Metastatic Melanoma Clinical Trial
Official title:
Phase 1 Study of Local Modulation of Immune Receptor Function to Enhance Immune Responses to Dendritic Cell Vaccination in Subjects With Metastatic Melanoma
Our proposed study is designed to test the safety of a new vaccine against melanoma. The
induction of immune activity against cancers such as melanoma is a promising approach to
cancer treatment, but to date, only a few clinically significant immune responses have been
seen following vaccine therapy. This is an important problem, since there are very limited
treatment options for patients with metastatic melanoma (melanoma that has spread to lymph
nodes and organs).
Studies suggest that monoclonal antibodies (mAbs) that block inhibitory receptors on immune
cells can enhance the immune responses against cancer, but the intravenous injection of such
mAbs has caused severe side effects in animals and humans. In our laboratory, we have
developed a method to deliver mAbs and other proteins that block such inhibitory receptors
locally at the site where immune responses against melanoma proteins are stimulated by
vaccination, enhancing anti-melanoma immunity while avoiding the side-effects associated
with intravenous injection of these immune modulators. This is achieved by loading dendritic
cells, a type of immune cell, with RNA that encodes the immune modulator. The RNA-loaded
dendritic cells then make the immune modulatory proteins and release them locally. By mixing
these dendritic cells with additional dendritic cells loaded with melanoma proteins, the
immune modulators are released at the site where anti-melanoma immune cells are stimulated.
In this phase I trial, subjects with metastatic melanoma will undergo the process of
leukapheresis, in which white blood cells are removed from the body. Monocytes, a type of
immune cell, will then be purified from the white blood cells and cultured under conditions
that will change them into dendritic cells. Half of these dendritic cells are then loaded
with melanoma antigen RNA, which will lead to the production of melanoma antigen proteins
within the dendritic cells. The remaining half of the dendritic cells will be either
untreated or loaded with RNA encoding immune modulators so that these dendritic cells will
release immune modulators at the site of vaccination. These dendritic cells will be mixed
with the melanoma antigen-loaded dendritic cells and injected as a vaccine into lymph nodes.
Each subject will receive six weekly injections of their own dendritic cells. Safety and
toxicity will be closely monitored. In addition, immune responses against melanoma, as well
as clinical responses, will be assessed.
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.
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Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Factorial Assignment, Masking: Open Label
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