Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: Laboratory-Treated (Central Memory/Naïve) CD8+ T Cells in Treating Patients With Newly Diagnosed or Relapsed Acute Myeloid Leukemia

Summary: This phase I/II trial studies the side effects of laboratory-treated (central memory/naive) cluster of differentiation 8+ T cells (autologous Wilms tumor [WT]1-T cell receptor [TCRc]4 gene-transduced CD8-positive central memory T-cells [TCM]/naïve T cells [TN] lymphocytes) and how well it works in treating patients with acute myeloid leukemia that is newly diagnosed or has come back. Genetically modified therapies, such as autologous WT1-TCRc4 gene-transduced CD8-positive TCM/TN lymphocytes, are taken from a patient's blood, modified in the laboratory so they specifically may kill cancer cells with a protein called WT1, and safely given back to the patient. The "genetically modified" T-cells have genes added in the laboratory to allow them to recognize leukemia cells that express WT1 and kill them.

Detailed description: PRIMARY OBJECTIVES:
  I. Determine the safety/potential toxicities associated with treating high-risk acute myeloid leukemia (AML) patients with polyclonal autologous CD8+ Tn and Tcm cells genetically-modified to express a high affinity WT1-specific TCR (TCRC4).
  II. Determine the feasibility of treating high-risk AML patients with polyclonal autologous CD8+ TN and TCM cells genetically-modified to express a high affinity WT1-specific TCR.
  III. Determine and compare the in vivo persistence in blood and at the primary tumor site (e.g. bone marrow, chloroma) of transferred polyclonal autologous CD8+ TN and TCM cells transduced to express TCRC4.
  SECONDARY OBJECTIVES:
  I. Determine whether adoptive transferred autologous TCRC4-transduced CD8+ cells have antitumor activity in patients with acute myeloid leukemia.
  II. In patients with measurable tumor burden prior to infusion of TCRC4-transduced CD8+ cells: measure the change in tumor burden by assessment of morphology, flow cytometry, cytogenetics and/or molecular testing at baseline and after infusion of T cells.
  III. In all patients (those with or without measurable tumor burden prior to T cell transfer): compare the probability of relapse, disease-free survival and overall survival of patients receiving TCRC4-transduced CD8+ cells with patients in the observation arm.
  IV. Determine and compare the migration to the primary tumor site of adoptively transferred polyclonal autologous TCRC4-transduced CD8+ TCM and TN cells.
  V. Determine and compare the in vivo functional capacity of transferred polyclonal autologous TCRC4-transduced CD8+ TCM to CD8+ TN cells.
  OUTLINE:
  Beginning 4 weeks after completion of last course of chemotherapy, patients receive autologous WT1-TCRc4 gene-transduced CD8+ TCM/TN lymphocytes intravenously (IV) over 1-4 hours on days 0 and 14. Beginning 6 hours after the second infusion of T cells, patients also receive aldesleukin subcutaneously (SC) twice daily (BID) for 14 days in the absence of disease progression or unacceptable toxicity. Patients who have clinically benefitted from T cell therapy may receive additional infusions of T cells and aldesleukin at the discretion of the principal investigator (PI) and the attending physician.
  After completion of study treatment, patients are followed up weekly for 4 weeks, monthly for 2 months, at 6 and 12 months for the first year, and then annually for 14 years thereafter.

Eligibility: Inclusion Criteria:
  -  Newly diagnosed or relapsed AML patients
  -  Patients must be >= 15 kg
  -  Patients or parents/legal guardian must be able to give informed consent
  -  Patients must be able to provide blood and marrow samples and to undergo the procedures required for this protocol
  -  ELIGIBILITY FOR APHERESIS/BLOOD COLLECTION:
  -  Human leukocyte antigen (HLA)-A*02:01 expression
  -  ELIGIBILITY FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
  -  Response to therapy and completion of at least one cycle of consolidation therapy, and with disease status meeting one of the following criterion within 3 weeks of first dose of WT1-specific CD8+ T cells:
  -  Minimal residual disease, as defined by detectable disease by flow cytometry but with marrow that is at least 10% cellular with < 5% blasts on morphologic review
  -  Minimal residual disease, as defined by persistently detectable, patient-specific molecular or cytogenetic abnormalities
  -  Complete remission with incomplete blood count recovery (CRi)/complete remission with incomplete platelet recovery (CRp), as defined by absence of detectable disease by flow cytometry, and marrow that is at least 10% cellular with < 5% blasts on morphologic review, but with neutrophil count < 1000/ul and/or platelet count < 100,000/ul
  -  Any complete remission (CR) with intermediate risk or high-risk cytogenetics
  -  Any CR obtained after re-induction/salvage therapy
  -  Recovery from induction/salvage therapy (absolute neutrophil count [ANC] > 200/ul, platelet count > 20,000/ul)
  -  In CR (high risk cytogenetics with or without minimal residual disease (MRD) or re-induction or salvage therapy required to attain CR), CRp, or CRi within 3 weeks of first dose WT-1 specific CD8+ T cells
  -  HLA-A*02:01 expression
  -  No plan for allogeneic stem cell transplantation within 3 months
  -  ELIGIBILITY FOR OBSERVATION ARM
  -  Response to therapy and completion of at least one cycle of consolidation therapy, and with disease status meeting one of the following criterion
  -  Minimal residual disease, as defined by detectable disease by flow cytometry but with marrow that is at least 10% cellular with < 5% blasts on morphologic review
  -  Minimal residual disease, as defined by persistently detectable, patient-specific molecular or cytogenetic abnormalities
  -  CRi/CRp, as defined by absence of detectable disease by flow cytometry, and marrow that is at least 10% cellular with < 5% blasts on morphologic review, but with neutrophil count < 1000/ul and/or platelet count < 100,000/ul
  -  Any CR with intermediate risk or high-risk cytogenetics
  -  Any CR obtained after re-induction/salvage therapy
  Exclusion Criteria:
  -  Active autoimmune disease (e.g. systemic lupus erythematosus, vasculitis, infiltrating lung disease, inflammatory bowel disease) in which possible progression during treatment would be considered unacceptable by the investigators
  -  Previous allogeneic hematopoietic cell transplant (HCT)
  -  Any condition or organ toxicity deemed by the Principal Investigator (PI) or the attending physician to place the patient at unacceptable risk for treatment on the protocol
  -  Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling or unable to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within two weeks prior to enrollment and initiation of treatment
  -  Clinically significant and ongoing immune suppression including, but not limited to: systemic immunosuppressive agents such as cyclosporine or corticosteroids (at an equivalent dose of 0.5 mg prednisone/kg per day, or higher), chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection
  -  EXCLUSION FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
  -  Lack of HLA-A*02:01 expression
  -  Unable to generate antigen-specific WT1-specific CD8+ T cells for infusions; however, if a lower than planned number of cells is available, the patient will have the option to receive the generated WT1-specific T cells
  -  In patients whose leukemic cells are available for evaluation, the expression of WT1 in the patient's peripheral blood and/or bone marrow will be determined; if WT1 expression in the patient specimen is not highly expressed, as measured by polymerase chain reaction (PCR), the patient will be ineligible for treatment with WT1-specific T cells, but will be moved to the observation arm of the study; patients with no evaluable leukemia will be eligible for treatment based on the high frequency of positive leukemias (> 90%) and leukemia will be evaluated for WT1 expression if recurrence is detected
  -  Documented infections or oral temperature > 38.2°C fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance therapy; however, if these problems resolve, the start of treatment can be initiated on a delayed schedule
  -  Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed
  -  Symptomatic and refractory central nervous system (CNS) disease
  -  Absolute neutrophil count (ANC) < 200/ul prior to treatment
  -  Platelets < 20,000/ul prior to treatment
  -  Ongoing >= grade 3 cardiac, pulmonary, renal, gastrointestinal or hepatic toxicities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicity criteria
  -  Eastern Cooperative Oncology Group (ECOG) performance status >= 3
  -  Medical or psychological conditions that, according to the PI, would make the patient unsuitable candidate for cell therapy
  -  Pregnancy or breast-feeding; women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test result within 14 days before the first dose of WT1-specific T cell infusion; woman of non-childbearing potential will be defined as being postmenopausal greater than one year or who have had a bilateral tubal ligation or hysterectomy; all recipients of WT1-specific T cells will be counseled to use effective birth control during participation in this study and for 12 months after the last T cell infusion

Relevance to patient case: not relevant