Adoptive transfer of vaccine-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion.
Cancer vaccines can induce the in vivo generation of tumor Ag-specific T cells in patients with metastatic melanoma yet seldom elicit objective clinical responses. Alternatively, adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL) can mediate tumor regression in 50% of lymphodepleted patients, but are logistically and technically difficult to generate. In this study, we evaluated the capability of vaccine-induced PBMC to mediate tumor regression after transfer to patients receiving the same chemotherapy-induced lymphodepletion used for TIL transfer therapy. Autologous PBMC from nine gp100-vaccinated patients with metastatic melanoma were stimulated ex vivo with the gp100:209-217(210M) peptide and transferred in combination with high-dose IL-2 and cancer vaccine. Transferred PBMC contained highly avid, gp100:209-217 peptide-reactive CD8(+) T cells. One week after transfer, lymphocyte counts peaked (median of 14.3 x 10(3) cells//microl; range of 0.9-59.7 x 10(3) cells/microl), with 56% of patients experiencing a lymphocytosis. gp100:209-217 peptide-specific CD8(+) T cells persisted at high levels in the blood of all patients and demonstrated significant tumor-specific IFN-gamma secretion in vitro. Melanocyte-directed autoimmunity was noted in two patients; however, no patient experienced an objective clinical response. These studies demonstrate the feasibility and safety of using vaccine-induced PBMC for cell transfer, but suggests that they are not as effective as TIL in adoptive immunotherapy even when transferred into lymphodepleted hosts.
Powell
Daniel J
DJ
Surgery Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. Daniel_Powell@nih.gov
Dudley
Mark E
ME
Hogan
Katherine A
KA
Wunderlich
John R
JR
Rosenberg
Steven A
SA
D019264:Adoptive Transfer; D000328:Adult; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D015789:HLA-A2 Antigen / Q000032:analysis; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000637:transplantation; D008212:Lymphocyte Depletion; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000032:analysis; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010455:Peptides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D058951:gp100 Melanoma Antigen
D015704:CD4 Antigens; D019496:Cancer Vaccines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015789:HLA-A2 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; C548637:PMEL protein, human; D010455:Peptides; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma