b7-h3-specific chimeric antigen receptor autologous t-cell therapy for pediatric patients with solid tumors (3car)

Conditions: Pediatric Solid Tumor; Osteosarcoma; Rhabdomyosarcoma; Neuroblastoma; Ewing Sarcoma; Wilms Tumor; Adrenocortical Cancer; Desmoplastic Small Round Cell Tumor; Germ Cell Cancer; Rhabdoid Tumor; Clear Cell Sarcoma; Hepatoblastoma; Melanoma; Carcinoma; Malignant Peripheral Nerve Sheath Tumors; Soft Tissue Sarcoma

Summary: 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.

Eligibility criteria:
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)