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Interleukin-2

Patients are treated with up to six injections of their gene-modified CD40L and IL-2 skin fibroblasts and leukemic blasts, separated by one-two weeks in an immunological treatment window.

Leukemic Blasts 2 x 10\^7; IL-2 Fibroblasts 2 x 10\^7; CD40L Fibroblasts 2 x 10\^5

Dose Level 1

Dose Level 2

Leukemic Blasts 2 x 10\^7; IL-2 Fibroblasts 2 x 10\^7; CD40L Fibroblasts 4.2 x 10\^7

Dose Level 3

Malcolm K Brenner, MD, PhD

This research study is to determine the safety and dosage of special cells that may make the patients own immune system fight the leukemia. To do this we will put special genes into cells called fibroblasts that we have grown in the laboratory from a skin sample. The genes we put in these fibroblasts make them produce substances called CD40 Ligand (CD40L) and interleukin-2 (IL-2). These are natural substances that may help the immune system kill leukemia cells. Some of these fibroblasts producing CD40L and IL-2 mixed with a small quantity of the leukemic cells will then be put back into the body.

Studies of cancers in animals and in cell lines suggest that substances like CD40L and IL-2 when mixed with cancer cells do help the body to recognize and kill these cancer cells. A treatment using IL-2 has been previously used in more than 40 children with neuroblastoma and similar treatments are being used in adults with other cancers. Some of the patients have shown significant tumor responses. However, we do not know if this treatment will work and we do not know the right amount of each of the special cells to use, so different patients will get different combination and numbers of cells.

The purpose of this study is to learn the side effects and safe dosage of these special cells.

Before starting in the treatment part of this study, leukemia cells and skin fibroblasts will be collected from the patient - called "procurement" - to allow us to make the vaccine. These leukemia cells are taken from either peripheral blood, leukopheresis product or bone marrow. The fibroblasts will be prepared in the laboratory with specially produced human viruses (adenoviruses) that carry the IL-2 or the CD40L gene. The viruses will "drop off" the genes inside the fibroblasts. The CD40L and IL-2 genes are meant to help stimulate the immune system to fight the leukemia. The modified fibroblasts will be injected with a number of leukemic cells under the skin. All the cells will be irradiated before injection to stop them growing. Patients will receive three shots. Depending on the response, patients may be able to have three additional shots.

In order to collect the skin fibroblasts at the very beginning of the study, and then during the study, we will perform small skin biopsies. In particular before the second shot, and then again about 1 week later, we will look for both the modified and leukemia cells that have been re-injected under the skin. We will do this by taking a skin biopsy from the place where the cells were injected. The area where the skin biopsy will be obtained will be sterilized and then numbed with a local acting agent. The skin will be removed with a "tissue punch" which will cut a circle of approximately 1/4th of an inch into the skin. The site where the skin was removed will be closed with suture, tape or stitches. The area will be covered with dry gauze and adhesive tape. These tests are to see whether the shots are killing leukemia cells and to make sure leukemia cells are not growing at the injection site.

To study how the immunity is working in the system, we will take blood samples before first injection, then weekly for 10 weeks, on week 12, once a month for a year, and then eventually once a year for fifteen years. These samples will be approximately 1 tablespoons of blood, which is considered a safe amount. If the patient has additional injections, blood will be drawn prior to each injection. Additional office visits may be necessary.

Also, patients will need to have a bone marrow test before enrolling on the study and at week 12. If the patient is not responding, they may have treatment with other chemotherapy or radiation. Patients will need to come to the clinic on the days of blood drawing and to be seen at Texas Children's Cancer Center/The Methodist Hospital at weekly intervals for 10 weeks, then every other week for 6 weeks, and then monthly for a year. Thereafter, patients will either be seen in the clinic or contacted by one of the research staff working on this study once a year for 15 years. Additional visits may be necessary.

Treating High Risk Leukemia With CD40 Ligand & IL-2 Gene Modified Tumor Vaccine

Treatment of High Risk Acute Leukemia With CD40 Ligand and IL-2 Gene Modified Autologous Skin Fibroblasts and Tumor Cells

The Methodist Hospital Research Institute

Center for Cell and Gene Therapy, Baylor College of Medicine

Baylor College of Medicine

Dist Serv Prof, Center for Gene Therapy

Immune System Diseases

Infections

Lymphoma

Lymphoma, Non-Hodgkin

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Extranodal NK-T-Cell

Burkitt Lymphoma

Lymphoma, Large-Cell, Immunoblastic

Neoplasms, Experimental

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Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Mantle Cell Lymphoma

Follicular Lymphoma

B-cell Lymphoma

Lymphoma, Large-cell, Immunoblastic

Antirheumatic Agents

Cyclophosphamide

Bendamustine Hydrochloride

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.

Cyclophosphamide \[1.5 g/m\^2 x 1 day Intravenous (IV)\] or Bendamustine \[120 mg/m\^2 x 2 days Intravenous (IV)\] is administered as Pre-treatment medication of CD19-CAR-T.

Cyclophosphamide or Bendamustine

CD19-CAR-T \[1 x 10\^5 cells/kg x 1 day and 2 x 10\^5 cells/kg x 1 day Intravenous (IV)\] are administered.

Dose Level -1

CD19-CAR-T \[1/3 x 10\^6 cells/kg x 1 day and 2/3 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

CD19-CAR-T \[1 x 10\^6 cells/kg x 1 day and 2 x 10\^6 cells/kg x 1 day Intravenous (IV)\] are administered.

CD19-CAR-T \[1/3 x 10\^7 cells/kg x 1 day and 2/3 x 10\^7 cells/kg x 1 day Intravenous (IV)\] are administered.

Ken Ohmine, MD, PhD

Keiya Ozawa, MD, PhD

The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.

Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1：1/3 dose, Day 2：2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing.

This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects.

The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with "Revised response criteria malignant lymphoma", at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.

Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen

Confirm the toxicity profile with CTCAE ver4.0.

Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry.

Confirm replication competent retrovirus (RCR) by PCR.

Confirm clonality by linear amplification mediated (LAM)-PCR.

Transduction efficiency, viability, sterility and potency.

Confirm the efficacy with "Revised response criteria for malignant lymphoma" J Clin Oncol. 25: 579-586 (2007).

Confirm the state of immune mechanism by flow cytometry.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Treating High Risk Leukemia With CD40 Ligand & IL-2 Gene Modified Tumor Vaccine	NCT00058799	Leukemia	Dose Level 1 Dose Level 2 Dose Level 3	- 75 Years	Baylor College of Medicine
Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes	NCT02134262	Relapsed or Ref...	Cyclophosphamid... Dose Level -1 Dose Level 1 Dose Level 2 Dose Level 3	20 Years - 70 Years	Jichi Medical University
Treating High Risk Leukemia With CD40 Ligand & IL-2 Gene Modified Tumor Vaccine	NCT00058799	Leukemia	Dose Level 1 Dose Level 2 Dose Level 3	- 75 Years	Baylor College of Medicine

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