Inclusion Criteria:
Screening Eligibility. 1. Age ≤ 21 years of age. 2. Primary CNS tumor. 3. For Cohort A, must have evidence of relapsed or refractory non-brainstem CNS tumor. 4. For Cohort B, must meet one of the following criteria:
- - Adequate tumor tissue from primary tumor resection or biopsy for central
pathology review (i.e., B7-H3 expression evaluation by immunohistochemistry
[IHC] or H3K27M mutation if pontine lesion)
- Has a diagnosis of diffuse midline glioma that harbors a mutation associated
with this entity (e.g. H3K27M)
- Has presumptive/suspected brainstem high-grade neoplasm with available imaging
for central imaging review.
5. Life expectancy of > 12 weeks. 6. Adult patient, parent or legal guardian can understand and is willing to sign a
written informed consent document according to institutional guidelines.
Exclusion Criteria:
Screening Eligibility All Participants. 1. Participant has other clinically significant medical disorders (e.g. serious
infections or significant cardiac, pulmonary, hepatic, psychiatric, or other organ
dysfunction) that could compromise their ability to tolerate protocol therapy or
would interfere with study procedure.
Inclusion Criteria:
Procurement and T-cell Production Eligibility. 1. Age ≤ 21 years of age. 2. Primary CNS tumor with measurable or evaluable disease and meets criteria for either
Cohort A or B:
- - Cohort A: relapsed/refractory non-brainstem CNS primary tumor AND tumor is
B7-H3 positive.
- - Cohort B: Diffuse midline glioma AND tumor is:
- B7-H3 positive if non-pontine.
- - OR H3K27-altered diffuse midline pontine glioma.
- - OR radiographically-confirmed classic/typical DIPG.
3. Estimated life expectancy of >12 weeks. 4. Karnofsky or Lansky performance score ≥50. 5. Participant of childbearing/child-fathering potential agrees to use contraception. 6. For females of childbearing age:
- - Not pregnant with negative serum pregnancy test.
- - Not lactating with intent to breastfeed.
7. Chemotherapy/biologic therapy must be discontinued ≥ 7 days prior to enrollment. 8. The last dose of antibody therapy (including check point inhibitor) must be at least
3 half-lives or 30 days, whichever is shorter, from the time of enrollment. 9. At least 30 days from most recent cell infusion prior to enrollment.
10. All systemically administered corticosteroid therapy must be stable or decreasing
for ≥1 week prior to enrollment, with a maximum dexamethasone dose of 2.8 mg/m^2/day. 11. Meets eligibility for apheresis, or has an apheresis product previously collected at
a FACT-accredited program. 12. Adult patient, parent or legal guardian can understand and is willing to sign a
written informed consent document according to institutional guidelines.
Exclusion Criteria:
Procurement and T-cell Production Eligibility. 1. Known primary immunodeficiency or acquired immunodeficiency.
2. Known HIV positivity. 3. Severe intercurrent bacterial, viral or fungal infection (e.g. active hepatitis B or
C infection or adenovirus infection).
4. Rapidly progressive disease. 5. Known underlying medical condition for which participation in this trial would not
be in the best interest of the participant or that could prevent, limit or confound
protocol assessments.
6. Adult patient, Parent, or legal guardian is unwilling or unable to provide consent
for participation in a 15 year long-term follow up study.
Inclusion Criteria:
Treatment Eligibility.Cohort A.
- - Relapsed/refractory non-brainstem CNS primary tumor.
- - Tumor must be considered B7-H3 positive.
Cohort B.
- - Diffuse Midline Glioma - Must meet one of the following criteria.
- - Tumor is considered B7-H3 positive.
- - H3K27-altered diffuse midline pontine glioma.
- - Radiographically-confirmed classic/typical DIPG.
- - Must complete standard radiation prior to Loc3CAR treatment and be a minimum of 6
weeks post-completion of radiation therapy.
All participants. 1. Age ≤ 21 years old. 2. Primary CNS tumor with measurable or evaluable disease. 3. Available autologous T-cell product that has met GMP release criteria. 4. Participant has a CNS reservoir catheter (e.g., Ommaya) or programmable shunt. 5. First CAR T cell infusion is planned/scheduled ≥ 5 days from CNS surgery, including
catheter placement. 6. The following treatments must be discontinued for the specified duration prior to
treatment enrollment:
- - Radiation therapy: ≥ 6 weeks.
- - Bevacizumab: ≥ 28 days.
- - Cytotoxic chemotherapy: ≥ 21 days.
- - Biologic agents: ≥ 7 days.
- - Antibody therapy: ≥ 3 half-lives or 30 days (whichever is shorter)
- Cellular therapy: ≥ 30 days.
- - Investigational agent: ≥ 3 half-lives or 30 days (whichever is shorter)
- Corticosteroids: All systemically administered therapy must be stable or
decreasing for ≥ 1 week prior to enrollment, with a maximum dexamethasone dose
of 2.8 mg/m^2/day.
Corticosteroid physiologic replacement therapy for
management of pituitary/adrenal axis insufficiency and/or topical
administration (e.g. inhaled or dermatologic) is allowed.
7. Estimated life expectancy of >8 weeks. 8. Karnofsky or Lansky performance score ≥ 50. 9. Echocardiogram with a left ventricular ejection fraction ≥ 50%
10. Adequate renal function defined as calculated creatinine clearance or radioisotope
GFR ≥ 50 mL/min/1.73m^2.
11. Adequate pulmonary function defined as forced vital capacity (FVC) ≥50% of predicted
value or pulse oximetry ≥90% on room air.
12. Total Bilirubin ≤3 times the upper limit of normal for age.
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 times the
upper limit of normal for age.
14. Hemoglobin >8.0 g/dL (can be transfused).
15. Platelet count >50,000/mm^3 (can be transfused).
16. Absolute neutrophil count (ANC) ≥1000/uL.
17. Taking anti-seizure medication, or agrees to initiate anti-seizure medication prior
to starting study therapy.
18. Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from
prior therapy.
19. Male participants of child-fathering potential agree to use contraception. 20. Female participants of childbearing potential:
- - Negative serum pregnancy test within 7 days prior to infusion.
- - Not lactating with intent to breastfeed.
- - If sexually active, agrees to use birth control until 3 months after T-cell
infusion.
Male partners should use a condom. 21. Adult patient, parent or legal guardian can understand and is willing to sign a
written informed consent document according to institutional guidelines.
Exclusion Criteria:
Treatment Eligibility-All Participants. 1. Participant has a non-programmable ventricular shunt that could compromise study
therapy. 2. Participant has a reservoir catheter or shunt in a location that could compromise
study therapy or patient safety. 3. Known primary immunodeficiency or acquired immunodeficiency.
4. Known HIV positivity. 5. Severe intercurrent bacterial, viral or fungal infection. 6. Myocardial infarction, unstable angina, New York Heart Association class III and IV
congestive heart failure, myocarditis, or ventricular arrhythmias requiring
medication within 6 months prior to study entry. 7. Receiving therapy as outlined above during the 'wash-out' period. 8. Rapidly progressing disease. 9. Received any live vaccines within 30 days. 10. Known underlying medical condition for which participation in this trial would not
be in the best interest of the participant or that could prevent, limit or confound
protocol assessments. 11. Adult patient, Parent, or legal guardian is unwilling or unable to provide consent
for participation in a 15 year long-term follow up study
