Adoptive Immunotherapy for Glioblastoma Multiforme (GBM)

Stephen Gottschalk, M.D.

Baylor College of Medicine

Funded in September, 2008: $200000 for 3 years
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LAY SUMMARY

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Improving T Cell Therapy for Glioma to Prevent Tumor Recurrence

Investigators have developed a line of genetically modified T cells that specifically target and destroy human glioma tumors transplanted into the brains of mice.  They now seek to improve the long-term efficacy of this treatment by further modifying the T cells and their mode of administration.

One mode of cancer immunotherapy is to inject tumors with cytotoxic T cells that recognize tumor cells and destroy them.  In previous work, the investigators had preliminary success in treating glioblastoma multiforme (GBM) tumors using genetically modified T cells called “HER2-T cells.”  These T cells bear receptors for human epidermal growth factor receptor 2 (HER2). This is a protein that is expressed at abnormally high levels by GBM tumor cells, and so these HER2-T cells are able to bind selectively to tumor cells.  In addition, the HER2 receptor on these T cells is engineered to include signaling areas (regions of the receptor that lie inside the cell) that activate the T cells after they bind to tumor cells, causing the HER2-T cells to proliferate and kill the tumor cells.

When HER2-T cells were injected into human GBM tumors that had been transplanted into the brains of mice, they destroyed the tumors.  Nonetheless, tumors later reappeared in the mice.  The investigators suspect that tumor reappearance might be due to one or several factors, including: (1) failure of the HER2-T cells to proliferate and remain active at the site of the injection; (2) failure of the HER2-T cells to migrate to and destroy small groups of tumor cells lying at a distance from the injection site; or (3) suppression of HER2-T cell activity by tumor cell-secreted factors.

The investigators will address each of these possibilities through specific modifications of their therapeutic design.   First, they will add to the engineered HER2 receptor another T cell-activating area and assess its effect on T cell proliferation and killing of GBM cells in laboratory cultures and in vivo.  Second, they will try to improve the migratory capacity of the HER2-T cells.  Third, they will determine whether HER2-T cell proliferation and killing of GBM cells in laboratory cultures and in vivo is enhanced by a drug that inhibits a specific protein, which is produced at high levels in GBM cells and promotes their secretion of immunosuppressant cytokines.

Significance:  This study will advance the development of more sophisticated T cell therapies for a particularly aggressive form of human brain tumor, for which no treatments with long-term efficacy currently exist.

ABSTRACT

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Adoptive Immunotherapy for Glioblastoma Multiforme (GBM)

The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for glioblastoma multiforme (GBM), the most aggressive primary human brain tumor. Current therapies for GBM result in five-year survival rates of less than 5% and new therapies are needed to improve current outcomes without increasing treatment-related morbidities. Immunotherapies have the potential to fulfill this need, since they are highly tumor-specific and cause minimal bystander cell damage.

We propose to use T cells to target the human epidermal growth factor receptor 2 (HER2), a surface antigen, which is overexpressed in GBM. Our preliminary studies have validated HER2 as a target for immunotherapy of brain tumors including medulloblastoma and GBM by showing that genetically modified T cells expressing engineered HER2-specific chimeric antigen receptors (CARs) with CD28 and TCR-ζ chain-signaling domains (HER2-T cells) can recognize and kill HER2-positive human GBMs growing in the brain of SCID mice after intra-tumoral injection. However, in experimental animals, HER2-positive GBMs recurred after initial regression. Tumor recurrence is most likely due to several factors including a) lack of T-cell persistence, b) limited migration of T cells to tumor micro deposits, and c) the inhibitory tumor environment created by GBMs.

Our central hypothesis is that eliminating two or more of these obstacles will enhance the anti-tumor activity of injected HER2-T cells. This hypothesis will be tested in 3 interrelated aims. In Aim 1 we will compare the expansion, persistence, and anti-tumor efficacy of HER2-T cells from GBM patients expressing CARs with improved signaling domains. In Aim 2 we will optimize the ability of patients’ HER2-T cells to migrate to GBMs by forced expression of appropriate chemokine receptors, and in Aim 3 we will compare the expansion, persistence, and anti-tumor efficacy of patients’ HER2-T cells in the presence or absence of the STAT3 inhibitor JSI-124.

Upon completion of these aims we will have advanced our understanding on how to modify T cells and the tumor microenvironment to redirect the immune system towards GBMs. We will have learned in Aim 1 how to effectively enhance the effector function of T cells to recognize and kill GBMs, and in Aim 2 how to augment T-cell trafficking to GBM micro deposits. In addition, we will know after completion of Aim 3 if inhibiting STAT3 overcomes the inhibitory tumor microenvironment resulting in enhanced anti-GBM activity of injected T cells.

INVESTIGATOR BIOGRAPHIES

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Stephen Gottschalk, M.D.

Dr. Gottschalk received his M.D. in 1992 from the Georg-August University in Göttingen, Germany, followed by a research fellowship in cell biology at Baylor College of Medicine, Houston, Texas.  He received residency training in pediatrics at Baylor College of Medicine, where he also completed a hematology/oncology fellowship. He is currently an Associate Professor in the Department of Pediatrics and Immunology at Baylor College of Medicine and a member of the Center for Cell and Gene Therapy, Texas Children's Cancer Center, and the L Duncan Cancer Center. Dr. Gottschalk's research interest is in adoptive immunotherapies with antigen-specific and genetically modified T cells. His research is focused on Epstein-Barr virus associated malignancies such as Hodgkin’s disease and nasopharyngeal carcinoma, and HER2-positive malignancies, including brain tumors and sarcomas. His group is currently conducting Phase I/II clinical studies using antigen-specific T cells and in the laboratory is investigating strategies on how to improve T-cell therapies for cancer.