GPC2 CAR T Cells for Relapsed or Refractory Neuroblastoma and Metastatic Retinoblastoma

Neuroblastoma Inclusion Criteria:

1. Patients must be ≥ 1 year of age

2. Patients must have high-risk neuroblastoma according to COG risk classification atthe time of study enrollment. Patients who were initially considered low- orintermediate-risk, but then reclassified as high-risk are also eligible.

3. Patients must have a previously histologically confirmed diagnosis of neuroblastoma:

4. That is recurrent/relapsed or refractory/persistent according to INRC (seeSection 21.1) AND

5. For which standard curative measures do not exist or are no longer effective.

6. patients at first relapse are eligible as no known curative therapies exist forrelapsed high-risk neuroblastoma.

7. Patients must have evaluable or measurable disease at enrollment.

8. In addition, patient must have experienced at least one of the following: a. New disease site documented on at least one of the following: i. 123I-meta-iodobenzylguanidine (MIBG) or 18F-mFBG (meta-fluorobenzylguanidine) scan;OR ii. CT/MRI; OR iii. FDG or Ga-68 Dotatate PET (in patients known to have MIBGnon-avid tumor) and MRI findings consistent with tumor (i.e., bone lesions), OR iv.Biopsy confirmed neuroblastoma for any new or progressing lesion. b. Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI and aminimum absolute increase of 5 mm in longest dimension in existing lesion(s).Previously irradiated lesions may be included. c. Bone marrow biopsy shows progressive disease according to the revised INRC (referto Table 17) d. Stable persistent disease, such that response at the completion ofupfront therapy or salvage therapy is less than partial response AND has a biopsy ofat least one site showing viable neuroblastoma. e. Responding persistent disease, defined as at least a partial response tofrontline therapy (i.e., at least a partial response to frontline therapy but stillhas residual disease by MIBG scan, CT/MRI, or bone marrow aspirations/biopsies).Patients in this category are required to have histologic confirmation of viableneuroblastoma from at least one residual site (tumor seen on routine bone marrowmorphology is sufficient).

9. Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 60 (See Table 13)

10. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN for age.

11. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients withGilbert's Disease)

12. Aspartate aminotransferase (AST) ≤ 2.5 ULN (exception: AST ≤ 5 x ULN for patientswith liver metastases).

13. Alanine aminotransferase (ALT) ≤ 2.5 ULN (exception: ALT ≤ 5 x ULN for patients withliver metastases).

14. Patients must have a baseline pulse oximetry of at least 92% on room air. Inaddition, a DLCO ≥ 60% (corrected for anemia) is required if PFTs are clinicallyappropriate as determined by the treating investigator.

15. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50%confirmed by Echo, or adequate ventricular function documented by a scan or acardiologist.

Neuroblastoma Exclusion Criteria:

1. Patients with active hepatitis B or active hepatitis C.

2. Patients with HIV infection.

3. Patients with uncontrolled active infection.

4. Patients with primary or acquired immunodeficiency disorder.

5. Patients with a known hypersensitivity to DMSO.

6. Concurrent use of systemic steroids or immunosuppression at the time of cellinfusion or cell collection, or a condition, in the treating physician's opinion,that is likely to require steroid therapy or immunosuppression during collection orafter infusion. Steroids for disease treatment at times other than cell collectionor at the time of infusion are permitted. Use of physiologic replacementhydrocortisone or inhaled steroids is permitted as well.

7. Patients with actively progressing CNS metastases, including parenchymal orleptomeningeal involvement. (Note: CNS imaging at screening is only required if thethere is a clinical indication of suspected CNS metastasis)

8. Active medical disorder that, in the opinion of the investigator, wouldsubstantially increase the risk of uncontrollable CRS and/or neurotoxicity.

9. Patients with congestive heart failure (as defined by New York Heart AssociationFunctional Classification III or IV), unstable angina, serious uncontrolled cardiacarrhythmia, a myocardial infarction within 6 months prior to study entry or ahistory of myocarditis.

10. Patients who have received any live vaccines within 30 days prior to enrollment.

11. Patients who are pregnant or nursing (lactating).

12. Patients who have a life expectancy < 6 months at time of consent.

Retinoblastoma Inclusion Criteria:

1. Patient age ≥ 6 months.

2. Patients must have metastatic retinoblastoma according to InternationalRetinoblastoma Staging System (IRSS) risk classification (4) at the time of studyenrollment: a. Retinoblastoma Cohort 1 (Extra-CNS metastasis) i. Stage IVa disease ii. Extra-CNSdisease must be confirmed as retinoblastoma by histology (either at diagnosis orrecurrence) iii. Measurable disease: Defined as > 1cm2 or biopsy-proven bone marrowdisease iv. Prior treatment: Recurrent or refractory disease following treatmentwith COG ARET0321-like or equivalent regimen as part of upfront or recurrent therapyb. Retinoblastoma Cohort 2 (CNS disease) i. Stage IVb disease ii. Histologicconfirmation is not required iii. CNS disease defined as measurable disease >1cm2,non-measurable, or CSF positivity alone c. Prior treatment: i. Stage IVb.1 andIVb.2: Recurrent after treatment with COG ARET0321-like or equivalent regimen aspart of upfront or recurrent therapy (see appendix 21.2) i. Stage IVb.3: Priortreatment is not required (i.e., eligible at initial diagnosis or recurrence) (seeappendix 21.2)

3. Patients must have a Lansky (≤ 16 years) or Karnofsky (> 16 years) score of ≥ 60 (See Table 13)

4. Patients must have adequate renal function defined as age-adjusted serum creatinine ≤1.5 ULN .

5. Total bilirubin ≤ 1.5 x ULN (exception: total bilirubin ≤ 3 ULN for patients withGilbert's Disease)

6. Aspartate aminotransferase (AST) ≤ 2.5 ULN (exception: AST ≤ 5 x ULN for patientswith liver metastases).

7. Alanine aminotransferase (ALT) ≤ 2.5 ULN (exception: ALT ≤ 5 x ULN for patients withliver metastases).

8. Patients must have a baseline pulse oximetry of at least 92% on room air. Inaddition, a DLCO ≥ 60% (corrected for anemia) is required if PFTs are clinicallyappropriate as determined by the treating investigator.

9. Left ventricular shortening fraction (LVSF) ≥28% or ejection fraction (LVEF) ≥ 50%confirmed by Echo, or adequate ventricular function documented by a scan or acardiologist.

Retinoblastoma Exclusion Criteria:

1. Patients with active hepatitis B or active hepatitis C.

2. Patients with HIV infection.

3. Patients with uncontrolled active infection.

4. Patients with primary or acquired immunodeficiency disorder.

5. Patients with a known hypersensitivity to DMSO.

6. Concurrent use of systemic steroids or immunosuppression at the time of cellinfusion or cell collection, or a condition, in the treating physician's opinion,that is likely to require steroid therapy or immunosuppression during collection orafter infusion. Steroids for disease treatment at times other than cell collectionor at the time of infusion are permitted. Use of physiologic replacementhydrocortisone or inhaled steroids is permitted as well.

7. Active medical disorder that, in the opinion of the investigator, wouldsubstantially increase the risk to the subject.

8. Patients with congestive heart failure (as defined by New York Heart AssociationFunctional Classification III or IV), unstable angina, serious uncontrolled cardiacarrhythmia, a myocardial infarction within 6 months prior to study entry or ahistory of myocarditis.

9. Patients who have received any live vaccines within 30 days prior to enrollment.

10. Patients who are pregnant or nursing (lactating).

11. Patients who have a life expectancy < 6 months at time of consent.

12. Retinoblastoma Cohort 1 (Extra-CNS disease):

13. Concurrent CNS disease (they may be eligible for Retinoblastoma Cohort 2)

14. Stage III disease (orbital or lymph node regional extension without otherhematogenous metastases).

15. Retinoblastoma Cohort 2 (CNS disease):

16. "Bulky" disease (>5 cm in diameter) within or compressing the brainstem orthalamus. Note: Tumors touching the brainstem/thalamus without evidence ofcompression and/or tumors in other CNS locations do not have a maximal sizecriterion.

17. Evidence of increased intracranial pressure.