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[Cancer Research 61, 8513-8519, December 1, 2001]
© 2001 American Association for Cancer Research

Immunology

Vaccination Of Pediatric Solid Tumor Patients with Tumor Lysate-pulsed Dendritic Cells Can Expand Specific T Cells and Mediate Tumor Regression1

James D. Geiger2, Raymond J. Hutchinson, Lyndon F. Hohenkirk, Elizabeth A. McKenna, Gregory A. Yanik, John E. Levine, Alfred E. Chang, Thomas M. Braun and James J. Mulé

Department of Surgery, Section of Pediatric Surgery, Section of General Surgery, the Tumor Immunology and Immunotherapy Program [J. D. G., L. F. H., E. A. M., G. A. Y., J. E. L., A. E. C., J. J. M.], Department of Pediatrics [R. J. H.], and Biostatistics the University of Michigan Medical School [T. M. B.], Ann Arbor, Michigan 48109-0245

Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 106 to 1 x 107 DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3–17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 108 peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-{gamma}-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16–30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.




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Copyright © 2001 by the American Association for Cancer Research.