Immunologic responses to xenogeneic tyrosinase DNA vaccine administered by electroporation in patients with malignant melanoma.
BACKGROUND
Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8(+) T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients.


METHODS
Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS).


RESULTS
Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine; PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. The only common toxicity was grade 1 injection site reaction. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8(+) T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. No Tyr-reactive CD8(+) T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Epitope spreading of CD8(+) T cell response to NY-ESO-1 was observed in one patient with vitiligo. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. After a median follow-up of 40.9 months, median survival has not been reached.


CONCLUSIONS
A regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort.


BACKGROUND
ClinicalTrials.gov NCT00471133.
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.
Jianda
J
Yuan
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Geoffrey Y
GY
Ku
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.
Matthew
M
Adamow
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.
Zhenyu
Z
Mu
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.
Sapna
S
Tandon
Ichor Medical System, Inc., San Diego, CA 92121, USA.
Drew
D
Hannaman
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Paul
P
Chapman
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Gary
G
Schwartz
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Richard
R
Carvajal
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York NY10065, USA.
Katherine S
KS
Panageas
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alan N
AN
Houghton
Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Institute, New York NY10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Jedd D
JD
Wolchok
DNA vaccine; Electroporation; Epitope spreading; Immune response; Melanoma patient; Tyrosinase