PRIMARY OBJECTIVES:
I. To assess the safety and feasibility of intravenous infusion of autologous peripheral
blood mononuclear cells (PBMC) and CD34+ peripheral blood stem cells (PBSC) that have been
genetically modified ex vivo to express NY-ESO-1 TCR, following a myeloablative conditioning
regimen.
Ia. Assessment of toxicities using Common Toxicity Criteria (CTC) and definition of a maximum
tolerated dose (MTD).
SECONDARY OBJECTIVES:
I. TCR engineered hematopoietic stem cell (HSC) engraftment. II. Functional assays for TCR
transgenic cells. III. Progression-free survival (PFS) (compare with the duration of the PFS
in the last treatment regimen).
IV. Durable tumor response in at least 30% of the patients defined as immune-related complete
response (irCR) or immune-related partial response (irPR) by immune-related Response
Evaluation Criteria in Solid Tumors (irRECIST) criteria at 6 months.
V. Long-term persistence of TCR transgenic cells (regardless of cell origin) as evidenced by
> 5% of CD3 lymphocytes being NY-ESO-1 specific by major histocompatibility complex (MHC)
tetramer assay at 3 and 6 months.
VI. Discrimination of TCR transgenic cells resulting from retrovirally-transduced mature
lymphocytes and lentivirally-transduced HSCs and their phenotyping.
VII. Long term monitoring for replication competent retrovirus and lentivirus. VIII. Analysis
of viral insertion sites in long term persisting NY-ESO-1 TCR clones: absence of a clonal
expansion of TCR transgenic cells with a particular transgene insertion site (defined as a
clone comprising > 20% of all PBSC-derived gene-marked cells).
IX. Gut microbiota pre and post treatment to evaluate the role of microbiota on the
therapeutic efficacy of the proposed therapy.
OUTLINE: This is a dose-escalation study of autologous NY-ESO-1-specific CD8-positive T
lymphocytes.
Patients receive melphalan intravenously (IV) over 30 minutes on day -1. Patients then
receive autologous NY-ESO-1 CD4-TCR CD34+ HSC IV on day 0 and autologous NY-ESO-1-specific
CD8-positive T lymphocytes IV between days 7 and 21. Patients also receive aldesleukin
subcutaneously (SC) twice daily (BID) for 14 days on the following day after the T cell
infusion (between days 8 and 22).
After completion of study treatment, patients are followed up every 6 months for 5 years,
then annually for up to 15 years.
Inclusion Criteria:
- Must have a diagnosis of platinum-sensitive or platinum-resistant recurrent or
refractory epithelial ovarian, primary peritoneal or fallopian tube carcinoma and have
progressed, relapsed, or recurred through at least one or more prior lines of
standard-of-care therapies. For platinum sensitive patients, the standard of care
therapies include additional platinum-containing regimens and bevacizumab
- Have been informed of other treatment options
- Must be HLA- A*02.1 and HLA-DP*04 positive. Retesting is not required for patients who
have previous documented positivity
- Patient's tumor must be positive by histological or molecular assay for NY-ESO-1
- Have an Eastern Cooperative Oncology group (ECOG) performance status of 0 or 1
- Life expectancy of > 4 months
- At least 4 weeks from prior chemotherapy, radiotherapy or immunotherapy, or prior
investigational agents
- Must have measurable disease as defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1
- Must have adequate venous access for apheresis (pheresis catheter placement for cell
collection is allowed)
- Since the study drug may affect pregnancy since it targets proteins present during
development, women of childbearing potential are requested to use acceptable methods
of birth control for the duration of the study and until persistence of the study drug
is no longer detected in the patient by polymerase chain reaction (PCR). This may be a
period of several years. Methods for acceptable birth control include: condoms,
diaphragm or cervical cap with spermicide, intrauterine device, and hormonal
contraception. It is recommended that a combination of two methods be used
- Leukocytes >= 3 x 10^9/L
- Absolute neutrophil count >= 1.5 x 10^9/L
- Platelets >= 100 x 10^9/L
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal
- Creatinine =< 2 x upper limit of normal (ULN); if creatinine level > 2 x ULN, then
creatinine clearance must be > 60 mL/min
- Patient must understand the investigational nature of this study and sign an
Independent Ethics Committee/Institutional Review Board approved written informed
consent form prior to receiving any study related procedure
- Participant must agree to and arrange for a caregiver (age >= 18 years old) available
24 hours a day/ 7 days a week and arrange for lodging within 45 minutes drive to
Roswell Park and transportation for a period of time after discharge from the
hospital. The exact amount of time will depend on the individual status as determined
by the treating physician
Exclusion Criteria:
- Patients may not be receiving any other investigational agents
- Known cases of clinically active brain metastases (brain magnetic resonance imaging
[MRI] as clinically indicated). 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
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to agents used in the study
- Prior malignancy (except non melanoma skin cancer) within 3 years
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements
- Use of chronic corticosteroids, hydroxyurea, or immunomodulating agents (e.g.,
interleukin 2, interferon alpha or gamma, granulocyte colony stimulating factors,
etc.) within 30 days prior to study entry
- NOTE: Recent or current use of inhaled steroids and topical steroids are not
exclusionary. If subjects are prescribed a brief course of oral corticosteroids,
the use should be limited to less than 7 days. Use of steroids before apheresis
and immune assessment blood draws should be discouraged as it will affect white
blood cell function
- Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV),
hepatitis C virus (HCV), or cytomegalovirus (CMV) as defined below, due to the
immunosuppressive effects of chemo-conditioning used and the unknown risks associated
with viral replication
- Positive serology for HIV
- Active hepatitis B infection as determined by test for hepatitis B surface
antigen (Ag)
- Active hepatitis C. Patients will be screened for HCV antibody. If the HCV
antibody is positive, a screening HCV ribonucleic acid (RNA) by any reverse
transcriptase (RT) PCR or branched deoxyribonucleic acid (bDNA) assay must be
performed at screening by a local laboratory with a Clinical Laboratory
Improvement Act (CLIA) certification or its equivalent. Eligibility will be
determined based on a negative screening value. The test is not required if
documentation of a negative result of a HCV RNA test performed within 60 days
prior to screening is provided.
- Serology (CMV IgG) positive for active CMV
- Received any previous gene therapy using an integrating vector within 6 months
- Pregnancy or breast-feeding
- Lack of availability of a patient for immunological and clinical follow up assessment
- Evidence or history of significant cardiac disease (including myocardial infarction
[MI] in the past 6 months, significant cardiac arrhythmia, stage III or IV congestive
heart failure [CHF]). Cardiac stress test will be done if clinically indicated. (The
specific test to be chosen at the discretion of the principal investigator [PI])
- Patients with pulmonary function test abnormalities as evidenced by a forced
expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 70% of predicted
for normality will be excluded
