Cancer
Stimulating the
immune system to recognize cancer cells has clear advantages
over classical and even targeted cancer therapies. One of
the most important distinguishing features of this treatment
strategy is the lack of toxicity. Studies of roughly 400
patients and volunteers who have received our Ii-Key hybrid
peptide vaccines show that these agents are remarkably safe and
well tolerated. This is very consistent with previous
peptide vaccine studies reported by other groups. A
further advantage is that Ii-Key hybrid peptides are synthetic
off-the-shelf products that are easy to use.
Antigen Express
is currently testing its lead immunotherapeutic in patients with
HER-2/neu positive breast cancer in a randomized and controlled
Phase II clinical trial. We have also completed a Phase I
trial in patients with prostate cancer. In addition to breast
and prostate cancer, a variety of other cancers express
HER-2/neu and thus are potential targets for immunotherapy using
the same compound.
Another
cancer-associated target being pursued at Antigen Express
(gp100) is specifically expressed in melanoma. Using
transgenic animal models (expressing human MHC class II alleles)
we have identified an Ii-Key/gp100 peptide hybrid that elicits a
robust antigen-specific response. Late pre-clinical stage
studies employing PBMC from patients with melanoma are
continuing to establish the feasibility of conducting clinical
trials.
HPV-related Cancers
Human papillomavirus (HPV) induced cancers are attractive
targets for active immunotherapy using Ii-Key hybrid technology.
The fact that some HPV proteins are both expressed by the cancer
cells and are also causative cancer agents indicates that they
are ideal targets for active immunotherapy. Furthermore,
these oncogenic gene products represent proteins naturally
foreign to the body, suggesting that we may be able to
capitalize on the body’s natural defense mechanisms in
generating a specific immune response against them and thereby
target the cancer cells. We have identified several active
Ii-Key hybrid peptides using transgenic animal models expressing
human MHC class II alleles. Late pre-clinical stage
studies are ongoing.
Influenza
Influenza viruses are endemic to the human population and easily
mutate, forming the various strains of virus that emerge year to
year. Common influenza causes many deaths throughout the world
each year but on occasion a more virulent and or more infectious
strain emerges that is very different from common influenza and
is not recognized by the human immune system. These pandemic
strains present a threat to human health that could be
catastrophic. As was seen with the H5N1 avian influenza
outbreak, traditional vaccine manufacturing may not be able to
generate sufficient amounts of vaccine for large populations
during the rapid spread of disease in a pandemic situation.
Given that our influenza vaccine is produced by entirely
synthetic means, it would be available far quicker and in larger
amounts than vaccine manufactured by traditional methods. Our
research has also indicated that there is shared homology
between different influenza virus strains. We believe that a
specific cellular immune response could provide some level of
protection against the potentially lethal effects of an emerging
pandemic influenza virus and, when combined with a traditional
vaccine, provide added protection required for elderly
individuals and others with compromised immune systems.
HIV
Antigen Express remains interested in development of an HIV
vaccine. Although no HIV vaccines have been efficacious
thus far, it is clear from the studies reported by many labs
that the CD4 and CD8 T cell response to Gag is critical in the
control of HIV replication following primary infection in humans
and primates, and that the T cell response to Gag in the
population of long term non progressors (LTNPs) is essential for
control of HIV. This suggests that HIV vaccines that
elicit a strong T cell response to Gag may be effective in
eliciting a controlling immunologic response in people who are
infected with HIV. Through a collaboration with Dr. Bruce
Walker (Professor of Medicine at Harvard, MIT and MGH) we have
identified Ii-Key/gag peptide hybrids that are recognized by
PBMC from HIV patients, suggesting their utility as an HIV
vaccine. Studies using a combination of HIV hybrids and
recombinant Gag protein are progressing in an effort to identify
an optimal dosing regimen for an HIV vaccine.
Diabetes
There is a strong association between specific MHC class II
alleles and Type I diabetes, which suggests the direct
involvement of CD4+ T helper cells in the etiology of this
autoimmune disease. Further, specific targets of the
autoimmune response include both insulin and glutamic acid
decarboxylase (GAD). Ii-Key/insulin or Ii-Key/GAD peptide
hybrids have two potential applications in the management of
diabetics, the first being diagnostic and the second
therapeutic. Given that Ii-Key peptide hybrids are more
potent at stimulating CD4+ T cells, they would be useful in
detecting the presence of GAD- or insulin-specific autoimmune T
cells in the blood. Initial studies done with outside
collaborators suggest that this is indeed an achievable goal.
The importance of detecting these auto-reactive T cells early is
that it would greatly facilitate the management of patients in
the early stages of the disease, for instance siblings of
previously diagnosed Type I diabetics. Using specific
dosing regimens, Ii-Key/GAD or Ii-Key/insulin peptides could be
used to specifically suppress the autoimmune response underlying
Type I diabetes.
Intracellular and DNA vaccines
In addition to our Ii-Key hybrid peptide platform, another
technology platform being developed at Antigen Express is based
on inhibition of the MHC class II-associated invariant chain (or
Ii protein). A number of studies from our group, as well
as others, have clearly documented that inhibition of the Ii
protein in cancer cells (generating the MHC class II+/Ii-
phenotype) turns them into very effective cancer cell vaccines.
We have developed active Ii-specific inhibitory agents
(antisense oligonucleotides, reverse gene and Ii-RNAi
constructs) to effectively suppress Ii protein expression in
murine and human cancer cell lines, as well as in fresh acute
myelogenous leukemia (AML) cells from patients. We are
optimizing methodology applicable to clinical trials.
Because the Ii protein prevents MHC class II molecules from
presenting antigenic epitopes present in the cytoplasm to CD4+ T
helper cells, inhibition of the Ii protein can also amplify the
immunogenicity of DNA vaccines. As DNA vaccines are expressed
intracellularly, producing antigens in the cytoplasm,
suppression of Ii expression can augment their specific
immunogenicity. We are assessing the potential of this
technology as applied to an HIV vaccine.
