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.
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
Grade 3 or more immediate infusion-related adverse event
Number of patients experiencing Grade 3 or higher immediate infusion-related adverse events, assessed using the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0; Grades 1-5; higher grades indicate worse severity), occurring during or immediately following the CAR-TA T cell infusion.
Grade 4 or more Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)
Number of patients experiencing Grade 4 or higher Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) CRS and ICANS Consensus Grading Criteria (Grades 1-5; higher grades indicate worse severity).
Grade 3 neurotoxicity or ICANS persisting for more than 72 hours
Number of patients experiencing Grade 3 neurotoxicity or ICANS with a duration greater than 72 hours. (severity grades assessed as per American Society for Transplantation and Cellular Therapy (ASTCT) CRS and ICANS Consensus Criteria)
Grade 4 or more Cytokine Release Syndrome (CRS)
Number of patients experiencing Grade 4 or higher Cytokine Release Syndrome (CRS), assessed using ASTCT CRS Consensus Grading Criteria (Grades 1-5; higher = worse).
Response to CAR-TA T cell therapy
Number of patients who respond to CAR-TA T cell therapy for treatment of relapsed or refractory rhabdomyosarcoma, Ewing sarcoma, neuroblastoma and Wilms tumor, defined as complete response, partial response, or stable disease following infusion of the CAR-TA T cell product. Disease response will be assessed using protocol-specified criteria.
Progression-free survival
Time from infusion of the investigational product to the first documented disease progression or death from any cause
Overall survival
Time from the from infusion of the investigational product to death from any cause.
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Children's National Research Institute
Lead sponsor
National Cancer Institute (NCI)
Collaborator
Cancer Research UK
Collaborator
The Mark Foundation for Cancer Research
Collaborator
