Th1/Tc1 Immunotherapy Following Stem Cell Transplantation in Multiple Myeloma

Phase 1

Terminated

Conditions: Myeloma, Plasma-Cell
Myeloma-Multiple
Myelomatosis

Interventions: Procedure: Adoptive Immunotherapy
Biological: Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells)
Biological: Th1/Tc1 Rapa Cell Therapy

Registration Number: NCT01239368

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort B - Relapsed Multiple Myeloma	Adoptive Immunotherapy	Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) .Rapamycin (Rapa) for Relapsed Multiple Myeloma
Cohort A - Prevention of Relapse	Adoptive Immunotherapy	Th1/Tc1.Rapa Prevention of Relapse
Cohort A - Prevention of Relapse	Th1/Tc1 Rapa Cell Therapy	Th1/Tc1.Rapa Prevention of Relapse
Cohort B - Relapsed Multiple Myeloma	Th1/Tc1 Rapa Cell Therapy	Th1 (type 1 T helper cells)/Tc1 (T cytotoxic cells, type 1) .Rapamycin (Rapa) for Relapsed Multiple Myeloma
Cohort A - Prevention of Relapse	Rapamycin-Generated Autologous Th1/Tc1 Cells (modified primary human T cells)	Th1/Tc1.Rapa Prevention of Relapse

Primary Outcome Measures

Name	Time	Method
Number of Participants With Progression Free Survival in Cohort A Th1 (Type 1 T Helper Cells)/Tc1 (T Cytotoxic Cells, Type 1) Rapa Prevention of Relapse	Study completion at 22 months	Progressive disease is assessed by the Consensus of the International Myeloma Working Group criteria and is defined as one or more of the following: Increases of greater or equal to 25% in serum M-component (minimum absolute increase of 0.5 g/dl) or urine M-component (minimum absolute increase of 200mg/24h) or percentage of bone marrow plasma cells (minimum absolute percentage of 10%) or size of bone lesions or new plasmacytoma, or development of hypercalcemia solely attributable to the disease.
Number of Patients Who Developed a Partial Response (PR)+Complete Response (CR) in Cohort B at Any Time Point Post Therapy With PR/CR Being Maintained Until Study Completed	Study completion at 22 months	Patients whose tumors shrunk and were disease free after therapy in cohort B. Partial response and complete response were assessed by the Consensus of the International Myeloma Working Group criteria. Partial response is defined as 50% or greater reduction in serum M-protein and 90% or greater reduction in 24-h urinary M-protein (or to less than 200 mg per 24h), 50% or greater reduction in the size of soft tissue plasmacytomas, if present at baseline, no evidence of progressive or new bone lesions if radiographic studies were performed (X-rays not required in absence of clinical indication). Complete response is defined as negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and 5% or less plasma cells in bone marrow and no evidence of progressive or new bone lesion if radiographic studies were performed. Progressive disease is increases of ≥25% in serum M-component/urine M-component, or size of bone lesions.
Number of Patients With an Adverse Event Attributable to the Investigational Therapy	2 months	Participants were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

Secondary Outcome Measures

Name	Time	Method
Immune Reconstitution in Recipients of Th1.(T Helper Cell) Rapa Cells.	Baseline, prior to chemotherapy, and 2 weeks, 1, 2, and 3 months after final T cell infusion	Immune reconstitution in recipients of Th1.rapa cells was determined by flow cytometry.
Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)	Date treatment consent signed to last date off study, 81 months and 6 days	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Trial Locations

Locations (2): Hackensack University Medical Center
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Hackensack, New Jersey, United States
National Institutes of Health (NIH) Clinical Center, 9000 Rockville Pike
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Bethesda, Maryland, United States