In several clinical trials, the adoptive transfer of tumor-reactive T cells has been shown to mediate the regression of established tumors in a small number of patients with extracranial tumors.10,11,17,36,44 The quality of the T cells is probably the most important component of adoptive immunotherapy, and the source, specificity, and number of T cells are essential determinants of efficacy. Using preclinical animal tumor models, we have determined that lymph nodes (LNs) draining a tumor inoculum are the optimum source of T cells sensitized to specific tumor antigens, in contrast to other lymph tissues.12,41,51 After ex vivo stimulation and expansion, these cells developed into potent therapeutic effector cells which, on systemic transfer, were capable of mediating the regression of tumors established in the lung and skin as well as in the brain.22,33,51 The reactivity of the tumor-draining LN T cells was exquisitely specific for the tumor that provided the in vivo stimulation. Independently derived tumors of similar histological composition were not affected, suggesting that tumor-specific rather than tissue-restricted antigens were the dominant antigens in this immune response. Although similar tumor-reactive T cells may exist in cancer patients, there is evidence that their ability to proliferate and function is suppressed.1,16
Most of the clinical applications of adoptive immunotherapy have been for melanoma and renal cell carcinoma. There are theoretical reasons to suggest that the application of T-cell immunotherapy delivered to malignant brain tumors might be difficult. First, the brain is considered an immune-privileged site, and diminished immune responses are generated against antigens introduced into the central nervous system.19,31 Second, it is well documented that many gliomas release substances such as transforming growth factor—β, prostaglandin E2, and interleukin (IL)-10, that cause immunosuppression.8,15,20,21,30 Third, because of the requirement for structural integrity and confined anatomical space, the brain may not tolerate the inflammation associated with an immune reaction. Despite these concerns, we have demonstrated in animal models that adoptive transfer of activated tumor-draining LN T cells mediated the regression of experimentally established intracranial malignancies.22,45,47 Transferred intravenously, T cells infiltrated intracranial tumors, demonstrating that there is no intrinsic barrier to the migration of activated T cells into intracranial tumors. The T-cell infiltrate was localized to the tumor; very few T cells were present in the normal brain parenchyma.34 A murine glioma was also successfully treated by adoptive transfer of activated tumor-draining LN T cells, and cured mice were neurologically normal and resisted a second intracranial tumor challenge.35 These data indicated that adoptive immunotherapy might be an alternative treatment for humans with malignant glioma. A phase I clinical trial was initiated to establish whether adoptive immunotherapy was feasible in patients with recurrent or residual malignant astrocytoma and to determine the toxicity associated with this treatment.
The authors are grateful to Margaret Loftus and James Walsh for technical and nursing assistance.
Dranoff GJaffee ELazenby Aet al: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony stimulating factor stimulates potent, specific and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 90:3539–35431993Proc Natl Acad Sci USA 90:
Kwak LWYoung HAPennington RWet al: Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response. Proc Natl Acad Sci USA 93:10972–109771996Proc Natl Acad Sci USA 93:
An earlier version of this manuscript was published in Neurosurg Focus 3 (5):Article 5, 1997.
This work was supported in part by USPHS Grant Nos. RO1 CA 74919 and RO1 CA 73834 from the National Cancer Institute; and the Immunex Corporation.