iC9-GD2-CAR-VZV-CTLs/Refractory or Metastatic GD2-positive Sarcoma and Neuroblastoma

Summary

The purpose of this study is to find the largest safe dose of GD2-T cells (also called iC9-GD2-CAR-VZV-CTLs) in combination with a varicella zoster vaccine and lymohodepleting chemotherapy. Additionally, we will learn what the side effects of this treatment are and to see whether this therapy might help patients with advanced osteosarcoma and neuroblastoma. Because there is no standard treatment for recurrent/refractory osteosarcoma and neuroblastoma at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells.

The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients.

Investigators have found from previous research that a new gene can be put into T cells that will make them recognize cancer cells and kill them. Investigators now want to see if a new gene can be put in these cells that will let the T cells recognize and kill sarcoma and neuroblastoma cells. The new gene is called a chimeric antigen receptor (CAR) and consists of an antibody called 14g2a that recognizes GD2, a protein that is found on sarcoma and neuroblastoma cells (GD2-CAR). In addition, it contains parts of the CD28 and OX40 genes which can stimulate T cells to make them live longer.

Investigators have found that CAR-T cells can kill some of the tumor, but they don't last very long in the body and so the tumor eventually comes back. T cells that recognize the virus that causes chicken pox, varicella zoster virus (VZV), remain in the bloodstream for many years especially if they are stimulated or boosted by the VZV vaccine. Investigators will therefore insert the GD2-CAR gene into T cells that recognize VZV. These cells are called iC9-GD2-CAR-VZV-specific T cells but are referred to as GD2-T cells for simplicity.

Conditions

• Osteosarcoma
• Neuroblastoma

Interventions

GENETIC

GD2 T cells

On dose levels 1 and 2 each patient receives one injection of GD2 T cells followed by VZV vaccine injection 42 days later. Dose Level 1: 1x10\^6 cells/m\^2 Dose Level 2: 1x10\^7 cells/m\^2 The next dose levels to be studied following Dose level 2 are Dose levels 7 and 8 where subjects will receive the VZV vaccine followed by a single infusion of iC9-GD2-CAR-VZV-CTLs within 48 hours after VZV vaccine: Dose Level 7: 1 x 10\^7 cells/m2 Dose Level 8: 1 x 10\^8 cells/m\^2 Dose levels 9-11 will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine prior to administration of the T cells. Dose Level 9: 1 x 10\^8 cells/m\^2 Dose Level 10: 5 x 10\^8 cells/m\^2 Dose Level 11: 1 x 10\^9 cells/m\^2 The previously planned dose levels 3-6 will not be studied.

BIOLOGICAL

VZV vaccine

Subjects will receive a VZV vaccine with CTL infusion within 48 hours after the vaccine.

DRUG

Fludarabine

Pre-infusion lymphodepletion for dose levels 9-11: Patients will receive 3 daily doses of cyclophosphamide together with fludarabine to induce lymphopenia, finishing at least 24 hours before T cell infusion. Cyclophosphamide will be given at a dose of 500 mg/m\^2/day followed by Fludarabine 30 mg/m\^2/day. Infusions should be given following hospital/pharmacy recommendations however at a minimum the cyclophosphamide should be infused over 1 hour and the fludarabine should be infused over 30 minutes. Mesna, IV hydration, and anti-emetics will be provided following local institutional guidelines. T cell infusion will take place the day after completion of chemotherapy. Zostavax will be administered two weeks after infusion of T cells.

DRUG

Cyclophosphamide

Pre-infusion lymphodepletion for dose levels 9-11: Patients will receive 3 daily doses of cyclophosphamide together with fludarabine to induce lymphopenia, finishing at least 24 hours before T cell infusion. Cyclophosphamide will be given at a dose of 500 mg/m\^2/day followed by Fludarabine 30 mg/m\^2/day. Infusions should be given following hospital/pharmacy recommendations however at a minimum the cyclophosphamide should be infused over 1 hour and the fludarabine should be infused over 30 minutes. Mesna, IV hydration, and anti-emetics will be provided following local institutional guidelines. T cell infusion will take place the day after completion of chemotherapy. Zostavax will be administered two weeks after infusion of T cells.

Sponsors & Collaborators

• National Cancer Institute (NCI)

  collaborator NIH

• Center for Cell and Gene Therapy, Baylor College of Medicine

  collaborator OTHER

• The Methodist Hospital Research Institute

  collaborator OTHER

• Baylor College of Medicine

  lead OTHER

Principal Investigators

• Lisa L Wang, MD · Baylor College of Medicine

• Cliona Rooney, PhD · Baylor College of Medicine

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-04-30

Primary Completion

2019-10-31

Completion

2034-10-31

Countries

• United States

Study Locations