Phase 1 Study of Local Modulation of Immune Receptor Function to Enhance Immune Responses to Dendritic Cell Vaccination in Subjects With Metastatic Melanoma
A variety of trials of immunotherapy in metastatic melanoma have clearly demonstrated that
immune responses against melanoma can be induced, but only a few patient have responded
clinically, suggesting that new strategies to enhance anti-cancer immune responses are
needed. Most of these immunotherapy trials have focused on antigen delivery and providing
stimulatory antigen-specific signals to T cells. However, the induction of antigen-specific
T cell-mediated immune responses is regulated not only by stimulatory signals, but also by
inhibitory receptor-mediated signals. Studies have demonstrated that administering mAbs
targeting such immune-modulating receptors on T cells enhances vaccine-induced anti-tumor
immunity, suggesting that such an approach might improve the efficacy of clinical cancer
vaccines. However, systemic administration such mAbs has been associated with severe,
sometimes fatal, autoimmunity. We have developed an approach for targeted delivery of such
immune modulatory proteins and mAbs, using immune modulator RNA-transfected dendritic cells
(DC), to sites where anti-tumor T cells are induced. Our preliminary studies indicate that
this approach may eliminate the adverse effects associated with systemic administration
immune modulators, while also enhancing vaccine-induced immune responses.
Therefore, the objective of this proposed Phase I immunotherapy trial is to determine the
safety and obtain preliminary data on the efficacy of vaccination of human subjects with
melanoma tumor associated antigen (TAA) RNA-transfected mature monocyte-derived DC
coadministered with additional untransfected DC (Study Arm A), DC transfected with RNA
encoding a soluble GITR-L fusion protein (Study Arm B), DC transfected with RNA encoding the
humanized heavy and light chains of an antagonistic anti-CTLA-4 mAb (Study Arm C), or DC
transfected with combined GITR-L and anti-CTLA-4 mAb RNA (Study Arm D). All study subjects
will undergo leukapheresis for collection of peripheral blood mononuclear cells (PBMC) and
purified monocytes will be cultured with the cytokines GM-CSF and IL-4 to produce immature
DC. After the induction maturation with a standard cytokine cocktail, half of the DC will
then be transfected with RNA encoding melanoma TAAs MART, tyrosinase, and gp100, and MAGE-3,
while the remaining half of the DC will be either untransfected (Study Arm A) or will be
transfected with immune modulator RNA (Study Arm B, C, and D). DC will be cryopreserved.
Subjects will then be immunized with these DC, weekly for six intranodal injections. For
each subject, safety and toxicity will be assessed, and anti-tumor immune responses will be
measured.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Safety and Tolerability will be assessed for all subjects during the vaccination period and then regularly during the post-vaccination period. All subjects will then be followed clinically as would be done any subject with melanoma for a total of 5 years.
A minimum of 6 months
Yes
Scott K Pruitt, MD, PhD
Principal Investigator
Duke University
United States: Food and Drug Administration
Pro00019239
NCT01216436
January 2010
June 2014
Name | Location |
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Duke University Medical Center | Durham, North Carolina 27710 |