Funded Grants

Effector Mechanisms of T Cell Immunotherapy of Brain Tumors

Adoptive T cell immunotherapy represents an attractive supplement to current treatments for malignant gliomas. The T lymphocyte response to neo-antigens expressed by tumor cells is highly specific, thus potentially sparing toxicity to normal tissues. We have completed a phase I clinical trial of adoptive immunotherapy for patients with malignant gliomas that was designed in accordance with an extensive series of preclinical studies using murine intracranial tumor models. Based on the lack of toxicity and clinical responses in patients, we have proceeded to phase II testing. Recently, we have performed experiments that have fundamentally altered our concept of the anti-tumor effector mechanism and may have broad implications for tumor immunology.

The fundamental hypothesis of this proposal is that co-ordinate interaction between CD4+ T cells, CD8+ T cells, and tumor-associated antigen presenting cells cause regression of intracranial tumors and development of memory.

Our preliminary data clearly indicate that macrophages and/or brain microglial cells play an important role in the anti-tumor immune response to intracranial tumors. Even under defined experimental conditions that prevent direct interactions between the T cells and tumor cells, T cell stimulation by tumor-associated antigen presenting cells is sufficient to cause tumor eradication. This important observation has provoked us investigate additional effector mechanisms besides cytolytic T cell function. In specific aim 1, we will define the process by which tumor associated macrophages and brain microglial cells participate in the anti-tumor response mediated by systemically transferred tumor-reactive T cells.

The development and perpetuation of an effective anti-tumor memory response is very important. We have observed patients on our adoptive immunotherapy protocol who have responded but later had tumor progression. This indicates a sufficient initial intensity but insufficient perpetuation of the immune response. In addition, in the preclinical models, there are intriguing features of the memory response that differ from the initial anti-tumor response to CNS tumors. In specific aim 2, we will investigate whether there are unique aspects of the anti-tumor memory response developed in the CNS and define the role of transferred T cells, host T cells and APC.