B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

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

Treatment will include a single infusion of B7-H3-CAR T cells after lymphodepleting chemotherapy, with dosing based on the number of CAR+ T cells and patient weight. The study will evaluate the safety and maximum tolerated dose (MTD) of B7-H3-CAR T cells, using a standard 3+3 study design and a 6-week evaluation period. The total study duration will be 1 year, at which point patients will enroll on our existing institutional long-term follow-up protocol.

Inclusion Criteria:

Procurement and T-cell production eligibility*

*a previously collected, autologous leukapheresis product can be used for T-cell production

• Age ≤21 years old
• B7-H3+ solid tumor with measurable disease; B7-H3 expression will be evaluated by standard immunohistochemistry (IHC) using a previously obtained biopsy; a tumor is considered B7-H3 positive with an H-score ≥100
• Estimated life expectancy of >12 weeks
• Karnofsky or Lansky (age-dependent) performance score ≥50
• For females of child bearing age:
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• Not lactating with intent to breastfeed
• Meets eligibility criteria to undergo autologous apheresis, or have previously undergone autologous apheresis

Exclusion Criteria:

• Known primary immunodeficiency
• Known HIV positivity
• Severe intercurrent bacterial, viral or fungal infection (e.g. active hepatitis B or C infection or adenovirus infection)
• History of hypersensitivity reactions to murine protein-containing products
• Rapidly progressive disease (in the opinion of the study PIs)

Inclusion criteria

Treatment eligibility

• Age ≤21 years old
• B7-H3+ solid tumor with measurable disease
• Evidence of relapsed or refractory disease after standard first-line therapy
• Estimated life expectancy of >8 weeks
• Karnofsky or Lansky (age-dependent) performance score≥50
• Echocardiogram with a ventricular ejection fraction
• >40%; or shortening fraction ≥25%
• Adequate renal function defined as creatinine clearance or radioisotope GFR 50 ml/min/1.73m2 (GFR 40 ml/min/1.73m2 if < 2 years of age)
• Adequate pulmonary function defined as pulse oximetry ≥92% on room air or forced vital capacity (FVC) ≥50% of predicted value
• Total Bilirubin ≤3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤5 times the upper limit of normal for age
• Hemoglobin≥ 7g/dL (can be transfused)
• Platelet count >50,000/uL (can be transfused)
• Absolute neutrophil count (ANC) ≥ 1000/uL
• Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy
• For females of child bearing age:
• Not pregnant with negative serum pregnancy test within 7 days prior to enrollment
• Not lactating with intent to breastfeed
• If sexually active, agreement to use birth control until 3 months after T-cell infusion. Male partners should use a condom.
• Available autologous transduced T-cell product that has met GMP release criteria
• Agreement to participate in long-term follow-up protocol for patients, who have received genetically modified cell products

Exclusion criteria

• Known primary immunodeficiency
• History of HIV infection
• Severe, uncontrolled intercurrent bacterial, viral or fungal infection
• History of hypersensitivity reactions to murine protein-containing products
• Receiving systemic steroid therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, in the 7 days prior to B7-H3-CAR T-cell infusion
• Receiving systemic therapy in the 14 days prior to CAR T-cell infusion, which will interfere with the activity of the B7-H3-CAR product (in the opinion of the study PIs).
• Rapidly progressing disease (in the opinion of the study PIs)