Genetically Engineered PBMC and PBSC Expressing NY-ESO-1 TCR after a Myeloablative Conditioning Regimen to Treat Patients with Advanced Cancer
- Stage IV or locally advanced unresectable cancers for subjects who have exhausted (or ineligible) all current available treatment options
- NY-ESO-1 positive malignancy by immunohistochemistry (IHC) utilizing commercially available NY-ESO-1 antibodies
- HLA-A*0201 (HLA-A2.1) positivity by molecular subtyping
- Age greater than or equal to 16 years old; if patients 16-17 years old are enrolled in the trial, they will only be enrolled after 3 patients >= 18 years old have been treated, and the treatment has been shown to be safe
- A minimum of one measurable lesion defined as: * Meeting the criteria for measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) or having at least one or more metastatic lesions that is/are at least double the size of the computed tomography (CT) or magnetic resonance imaging (MRI) slice thickness * Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be accurately measured and recorded by color photography with a ruler to document the size of the target lesion(s)
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
- Adequate bone marrow and major organ function to undergo a PBSC transplant determined within 30-60 days prior to enrollment using standard phase 1 criteria for organ function defined as: * Absolute neutrophil count (ANC) >= 1.5 x 10^9 cells/L * Platelets >= 100 x 10^9/L * Hemoglobin >= 9 g/dL * Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x ULN (=< 5 x ULN, if documented liver metastases are present) * Total bilirubin =< 2 x ULN (except patients with documented Gilbert’s syndrome) * Creatinine < 2 mg/dl (or a glomerular filtration rate > 60)
- Must be willing and able to accept at least three leukapheresis procedures
- Must be willing and able to undergo three research PET scans
- Must be willing and able to provide written informed consent
- Inability to purify >= 2.5 x 10^6 CD34-enriched cells/kg of patient weight from the pooled G-CSF mobilized leukapheresis products; Note: This information will not be available until after the stem cell mobilization and the subsequent assessments are complete; therefore, this information will not be available for the initial verification of eligibility
- Previously known hypersensitivity to any of the agents used in this study; known sensitivity to busulfan or fludarabine
- Received systemic treatment for cancer, including immunotherapy, within 28 days prior to initiation of conditioning chemotherapy administration within this protocol
- Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 2 weeks prior to enrollment (inhaled or topical steroids at standard doses are allowed)
- Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired immune deficiency state, which would increase the risk of opportunistic infections and other complications during chemotherapy-induced lymphodepletion; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
- Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would increase the likelihood of hepatic toxicities from the chemotherapy conditioning regimen and supportive treatments; if there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist
- Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol
- Known clinically active brain metastases; prior evidence of brain metastasis successfully treated with surgery or radiation therapy will not be exclusion for participation as long as they are deemed under control at the time of study enrollment and there are no neurological signs of potential brain metastases
- Pregnancy or breast-feeding; female patients must be surgically sterile or be postmenopausal for two years, or must agree to use effective contraception during the period of treatment and for 6 months afterwards; all female patients with reproductive potential must have a negative pregnancy test (serum/urine) within 14 days from starting the conditioning chemotherapy; the definition of effective contraception will be based on the judgment of the study investigators
- Since IL-2 is administered following cell infusion: * Patients will be excluded if they have a history of clinically significant electrocardiogram (ECG) abnormalities, symptoms of cardiac ischemia with evidence of ischemia on a cardiac stress test (stress thallium, stress multigated acquisition [MUGA], dobutamine echocardiogram or other stress test) * Similarly, patients with a baseline left ventricular ejection fraction (LVEF) < 45% will be excluded. * Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT [QTC] > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (heart rate >120 beats per minute) will be evaluated by a cardiologist prior to starting the trial; patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular contractions [PVCs] per minute), ventricular tachycardia or 3rd degree heart block will be excluded from the study unless cleared by a cardiologist * Patients with pulmonary function test abnormalities as evidenced by a (forced expiratory volume 1 [FEV1]/forced vital capacity [FVC ] < 70% of predicted for normality will be excluded
- Bone marrow involvement based on prior CT or PET scans
- Active or recent herpes simplex virus (HSV) infection or cytomegalovirus (CMV) based on symptoms with positive swab culture and/or positive IgM screening, which would complicate the post-conditioning period
- Liver metastases with no other metastatic sites based on prior scans; there is a significant amount of liver uptake with [18F]FHBG; if there are only liver metastases, the signal of the PET tracer may be obscured by the high background level in the liver and no signal would be observed in the subject
I. To determine the safety of administering the combination of autologous peripheral blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) following a reduced intensity conditioning regimen, both of which have been genetically modified to express NY-ESO-1 TCR.
I. To determine the feasibility of delivering the combination of TCR transduced autologous PBMC and CD34+ PBSC to patients.
II. To determine the persistence of NY-ESO-1 TCR transduced PBMC and the progeny of TCR transduced PBSC in serial peripheral blood samples.
III. Objective response rate (ORR).
I. To explore the use of positron emission tomography (PET)-based imaging using the PET tracer 9-4-[18F]fluoro-3-(hydroxymethyl)butylguanine ([18F]FHBG) with the goal of determining whether the adoptively transferred NY-ESO-1 TCR transduced PBSC home to bone marrow, differentiate into T cells and expand in secondary lymphoid organs and tumor deposits.
G-CSF AND PLERIXAFOR MOBILIZED LEUKAPHERESIS: Between 6 months and 3 weeks before infusion of cells, patients undergo G-CSF and plerixafor mobilization of CD34+ peripheral blood stem cells. Patients receive G-CSF subcutaneously (SC) on mobilization days 1-8 and plerixafor SC on mobilization days 4-7, during mobilization, patients will undergo mobilized leukapheresis to obtain PBSC. Patients also undergo an unmobilized leukapheresis on day -5 before infusion of cells in order to obtain PBMC.
CHEMOTHERAPY CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) on days -4 to -2 and fludarabine IV over 30 minutes on days -3 to -2.
Patients receive LV-NYESO TCR/sr39TK PBSC IV on day 0, and after approximately 24 hours, patients receive RV-NYESO TCR PBMC IV on day 1. Beginning on day 2, patients receive aldesleukin (interleukin-2 or IL-2) SC twice daily (BID) for up to 7 days. Patients undergo blood collection for safety and immune monitoring on days 0, 1, 3, 5, 7, 14, 30, 60, 90, and 120. Patients receive the PET tracer 18F-FHBG IV, and after 1 hour, undergo PET/computed tomography (CT) on days 25 and 120.
After completion of study treatment, patients are followed up every 2-3 months for 2 years, every 6 months for 5 years, and annually for 15 years.
Trial Phase Phase I
Trial Type Treatment
UCLA / Jonsson Comprehensive Cancer Center
Theodore Scott Nowicki
- Primary ID 15-000511
- Secondary IDs NCI-2017-00896, Ribas NYESO SCT Cancer
- Clinicaltrials.gov ID NCT03240861