Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma
Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma
Background:

 - Cancer development is associated with problems in immune system functions, which prevent
 the body from attacking and destroying the abnormal cells that lead to tumor growth. Research
 has suggested that certain white blood cells, known as Th1 (type 1 T helper cells) and Th2 T
 cells (type 2 T helper cells), are affected in individuals with some kinds of cancer -- when
 the proportion of Th2 cells is greater than Th1 cells, the immune systems ability to fight
 off the growth of malignant tumors is weakened. Researchers are interested in determining if
 an infusion of specially modified Th1 cells, in addition to stem cell transplant, is a safe
 and effective treatment for individuals with forms of multiple myeloma that might not respond
 well to standard treatments alone.

 Objectives:

 - To determine the safety and effectiveness of the infusion of modified Th1 white blood
 cells, in conjunction with standard treatment, as a treatment for individuals who have been
 diagnosed with high-risk forms of multiple myeloma.

 Eligibility:

 -  Individuals age 18 to 75 who have been newly diagnosed with high-risk multiple myeloma
 and who have received no or minimal treatment (Cohort A).

 -  Individuals age 18 to 75 who have relapsed multiple myeloma, as defined by measurable
 disease after at least 2 prior treatment regimens.

 Design:

 -  Participants will be screened with a medical history, physical examination, blood and
 urine tests, and imaging studies. Some participants may also have a bone marrow or other
 type biopsy to evaluate the state of their disease.

 -  White blood cells will be collected from the participants through an apheresis
 procedure, which will collect and separate the white blood cells and return the rest of
 the blood to the participant.

 -  The collected cells will be grown and expanded under special conditions in the
 laboratory and stored frozen until participants receive standard of care treatment for
 multiple myeloma, including a stem cell transplant.

 -  Participants will receive an infusion of the modified Th1 cells a few weeks after the
 transplant, and will remain in the hospital for a few days after receiving the cells to
 monitor the possible immediate effects of the treatment.

 -  Participants will have regular follow-up visits to study the long-term effects of the
 modified Th1 cell infusion.
Background:

 -  Autologous Hematopoietic Cell Transplantation (AHCT), which represents the standard of
 care for newly diagnosed Multiple Myeloma (MM), is not curative therapy. New approaches
 to prevent relapse after AHCT and to treat relapse are needed.

 -  In murine models, we used ex vivo culture to generate rapamycin-resistant, Th1 (type 1 T
 helper cells)/Tc1 (T cytotoxic cells, type 1) polarized T cells (Th1/Tc1.Rapamycin
 (Rapa) cells) that were both rapamycin-resistant and apoptosis-resistant with an
 increased in vivo survival and in vivo function.

 -  Because Th1 /Tc1 polarized lymphocytes are pivotal in anti-tumor effects, we hypothesize
 that adoptive transfer of Th1/Tc1Rapa cells will be of benefit to MM patients.

 Objectives:

 Primary

 Dose escalation study

 Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo
 rapamycin-generated, anti-cluster of differentiation 3 (CD3) and anti-cluster of
 differentiation 28 (CD28) co-stimulated, Th1/Tc1 lymphocytes (Th1/Tc1.Rapa cells) in subjects
 diagnosed with high-risk multiple myeloma following AHCT.

 MM Relapse Prevention and Treatment Cohorts

 -  For Cohort A, in newly diagnosed MM patients who have received AHCT, evaluate the safety
 of a defined regimen of Th1/Tc1.Rapa cell therapy and determine progression-free
 survival.

 -  For Cohort B, in relapsed MM, determine the partial response (PR)/complete response (CR)
 rate of Th1/Tc1.Rapa cell therapy.

 Eligibility:

 -  For Cohort A relapse prevention, patients with MM (normal- or high-risk) who are
 receiving induction therapy and subsequent AHCT.

 -  For Cohort B relapse therapy, patients with MM who have measurable disease after at
 least 2 prior treatment regimens.

 Design:

 -  For Cohort A, patients will receive two infusions of autologous Th1/Tc1.Rapa cells (at
 one and two months post-AHCT; each infusion preceded by a 7-day course of immune
 modulating chemotherapy [pentostatin plus low-dose cyclophosphamide; PC regimen].

 -  For Cohort B relapse therapy, patients will up to four infusions of Th1/Tc1.Rapa cells,
 with each infusion preceded by either a 7-day or 14-day PC regimen.
-  INCLUSION CRITERIA:

 MULTIPLE MYELOMA CRITERIA:

 Criteria for Cohort A (recently diagnosed subjects; to receive autologous hematopoietic
 cell transplantation (AHCT)):

 -  Must have presence of clonal plasma cells in the bone marrow greater or equal to 10%
 or biopsy proven plasmacytoma

 -  Must have either:

 1. presence of an M-component (Immunoglobulin G (IgG) or Immunoglobulin G (IgA)) in
 serum greater or equal to 1g/dl or in urine greater or equal to 200 mg/24 h; or

 2. presence of an abnormal serum free light chain (FLC) ratio on the serum FLC
 assay.

 Criteria for Cohort B (multiply relapsed multiple myeloma):

 -  Must have measurable multiple myeloma (MM), as defined by: serum M-protein greater
 than or equal to 1 g/dL, urine M-protein greater than or equal to 200 mg/24 hours,
 involved serum free light chain (FLC) level greater than or equal to 10 mg/dL, biopsy
 proven plasmacytoma, or more than 30% bone marrow plasma cells.

 -  Must have received at least 2 different treatment regimens for MM.

 Other eligibility criteria (applies to both Cohort A and Cohort B, unless specified):

 -  Age greater than or equal to 18 years and less than or equal to 75 years. In subjects
 between 65 and 75 years of age, physiologic age and co-morbidity will be thoroughly
 evaluated before enrolling. Specifically, any history of cardio-vascular pathology or
 symptoms, not clearly fitting the exclusion criteria will prompt an evaluation by a
 Clinical Center Cardiologist and eligibility will be considered on a case-by-case
 basis.

 -  For Cohort A only, high-dose chemotherapy and AHCT must be planned; with amendment K,
 post-transplant maintenance therapy will not be permitted.

 -  Karnofsky performance status (KPS) of 70% or greater. Lower KPS down to 50% may be
 acceptable if the restriction of activity is solely due to intractable pain from
 myeloma lesions.

 -  Ejection fraction (EF) by multi-gated acquisition scan (MUGA) or two-dimensional (2-D)
 echocardiogram within institution normal limits. In case of low EF, the subject may
 remain eligible after a stress echocardiogram is performed if the EF is more than 35%
 and if the increase in EF with stress is estimated at 10% or more.

 -  Serum creatinine less than or equal to 2.5 mg/dl,

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal
 to 3 times the upper limit of normal.

 -  Bilirubin less than or equal to1.5 (except if due to Gilbert's disease).

 -  Corrected carbon monoxide diffusing capacity (DLCO) greater than or equal to 50% on
 Pulmonary Function Tests

 -  No history of abnormal bleeding tendency or predisposition to repeated infections.

 -  Patients must be able to give informed consent

 EXCLUSION CRITERIA:

 -  Prior allogeneic stem cell transplantation

 -  Hypertension not adequately controlled by 3 or less medications.

 -  History of cerebro-vascular accident within 6 months of enrollment.

 -  History of documented pulmonary embolus within 6 months of enrollment.

 -  Clinically significant cardiac pathology: myocardial infarction within 6 months prior
 to enrollment, Class III or IV heart failure according to New York Heart Association
 (NYHA), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
 electrocardiographic evidence of acute ischemia or active conduction system
 abnormalities.

 -  Patients with a history of coronary artery bypass grafting or angioplasty will receive
 a cardiology evaluation and be considered on a case-by-case basis.

 -  Human immunodeficiency virus (HIV) seropositive

 -  Patients known or found to be pregnant or who is unwilling to stop breast-feeding.

 -  Patients of childbearing age who are unwilling to practice contraception or other
 means of avoiding pregnancy.

 Patients may be excluded at the discretion of the principal investigator (PI) if it is
 deemed that allowing participation would represent an unacceptable medical or psychiatric
 risk.