This is a phase I dose-escalation study to determine the safety and feasibility of autologous CAR-TA T cells (B7-H3 CAR+ T cells administered with DNR-PRAME Tumor Antigen-specific T cells) following lymphodepleting chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
Patients will be enrolled to one of three planned dose levels with B7-H3 CAR T cell dose determined based on the percentage of B7-H3 transduced cells (B7-H3+ population of cells), and dTBRII-transduced PRAME TA-specific T cell dose based on the total cell population. Both doses will be based on the recipient's body weight and combined in a 1:1 ratio.
The safety of the CAR-TA T cell product will be evaluated and the maximum tolerated dose (MTD) will be determined. The safety endpoint will be assessed by monitoring for dose limiting toxicities for 28 days following CAR-TA T cell administration.
Diagnosis of relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma, or Wilms tumor
Refractory disease, residual detectable disease or relapsed disease following available standard of care therapies with known clinical benefit for their specific tumor type, or unable to receive such therapies due to unacceptable toxicity or contraindication
Measurable or evaluable disease by imaging, as determined following most recent therapy
Age ≥ 1 year and < 24 years
Patients with known CNS disease.
Patients with uncontrolled infection/s or known HIV infection
Pregnant or lactating females.
Patients who have undergone previous allogeneic stem cell transplant.
Single group
Selective Antigen Specific dTβRII-expressing T cells combined with B7-H3 CAR T cells
Biological/VaccineSelective Antigen Specific dTβRII-expressing T cells combined with B7-H3 CAR T cells
To determine the safety of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
The safety endpoint will be assessed by monitoring for dose limiting toxicities (DLT) for 28 days following CAR-TA T cell investigational product administration.
To determine the manufacturing feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
Manufacturing feasibility will be determined by the number of CAR-TA T cell products produced in sufficient quantities to meet the participant's assigned dose level for at least one infusion, with all product release testing criteria met.
To determine the clinical feasibility of autologous CAR-TA T cells following LD chemotherapy in participants with relapsed/refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor.
Clinical feasibility will be determined by the number of participants with a released product who are eligible and receive at least 1 infusion.
Determine number of patients who respond to CAR-TA T cell therapy for treatment of diseases under study
To determine the number of patients who respond to CAR-TA T cell therapy for treatment of relapsed or refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor as defined by those that achieve a complete response, partial response, or stable disease following infusion of the CAR-TA T cell product.
Overall Survival
To determine overall survival at 3-, 6-, and 12-months following CAR-TA T cell infusion.
To characterize the in vivo immune milieu pre- and post-infusion of CAR-TA T cell product.
To measure levels of circulating cytokines all assessed pre-infusion and post-infusion.
To characterize transgene transduction efficiency (B7-H3 CAR and dTBRII) of the CAR-TA T cell product generated prior to infusion.
To characterize the CAR-TA T cell products generated prior to infusion in terms of transduction efficiency (B7-H3 CAR and dTBRII), with correlation to clinical and immune response.
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Children's National Research Institute
Lead sponsor
National Cancer Institute (NCI)
Collaborator
Cancer Research UK
Collaborator
