children's Research Hospital

Chief Executive Officer since 2014

MD from University of Michigan Medical School

Dr. Ellis J. Neufeld

St. Jude Children's Research Hospital

Chief Medical Officer since 2017

MD, PhD from Harvard Medical School

Findings from Research

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]

B7-H3 is widely expressed in various human solid tumors but has limited expression in normal tissues, making it a promising target for CAR T-cell therapy.

Combining B7-H3.CAR T cells with the epigenetic drug SAHA significantly boosts their ability to kill solid cancer cells, suggesting this combination could improve treatment outcomes in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors. Lei, X., Ou, Z., Yang, Z., et al.[2022]

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]

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]

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]

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]

CAR-T cell therapy shows promise in treating relapsed or refractory malignancies, particularly in hematological cancers like acute B-cell lymphoblastic leukemia and B-cell lymphomas, with ongoing research into its application for solid tumors.

This systematic review aims to comprehensively assess the safety and efficacy of CAR-T cell therapy by analyzing various studies, focusing on outcomes such as complete response rates and adverse events, to better understand its potential risks and benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. Grigor, EJM., Fergusson, DA., Haggar, F., et al.[2019]

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]

CAR-T cell therapy, while currently approved only for B cell malignancies, shows promising potential for treating pediatric brain tumors, with early clinical trials indicating some positive responses.

Recent preclinical studies have identified new tumor antigens and combination strategies that enhance the effectiveness of CAR-T cells, particularly when administered directly to the tumor site.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. Leruste, A., Beccaria, K., Doz, F.[2021]

References

1. 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]

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

A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors. [2022]

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. 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]

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. 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]

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

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

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

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

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in patients with haematological and solid malignancies: protocol for a systematic review and meta-analysis. [2019]

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

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

11. France pubmed.ncbi.nlm.nih.gov

CAR-T cells for pediatric brain tumors: Present and future. [2021]