Sponsor: St. Jude Children's Research Hospital (other)
Phase: 1
Start date: Oct. 30, 2025
Planned enrollment: 42
B7-H3 CAR-T therapies are autologous or allogeneic chimeric antigen receptor T cells engineered to recognize B7-H3 (CD276), a checkpoint-like immunomodulatory molecule overexpressed across many solid tumors and associated with poor outcomes. Clinical-stage programs include TX103 for recurrent glioblastoma (rGBM) and a fourth‑generation construct 4SCAR‑276 being studied in B7‑H3–positive solid tumors. Interim human data have been presented for TX103 in rGBM; other programs (e.g., 4SCAR‑276) remain in early-phase evaluation without published response outcomes to date. (aacrjournals.org)
TX103 (autologous B7‑H3 CAR‑T; rGBM) - Study: Phase 1, single‑arm, dose‑escalation with intracavitary and/or intraventricular administration via Ommaya; NCT05241392. Interim ASCO 2024 abstract reported 13 treated patients between March 2022 and January 2024. (ascopubs.org) - Outcomes (interim): Among six patients from dose levels 1–2 evaluable for 12‑month survival as of January 2024, 12‑month OS was 83.3% (95% CI 58.3–100); median OS 20.3 months (95% CI 20.3–not reached). In dose level 2, two of three patients achieved partial and complete responses, respectively. CSF cytokines (e.g., IL‑6, IFN‑γ) and CAR transgene copies increased post‑infusion, with minimal peripheral changes. (ascopubs.org)
Allogeneic B7‑H3 CAR‑T in recurrent high‑grade glioma (for context; different product) - MT027 UCAR‑T IIT (ChiCTR2100047968): ASCO 2023/2024 abstracts reported favorable tolerability with no grade ≥3 toxicities; 12‑month OS 85.7% (95% CI 48.7–97.4) in one analysis; PK/PD showed CSF persistence and cytokine increases. These are single‑center, early‑phase data. (ascopubs.org)
4SCAR‑276 (B7‑H3 CAR‑T; fourth‑generation) - Multicenter Phase I/II trial in B7‑H3–positive solid tumors (NCT04432649) is listed; as of the latest registry snapshots, no results are posted. (cdek.pharmacy.purdue.edu)
TX103 (NCT05241392; interim)
- No dose‑limiting toxicities or treatment‑related deaths reported among 13 patients.
- Treatment‑related adverse events included cytokine release syndrome, increased intracranial pressure, headache, seizures, decreased consciousness, vomiting, and fever; most were grade 1–2. Three grade‑3 events occurred (increased intracranial pressure at dose level 2; seizure and decreased level of consciousness at dose level 3). (ascopubs.org)
Allogeneic B7‑H3 UCAR‑T (context) - Early reports noted no grade ≥3 toxicities, with most common events being fever and headache; no CRS/ICANS/GvHD observed in the presented dataset. (ascopubs.org)
Notes: Published evidence to date is primarily from conference abstracts and trial registries; peer‑reviewed, full clinical manuscripts for these specific products were not identified as of October 7, 2025.
Last updated: Oct 2025
Goal: To establish the safety and tolerability of autologous B7-H3 (CD276) CAR T-cell therapy administered after hypofractionated radiation priming and fludarabine/cyclophosphamide lymphodepletion in children, adolescents, and young adults with relapsed/refractory B7-H3–positive sarcomas, and to generate preliminary signals of antitumor activity and tumor trafficking.
Patients: Patients 21 years or younger with relapsed or refractory B7-H3–positive sarcomas (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma soft tissue sarcomas) with evaluable disease including at least one lesion amenable to hypofractionated radiation. B7-H3 positivity is defined by IHC with an H-score of at least 100. Treatment eligibility requires adequate organ function (including LVEF at least 50%, oxygen saturation at least 92% on room air, and prespecified hematologic/renal/hepatic parameters) and performance status at least 60. Key exclusions include intracranial/spinal cord disease, uncontrolled infection, HIV, primary immunodeficiency, rapidly progressive disease, recent radiation (within 4 weeks), and recent therapies that could interfere with CAR activity; systemic steroids above 0.5 mg/kg/day methylprednisolone equivalent are not allowed within 7 days of infusion.
Design: Single-arm, open-label phase I study with a two-step process: eligibility for leukapheresis/manufacturing (or use of a previously collected autologous leukapheresis product) followed by separate eligibility confirmation to proceed to protocol therapy. Participants receive radiation to at least one tumor site with concurrent lymphodepleting chemotherapy, then CAR T-cell infusion, with early safety follow-up focused on the first 4 weeks. Tumor biopsies are incorporated for correlative assessment of trafficking (post-treatment required/expected per protocol language; pre-treatment biopsy optional), and participants meeting criteria may receive optional additional treatment courses.
Treatments: Participants undergo autologous PBMC collection by leukapheresis for manufacturing of B7-H3–directed CAR T cells (or use of banked product). Protocol therapy consists of hypofractionated radiation therapy delivered to at least one disease site, administered in parallel with a single course of lymphodepleting chemotherapy using fludarabine and cyclophosphamide, followed by infusion of autologous B7-H3-CAR T cells. B7-H3-CAR T cells are genetically engineered autologous T cells that recognize the tumor-associated antigen B7-H3 (CD276), which is broadly expressed across many pediatric solid tumors with limited normal-tissue expression; the intent is antigen-specific cytotoxicity and immune activation within tumor sites. Early clinical experience with B7-H3 CAR T-cell platforms in other pediatric/young adult tumors (notably CNS settings using locoregional delivery) has shown feasibility with manageable cytokine-related and neurologic toxicities and occasional objective responses, supporting ongoing evaluation; this trial tests an intravenous strategy in sarcomas combined with radiation priming and lymphodepletion to potentially enhance trafficking and activity.
Outcomes: Primary endpoints are dose-limiting toxicity rate and overall incidence of adverse events through 4 weeks after CAR T-cell infusion, with AEs graded by CTCAE v5.0 and CRS/ICANS graded by ASTCT criteria. Secondary endpoints include best overall response by RECIST v1.1 (and bone marrow evaluation if applicable) assessed approximately 4–12 weeks post-infusion, and evidence of CAR T-cell trafficking to tumor sites assessed by detection of CAR T cells in a post-treatment tumor biopsy around 2 weeks post-infusion.
Burden on patient: High. The trial requires leukapheresis (or provision of a prior product), coordination of hypofractionated radiation and inpatient-typical lymphodepleting chemotherapy, followed by CAR T-cell infusion with intensive early monitoring for CRS/ICANS and other toxicities during the first month. Imaging-based response assessments occur within the first 4–12 weeks, and the protocol includes a post-treatment tumor biopsy with an optional pre-treatment biopsy, adding procedural burden and potential anesthesia needs in younger patients. The need for specialized cellular therapy manufacturing and delivery at a tertiary center, plus close post-infusion safety surveillance, is likely to increase travel and time away from home compared with standard sarcoma care in the relapsed/refractory setting.
Last updated: Jan 2026
INCLUSION CRITERIA
\*a previously collected, autologous leukapheresis product can be used for T cell production
Collection and manufacturing eligibility
* Age ≤ 21 years old
* B7-H3+ sarcoma; B7-H3 expression will be evaluated by standard immunohistochemistry (IHC) using any previously obtained biopsy; a tumor is considered B7-H3 positive with a H score greater than or equal to 100
* Osteosarcoma
* Ewing Sarcoma
* Rhabdomyosarcoma Non-rhabdomyosarcoma soft tissue sarcomas
* Evidence of relapsed (cancer that has completely responded \[i.e., no evidence of disease using standard imaging modalities\] to first-line therapy but has recurred for the first or subsequent time); or refractory (cancer that does not respond completely to treatment; cancer may be resistant at the beginning or may become resistant during treatment) disease after standard first-line therapy
* Evaluable disease with presence of at least one lesion amenable to hypofractionated radiation therapy
* For dose expansion cohort: participants must also have additional evaluable disease beyond planned radiation field
* Estimated life expectancy of \> 12 weeks
* Karnofsky or Lansky (age-dependent) performance score ≥ 60
* Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive devices will be considered ambulatory for the purpose of performance score determination
* 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
* Participants must be eligible to undergo autologous apheresis or have an available previously collected autologous apheresis product
Treatment eligibility
* Age ≤ 21 years old at the time of manufacturing
* B7-H3+ sarcoma
* Evidence of relapsed or refractory disease after standard first-line therapy
* Evaluable disease with the presence of at least one lesion amenable to hypofractionated radiation therapy
• For dose expansion cohort: participants must also have additional evaluable disease beyond the planned radiation field
* Estimated life expectancy of \> 8 weeks
* Karnofsky or Lansky (age-dependent) performance score ≥ 60
• Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive device will be considered ambulatory for purpose of performance score determination.
* Adequate cardiac function defined by echocardiogram with left ventricular ejection fraction ≥ 50%
* Adequate renal function as defined by not exceeding the maximum serum creatinine listed below by age:
* 1 to \<2 years: 0.6
* 2 to \<6 years: 0.8
* 6 to \<10 years: 1
* 10 to \<13 years: 1.2
* 13 to \<16 years: male 1.5, female 1.4
* ≥ 16 years: male 1.7, female 1.4
* Adequate pulmonary function defined as pulse oximetry ≥ 92% on room air
* 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/μL (can be transfused)
* Absolute neutrophil count (ANC) ≥ 1000/μL
* 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 contraception until 3 months after T cell infusion
EXCLUSION CRITERIA
Collection and manufacturing eligibility
* Known primary immunodeficiency
* Known HIV positivity
* Severe, uncontrolled intercurrent bacterial, viral, or fungal infection
* Known active malignancy other than the B7-H3+ sarcoma being treated on study
* Rapidly progressive disease (as assessed by the study PIs, with consideration for proximity to critical structures)
* Presence of intracranial or spinal cord disease
* Known underlying medical condition(s) for which, in the investigator's opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments
* Known severe hypersensitivity to corn starch or hydroxyethyl starch
Treatment eligibility
* Known primary immunodeficiency
* Known HIV positivity
* Severe, uncontrolled intercurrent bacterial, viral, or fungal infection
* Known active malignancy other than the B7-H3+ sarcoma being treated on study
* Receiving systemic steroid therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, \< 7 days prior to CAR T cell infusion
* Receiving systemic therapy \< 14 days prior to start of protocol therapy, which will interfere with the activity of the CAR product (in the opinion of the study PIs)
* Received radiation therapy within the 4 weeks prior to start of protocol therapy
* Rapidly progressive disease (as assessed by the study PIs, with consideration for proximity to critical structures)
* Presence of intracranial or spinal cord disease
* Known underlying medical condition(s) for which, in the investigator's opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments
* Known severe hypersensitivity to corn starch or hydroxyethyl starch
Memphis, Tennessee, 38105, United States
[email protected] / 866-278-5833
Status: Recruiting