High-dose Chemotherapy and Adoptive Immunotherapy in the Treatment of Recurrent Pediatric Brain Tumors

Abstract

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

bone marrow transplant - brain tumors - immunotherapy - high-dose chemotherapy

References

• 1 Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses.  Science. 2004;  305 ((5681)) 200-205
• 2 Chen Q, Daniel V, Maher DW. et al . Production of IL-10 by melanoma cells: examination of its role in immunosuppression mediated by melanoma.  Int J Cancer. 1994;  56 755-760
• 3 Constam DB, Philipp J, Malipiero UV. et al . Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia.  J Immunol. 1992;  148 1404-1410
• 4 Coughlin CM, Vonderheide RH. Targeting adult and pediatric cancers via cell-based vaccines and the prospect of activated B lymphocytes as a novel modality.  Cancer Biol Ther. 2003;  2 466-470
• 5 Dranoff G, Jaffee E, Lazenby A. et 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. 1993;  90 3539-3543
• 6 Durando X, Lemaire J-J, Tortochaux J. et al . High-dose BCNU followed by autologous hematopoietic stem cell transplantation in supratentorial high-grade malignant gliomas: a retrospective analysis of 114 patients.  Bone Marrow Transpl. 2003;  31 559-564
• 7 Finlay JL, August C, Packer R. et al . High-dose multi-agent chemotherapy followed by bone marrow ‘rescue’ for malignant astrocytomas of childhood and adolescence.  J Neuro-Oncol. 1990;  9 239-248
• 8 Gabrilovich DI, Ishida T, Nadaf S. et al . Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function.  Clin Cancer Res. 1999;  5 2963-2970
• 9 Geiger JD, Hutchinson RJ, Hohenkirk LF. et al . Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression.  Cancer Res. 2001;  61 8513-8516
• 10 Hao C, Parney IF, Roa WH. et al . Cytokine and cytokine receptor mRNA expression in human glioblastomas: evidence of Th1, Th2 and Th3 cytokine dysregulation.  Acta Neuropathol (Berl). 2002;  103 171-178
• 11 Kew Y, Levin VA. Advances in gene therapy and immunotherapy for brain tumors.  Curr Opin Neurol. 2003;  16 665-670
• 12 Liau LM, Black KL, Prins RM. et al . Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens.  J Neurosurg. 1999;  90 1115-1124
• 13 Marincola FM, Jaffee EM, Hicklin DJ. et al . Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance.  Adv Immunol. 2000;  74 181-273
• 14 Perek D, Perek-Polnik M. Brain tumors in children.  Przegl Lek. 2003;  60 ((Suppl 5)) 27-34
• 15 Rosenberg SA, Dudley ME. Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes.  Natl Cancer Inst. 2004;  ((Suppl 2) 85 (622)) 14639-14645
• 16 Sampson JH, Archer GE, Ashley DM. et al . Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell mediated immunity against tumors located in the “immunologically privileged” central nervous system.  Proc Natl Acad Sci USA. 1996;  93 10399-10404
• 17 Satoh J, Lee YB, Kim SU. T-cell costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are expressed in human microglia but not in astrocytes in culture.  Brain Res. 1995;  704 92-99
• 18 Tianhong W, Niu G, Kortylewski M. et al . Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells.  Nature Med. 2004;  10 48-54
• 19 Yang L, Ng KY, Lillehei KO. Cell-mediated immunotherapy: a new approach to the treatment of malignant glioma.  Cancer Control. 2003;  10 138-147 , This review updates recent immunotherapeutic approaches for the treatment of malignant glioma.
• 20 Yu JS, Wheeler CJ, Zeltzer PM. et al . Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration.  Cancer Res. 2001;  61 842-847

Correspondence