Autologous hALK. Chimeric Antigen Receptor T Cells (hALK.CAR T) for the Treatment of Relapsed or Refractory High-Risk Neuroblastoma

Inclusion Criteria

• Age ≥ 12 months and < 30 years at the time of consent. The first patient on each dose level will need to be age ≥ 6 years old.
• Patients must have a diagnosis of neuroblastoma that is recurrent or refractory and for which standard curative measures do not exist or are no longer effective. Patients must have histologic verification of neuroblastoma at diagnosis or at relapse. Given the high prevalence of ALK expression in neuroblastoma, histological confirmation of ALK expression is NOT required for eligibility.
• Patients must have high risk neuroblastoma according to Children's Oncology Group (COG) risk classification at the time of study registration. Patients who were initially considered low or intermediate risk, but then reclassified as high risk are also eligible.
• Patients must have persistent/refractory or relapsed disease, defined as at least ONE of the following: * Recurrent/progressive disease after the diagnosis of high-risk neuroblastoma at any time prior to study enrollment, regardless of response to frontline therapy. Note that this excludes patients initially considered low or intermediate risk that progressed to high-risk disease but have NOT progressed after the diagnosis of high-risk neuroblastoma. * Refractory disease: A best overall response of no response/stable disease since diagnosis of high-risk neuroblastoma AND after at least 4 cycles of multidrug induction therapy. * Persistent disease: A best overall response of partial response since diagnosis of high-risk neuroblastoma AND after at least 4 cycles of multidrug induction therapy: ** If a patient with persistent disease has 3 or more MIBG avid sites (including all soft tissue and/or bone lesions) OR a Curie Score of ≥ 3, then no biopsy is required for eligibility. ** If a patient with persistent disease has only 1 or 2 MIBG avid sites (including all soft tissue and/or bone lesions) then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one site (bone marrow, bone, or soft tissue) is required.
• Subjects must have measurable or evaluable disease per the Revised International Neuroblastoma Response Criteria.
• Prior therapy: There is no limit to the number of prior treatment regimens. At enrollment (these criteria do not apply to patients with available leukapheresis products; however, patients must meet all other eligibility criteria and meet criteria to start lymphodepleting chemotherapy): * Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy or radiation prior to study enrollment and receive no disease-directed therapy within the screening period. * Patients must not have received the therapies indicated within the specified restricted time prior to enrollment. Prior treatment with an ALK inhibitor, including lorlatinib is allowed.
• Left ventricular ejection fraction (LVEF) >= 50% or shortening fraction >= 28%.
• No clinically significant electrocardiogram (ECG) findings.
• Baseline oxygen saturation > 92% on room air.
• No clinically significant pleural effusion.
• Total bilirubin < 3 x institutional x upper limit of normal (ULN) (except in case of subjects with documented Gilbert’s disease > 3 x institutional ULN).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT)(serum glutamic-pyruvic transaminase [SGTPT]) < 3 x institutional ULN.
• Serum creatinine ≤ 1.2 x institutional ULN according to age OR creatinine clearance (CrCl) ≥ 70ml/min/1.73m^2 (measured by 24hr urine collection or radioisotope glomerular filtration rate [GFR]).
• No active uncontrolled seizure disorder.
• No known current central nervous system (CNS) disease (Prior CNS metastatic disease is allowable if prior resection or radiation occurred at least 8 weeks prior to enrollment without any intervening CNS metastasis).
• Patients with skull-based tumors with direct intracranial extension are eligible as long as there are no neurologic signs or symptoms related to the lesion.
• Lack of a clinically significant coagulopathy.
• Platelet count ≥ 75,000/mcL (no platelet transfusions or platelet growth factors within 7 days of blood draw documenting eligibility). Patients with disease-related and not therapy related thrombocytopenia are exempt. Patients must not be refractory to transfusions.
• Absolute neutrophil count > 750/mcL (no short-acting hematopoietic growth factors within 7 days and no long-acting hematopoietic growth factors within 14 days of blood draw documenting eligibility.) Patients with disease-related and not therapy-related neutropenia are exempt.
• Lansky/Karnofsky performance status ≥ 50%.
• Females of childbearing potential must have a negative serum pregnancy test at enrollment. Premenarchal females do not require pregnancy testing.
• Subject is willing and able to comply with study procedures as determined by the enrolling investigator.
• The effects of hALK.CAR T cells on the developing human fetus are unknown. For this reason and because other chemotherapeutic agents are used in the study are known to be teratogenic, women of child-bearing potential and men of reproductive potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and at least 4 months after completion of the last hALK.CAR T cell administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Patients ≥ 18 years must be able to understand sign a written informed consent document or have a legally authorized representative who can give consent for the patient. For patients < 18 years their legally authorized representative (i.e. parent or legal guardian) must give informed consent. Pediatric patients will be included in the consent discussion as age-appropriate and will provide written informed assent as applicable per institutional standard.

Exclusion Criteria

• Pregnant women are excluded from this study because the effects of hALK.CAR T cells on the developing fetus are unknown and because chemotherapeutic agents with the potential for teratogenic or abortifacient effects are used in this study. Because there is an unknown but potential risk for adverse events in nursing infants, secondary to treatment of the mother with hALK.CAR T cells, and chemotherapy, breastfeeding should be discontinued if the mother is treated with hALK.CAR T cells on this study (NOTE: breast milk cannot be stored for future use while the other is being treated on study).
• Active or uncontrolled viral, bacterial or fungal infection. Subjects may be receiving ongoing therapy for controlled infection.
• Patients who are concurrently receiving other investigational agents.
• Patients who have received prior CART-cell or other gene-modified immune-effector cell therapy are not eligible, unless they are > 8 weeks from the time of infusion, have fully recovered from any associated toxicities AND have documented lack of persistence of the product.
• Subjects with a known additional malignancy other than non-melanomatous skin cancer or carcinoma in situ, unless not requiring active treatment and stable or disease-free for at least 3 years.
• Uncontrolled CNS metastasis. Patients with prior CNS tumor involvement that has been treated and is stable for at least 8 weeks following completion of therapy are permitted. Patients who are clinically stable as evidenced by no requirements for corticosteroids, no evolving neurologic deficits, and no progression of residual brain abnormalities without specific therapy, are permitted.
• CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in the judgement of the investigator may impair the ability to evaluate neurotoxicity.
• History of severe hypersensitivity reaction to compounds of similar chemical or biologic compositions to any agents used in the study or in the manufacturing of cells.
• HIV/hepatitis B virus (HBV)/hepatitis C virus (HCV) infection: Patients are required to be negative for HIV Antibody or HIV viral load, negative for Hepatitis surface antigen (HbsAg) or viral load and negative for HCV antibody or HCV viral load. These patients are ineligible because of the potential for in vivo retroviral recombination events that could lead to replication-competent a-retrovirus. A history of HIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing.
• Steroid therapy: * Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone 6-12mg/m2/day or equivalent. * Inhaled steroids are allowed. * Hydrocortisone for blood product premedication is allowed. * Other than the above, systemic steroids must be stopped prior to cell procurement and prior to lymphodepletion.
• Primary immunodeficiency or history of systemic autoimmune disease requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Subjects who, in the judgement of the investigator, are unlikely to comply with the study requirements for participation or are likely to develop significant toxicity and morbidity from CAR-T cell therapy related inflammation based on the location of the tumor site.