T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
T-cells Expressing an Anti-SLAMF7 CAR for Treating Multiple Myeloma
Background:

 Multiple myeloma is a blood cancer that is usually incurable. T cells are part of the immune
 system. Researchers think changing a person s T cells to recognize their cancer could help
 the person s body kill tumor cells. This is a new approach that uses a patient s own cells to
 target multiple myeloma.

 Objective:

 To see if giving anti-SLAM7 CAR T cells with a stop switch to people with multiple myeloma is
 safe andto see if adding a gene to stop T-cell activity can limit toxicity of this therapy.

 Eligibility:

 People ages 18-73 with multiple myeloma for which prior standard treatment has not worked

 Design:

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Blood, urine, and heart tests

 -  Bone marrow samples: A needle inserted into the participant s bone will remove marrow.

 -  Imaging scans: Participants will lie in a machine that takes pictures of the body.

 Participants will have apheresis. They will receive a catheter or central line: A plastic
 tube will be inserted into a chest or arm vein. Blood will be removed and the T cells
 separated. The rest of the blood will be returned to the participant. The T cells will be
 manipulated in the lab.

 Participants will get chemotherapy through the central line for 3 days.

 Participants will receive the manipulated T cells through the central line. They will stay in
 the hospital at least 9 days.

 Participants will have follow-up visits 2 weeks then 1, 2, 3, 4, 6, 9, and 12 months after
 the infusion. They will then have visits every 6 months for 3 years. Then they will be
 contacted once per year for 15 years. All visits will include blood tests, and 3 visits will
 include bone marrow biopsies....
Background:

 -  Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells.

 -  T cells can be genetically modified to express chimeric antigen receptors (CARs) that
 target malignancy-associated antigens.

 -  SLAMF7 is highly and uniformly expressed on MM cells but is absent on normal tissues
 except for some leukocytes, including a subset of CD8+ T cells, natural killer (NK)
 cells, B cells, plasma cells and monocytes.

 -  We have constructed a novel anti-SLAMF7 CAR that can specifically recognize SLAMF7-
 expressing target cells and eradicate SLAMF7-expressing tumors in mice.

 -  This protocol will test genetic modification of autologous T cells with genes encoding
 an inducible caspase 9 (IC9) cell-suicide system plus the anti-SLAMF7 CAR.

 -  Administration of the dimerizer drug Rimiducid (AP1903) is necessary to activate the IC9
 suicide gene and eliminate CAR T cells.

 -  In this protocol, the suicide gene system will be used to eliminate CAR-expressing T
 cells in case of severe toxicities caused by the CAR T cells.

 -  Possible toxicities include cytokine-associated toxicities such as hypotension, and
 neurological toxicities. Elimination of NK cells and normal plasma cells could make
 patients more susceptible to infections. Unknown toxicities are also possible.

 Objectives:

 Primary

 - Determine the safety, feasibility of administering T cells expressing an anti-SLAMF7 CAR
 plus IC9 cell-suicide system to patients with MM.

 Eligibility:

 -  Greater than or equal to 18 years of age and less than or equal to age 73.

 -  Patients must have measurable MM defined as a serum M-protein >=0.6 g/dL or a urine
 M-protein >=200 mg/24 hours or an involved serum free light chain (FLC) level >=10 mg/dL
 (provided FLC ratio is abnormal) or a biopsy-proven plasmacytoma of 1.5 cm or more in
 largest dimension, or greater than or equal to 30% bone marrow plasma cells.

 -  Patients must have previously received at least 3 different treatment regimens for MM.

 -  Patients must have prior exposure to an immunomodulatory drug (IMiD) such as
 lenalidomide, and a proteasome inhibitor

 -  Patients must have a creatinine level of less than or eual to 1.5 mg/dL

 -  Patients must have a cardiac ejection fraction >= 50%.

 -  An ECOG performance status of 0-2 is required.

 -  Patients on any anticoagulant medications except aspirin are not eligible.

 -  No active infections are allowed.

 -  Absolute neutrophil count >= 1000/microL, platelet count >= 55,000/microL, hemoglobin >=
 8g/dL

 -  ALT and AST less thanor equal to 2.5-fold higher than the upper limit of normal.

 -  At least 14 days must elapse between the time of any prior systemic treatment (including
 corticosteroids) and the required leukapheresis.

 -  At least 14 days must elapse between the time of any prior systemic treatment and
 initiation of protocol treatment. Systemic therapy includes corticosteroids at a dose
 equivalent to more than 5 mg of prednisone.

 -  Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow
 cells less than or equal to 24 days prior to the start of protocol treatment.

 -  The patient s MM will need to be assessed for SLAMF7 expression by flow cytometry or
 immunohistochemistry performed at the NIH. The myeloma must express SLAMF7. If
 unstained, paraffin-embedded bone marrow or plasmacytoma sections are available from
 prior biopsies, these can be used to determine SLAMF7 expression by
 immunohistochemistry; otherwise patients will need to come to the NIH for a bone marrow
 biopsy or other biopsy of a plasmacytoma to determine SLAMF7 expression. The sample for
 SLAMF7 expression can come from a biopsy obtained at any time before enrollment.

 Design:

 -  This is a phase I dose-escalation trial

 -  Patients will undergo leukapheresis, and T cells will be modified to express the
 IC9-anti-SLAMF7 CAR construct.

 -  The chemotherapy conditioning regimen is cyclophosphamide 300 mg/m^2 daily for 3 days
 and fludarabine 30 mg/m^2 daily for 3 days. The intent of chemotherapy is to enhance CAR
 T-cell activity.

 -  After the chemotherapy ends, the patients will have two days with no treatments and then
 receive an infusion of CAR T cells.

 -  The initial dose level will be 0.66x10^6 Anti-SLAMF7-CAR + T cells/kg of recipient
 bodyweight.

 -  The cell dose administered will be escalated for up to 4 doses until a maximum tolerated
 dose is determined.

 -  Following the T-cell infusion, there will be a mandatory 9-day minimum inpatient
 hospitalization to monitor for toxicity.

 -  Outpatient follow-up is planned for 2 weeks, and 1, 2, 3, 4, 6, 9, and 12 months after
 the CAR T-cell infusion. Afterwards, follow-up will be every six months up to at least 3
 years after infusion.
-  INCLUSION CRITERIA - MULTIPLE MYELOMA:

 -  SLAMF7 expression must be detected on malignant plasma cells from either bone marrow
 or a plasmacytoma by flow cytometry or immunohistochemistry. A specific quantitative
 level of SLAMF7 expression for eligibility is not specified, but patients with
 multiple myeloma cells that are negative for SLAMF7 by flow cytometry and
 immunohistochemistry will not be enrolled. These assays must be performed at the
 National Institutes of Health (NIH). It is not required that the specimen used for
 SLAMF7 determination comes from a sample that was obtained after the patient s most
 recent treatment. If paraffin embedded unstained samples of bone marrow involved with
 MM or a plasmacytoma are available, these can be shipped to the NIH for SLAMF7
 staining, otherwise new biopsies will need to be performed for determination of SLAMF7
 expression.

 -  SLAMF7 expression will need to be documented on the majority of malignant plasma cells
 by flow cytometry at the NIH at some time after the original CAR-SLAMF7 T-cell
 infusion in all patients undergoing a second CAR-SLAMF7 T-cell infusion on this
 clinical trial.

 -  Bone marrow plasma cells must make up less than or equal to 50% of total bone marrow
 cells based on a bone marrow biopsy performed within 24 days of the start of protocol
 treatment.

 -  Patients must have received at least 3 different prior treatment regimens for multiple
 myeloma

 -  Must have prior exposure to an immunomodulatory drug (IMiD) such as lenalidomide and a
 proteasome inhibitor

 -  Patients must have measurable MM as defined by at least one of the criteria below.

 -  Serum M-protein greater or equal to 0.6 g/dL.

 -  Urine M-protein greater or equal to 200 mg/24 h.

 -  Serum free light chain (FLC) assay: involved FLC level greater or equal to 10
 mg/dL (100 mg/L) provided serum FLC ratio is abnormal.

 -  A biopsy-proven plasmacytoma at least 1.5 cm in largest dimension

 -  Bone marrow core biopsy with 30% or more plasma cells

 INCLUSION CRITERIA - OTHER:

 -  Greater than or equal to 18 years of age and less than or equal to age 73.

 -  Able to understand and sign the Informed Consent Document.

 -  Clinical performance status of ECOG 0-2

 -  Patients of both sexes must be willing to practice birth control from the time of
 enrollment on this study and for four months after last day of receiving protocol
 treatment.

 -  Seronegative for HIV antibody. (The experimental treatment being evaluated in this
 protocol depends on an intact immune system. Patients who are HIV seropositive can
 have decreased immune-competence and thus are less responsive to the experimental
 treatment and more susceptible to its toxicities.)

 -  A patient with a negative blood PCR test for hepatitis B DNA test can be enrolled. If
 hepatitis B DNA (PCR) testing is not available, patients with a negative hepatitis B
 surface antigen and negative hepatitis B core antibody can be enrolled.

 -  Patients must be tested for the presence of Hepatitis C antigen by PCR and be HCV RNA
 negative in order to be eligible. Only if Hepatitis C PCR testing is not available in
 a timely manner, patients who are Hepatitis C antibody-negative can be enrolled.

 -  Absolute neutrophil count greater than or equal to 1000/mm^3 without the support of
 filgrastim or other growth factors within the previous 10 days.

 -  Platelet count greater than or equal to 55,000/mm^3 without transfusion support in the
 past 14 days.

 -  Hemoglobin greater than or equal to 8.0 g/dL.

 -  Less than 5% plasma cells in the peripheral blood leukocytes

 -  Serum ALT and AST less or equal to 2.5 times the upper limit of the institutional
 normal.

 -  Serum creatinine less than or equal to 1.5 mg/dL.

 -  Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert's
 Syndrome who must have a total bilirubin less than 3.0 mg/dL.

 -  At least 14 days must have elapsed since any prior systemic therapy at the time the
 patient starts the cyclophosphamide and fludarabine conditioning regimen, and patients
 toxicities must have recovered to a grade 1 or less (except for toxicities such as
 alopecia or vitiligo or cytopenias).

 -  Because this protocol requires collection of autologous blood cells by leukapheresis
 in order to prepare CAR-SLAMF7 T cells, systemic anti-myeloma therapy including
 systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or
 equivalent dose of another corticosteroid are not allowed within 14 days prior to the
 required leukapheresis.

 -  Normal cardiac ejection fraction (greater than or equal to 50% by echocardiography)
 and no evidence of hemodynamically significant pericardial effusion as determined by
 an echocardiogram.

 -  For patients with past participation in gene-therapy, cryopreserved PBMC that have not
 been genetically-engineered must be available.

 -  Patients receiving prior gene therapy outside of NIH will not be eligible. Patients
 who previously received CAR T-cell therapy at the NCI will be potentially eligible.

 EXCLUSION CRITERIA:

 -  Patients who are receiving any other investigational agents.

 -  Patients on any anticoagulants except aspirin

 -  Patients that require urgent therapy due to tumor mass effects or spinal cord
 compression.

 -  Patients that have active hemolytic anemia.

 -  Patients with second malignancies in addition to multiple myeloma are not eligible if
 the second malignancy has required treatment within the past 3 years or is not in
 complete remission. There are two exceptions to this criterion: successfully treated
 non-metastatic basal cell or squamous cell skin carcinoma.

 -  Women of child-bearing potential who are pregnant or breastfeeding because of the
 potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
 Women of child bearing potential cannot have a positive pregnancy test. Women of
 childbearing potential are defined as all women except women who are post-menopausal
 or who have had a hysterectomy. Postmenopausal will be defined as women over the age
 of 55 who have not had a menstrual period in at least 1 year.

 -  Active systemic infections (defined as infections causing fevers or requiring
 anti-microbial treatment), active coagulation disorders or other major uncontrolled
 illnesses of the cardiovascular, respiratory, endocrine, renal, gastrointestinal,
 genitourinary, neurologic, psychiatric, or immune system, history of myocardial
 infarction, active cardiac arrhythmias, active obstructive or restrictive pulmonary
 disease.

 -  Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
 Disease).

 -  Systemic corticosteroid steroid therapy of greater than 5 mg/day of prednisone or
 equivalent dose of another corticosteroid (prednisone, dexamethasone, etc.) is not
 allowed within 14 days prior to either the required leukapheresis or within 14 days
 prior to CAR Tcell infusion (and at any time after the CAR T cell infusion unless
 approved by the Principal Investigator or an Associate Investigator).

 -  History of severe immediate hypersensitivity reaction to any of the agents used in
 this study.

 -  Patient unwilling to undergo intensive care unit treatment including mechanical
 ventilation, cardiopulmonary resuscitation, vasoactive drugs, and hemodialysis.

 -  History of allogeneic stem cell transplantation

 -  Patients with currentspinal cord compression (without intradural myeloma involvement.

 -  Patients who have a history (or current evidence) of cerebrospinal fluid multiple
 myeloma, or intra-dural central nervous system masses.

 -  Patients with active autoimmune skin diseases such as psoriasis or other active
 autoimmune diseases such as rheumatoid arthritis.

 -  Patients must not have required supplemental oxygen within the past month unless it
 was for a resolved infection.