Multiple Myeloma Clinical Trial
Official title:
A Pilot Trial of a WT1 Analog Peptide Vaccine in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation
The purpose of this study is to see if the investigator can help the immune system to work
against myeloma through the use/administration of a peptide vaccine (immunotherapy agent)
directed against the Wilms Tumor 1 (WT1) protein called galinpepimut-S (or GPS, for brief).
Because cancer is produced by the patient's own body, the immune system does not easily
recognize and fight cancer cells. The immune system needs to be "trained" to do this; the
latter goal is accomplished by using a vaccine consisting of selected fragments of the target
antigen, in this case, WT1.
This disease has been selected for this study because the WT1 protein is often present in
myeloma cells. WT1 is a gene that is involved in the normal development of kidneys and other
organs. When the WT1 gene becomes abnormal, it can make proteins involved in the development
of cancer, i.e., can acquire the properties of a true "oncogene". This study will determine
whether the vaccine against the WT1 antigen (present in malignant plasmacytes) can cause an
immune response which is safe, but also able to keep the myeloma from either coming back or
progressing.
Key Features:
- This is a Phase 1/2 clinical study conducted in patients with newly diagnosed high-risk
multiple myeloma to examine the effects of GPS immunotherapy on clinical and immunobiological
indices. The study is titled "A Pilot Trial of a WT1 Analog Peptide Vaccine (Galinpepimut-S)
in Patients With Multiple Myeloma Following Autologous Stem Cell Transplantation" and is
designed as a single-arm, single-institution, open-label study.
Rationale:
- Overexpression of WT1 in multiple myeloma (MM) cells has been demonstrated by
immunocytochemistry (IHC) and in HLA-A*0201 patients by staining with a high-affinity fully
human IgG1 mAb (ESK1) specific to the RMFPNAPYL/HLA-A*0201 complex on malignant plasma cells.
WT1 also serves as a target for antigen-specific directly immunizing immunotherapeutic
approaches, such as peptide vaccines (in this case, galinpepimut-S), in patients with
multiple myeloma. Patients with persistent plasma cell leukemia following CD34+-selected
allografts treated with adoptive transfer of donor-derived WT1-specific cytotoxic T cells are
capable of achieving long-lasting complete remission (CR) status, thus underscoring the
therapeutic potential of activated T-cells specifically immunized against WT1 peptides. The
above provide the theoretical basis for the possibility of successful immunization after
exposure to a WT1-specific vaccine (such as galinpepimut-S), whereby WT1-sensitized
T-lymphocytes (both CD8+ and CD4+) from vaccinated MM could be directed to antigen (WT1)
expressed on malignant plasma cells.
Galinpepimut-S (GPS) - Key features:
- GPS is a tetravalent peptide vaccine, consisting of an equiweight mixture of 4 WT1-derived
peptides which have been chosen to strengthen antigenicity, but also broaden immunogenicity
over a wide range of HLA subtypes, being able to stimulate both CD8+ (MHC Class I)- and CD4+
(MHC Class II)-dependent responses. Of note, 2 of the 4 peptides are heteroclitic, i.e.,
carry by-design introduced missense mutations, in order to decrease tolerogenicity (as these
modified peptides are no longer identified as "self" moieties by the vaccinated host's immune
system. GPS contains one heteroclitic peptide (WT1-A1) to stimulate CD8+ responses, two
longer native peptides (427 long and 331 long) to stimulate CD4+ responses and one longer
heteroclitic peptide (122A1 long) that is capable of stimulating both CD8+ and CD4+ cells
(with the CD8-activating shorter sequence/locus 'buried' with the lengthier CD4-activating
one). Galinpepimut-S is always mixed in emulsion with the immunological adjuvant Montanideā¢
and is administered after granulocyte-macrophage colony-stimulating factor (GM-CSF;
sargramostine; Leukine®) pre-stimulation.
Putative Mechanism of action (MOA) of galinpepimut-S in MM:
- Galinpepimut-S (GPS) is a peptide immunogen of the vaccine type, capable of inducing in the
treated host WT1-specific antigenicity and eventual systemic immunogenicity against
WT1-expressing deposits of cancerous cells. The above principles are applicable in MM
patients treated with this immunotherapeutic. It is very likely that the antigen presenting
cell (APC)-CD8-CD4 cross-activating circuits are markedly amplified in subjects receiving
galinpepimut-S, leading to specific and direct immunization against WT1 and eventual killing
of WT1-expressing malignant plasma cells via activated immunocytes (mainly lymphocytes and
natural killer [NK] cells). This MOA represents a plausible model for the immunobiological
basis of the observed clinical activity of galinpepimut-S against various tumor types (other
than MM) tested to-date, and is poised to be applicable in MM as well.
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