Biomedical Engineering Reference
In-Depth Information
development of murine, chimeric, humanized, and fully
human mAbs, several novel therapeutic mAb currently
approved for cancer immunotherapy have been mass pro-
duced [3]. Moreover, it is possible to generate a variety of
smaller fragments of the IgG molecule that retain or have
improved binding affinities. One of the most common forms
is the single chain variable fragment (scFv), produced by
combination of V H and V L joined by a flexible peptide
linker. These mAbs as a class of oncology therapeutics are
best used in patients with tumors driven by numerous
antigens that are overexpressed on certain types of cancer
cells compared with normal tissues. Therefore, immuno-
therapy is a powerful therapeutic modality that is marked by
excitement since it can be employed for the treatment of
cancer patients [4]. In addition, many investigators have
proposed that if the proper immunoregulatory ligands, tox-
ins, or enzymes can be targeted to the tumor, an effective
antitumor response can be mounted to treat patients with
both high-risk primary tumors and distant metastatic lesions.
Another approach to delivery of these large proteins to the
tumor is to create untargeted Fc fusion proteins consisting of
a single protein molecule conjugated to a dimeric Fc frag-
ment of an IgG. This FcRn-mediated approach offers evi-
dence that it can exhibit enhanced pharmacokinetic and
pharmacodynamic properties [5]. Thus, the present review
demonstrates the current use of multiple antibody-targeted
and untargeted soluble Fc fusion proteins with emphasis on
in vitro and in vivo properties including the identification of
relevant cellular processes associated with effective solid
tumor immunotherapy. Those cellular and molecular com-
ponents of the immune system that have the capacity to treat
tumor need to be harnessed and properly presented in order
to generate effective cancer therapy.
For this to happen, however, two key events must occur,
namely, the reversal of immune tolerance and the activation
of effective immunity with memory. One of the most
powerful methods nature has evolved to control the immune
system is the generation of T regulatory (T reg ) cells, the same
cells now believed to be one of the major mechanisms
responsible for the protection of the fetus in the mother's
womb [8]. As confirmed previously, histopathologic, and
flow cytometric studies, respectively, have shown an
increase in T reg cells in the parenchyma of solid tumors
or circulating in the blood or cavity fluids of cancer
patients [9]. Experimentally, methods to suppress T reg cells
in tumor-bearing animals using anti-cytotoxic T lymphocyte-
associated antigen 4 (CTLA4) [10], anti-CD4 [11], or anti-
CD25 [12,13] antibodies, have provided improved immuno-
therapy when used alone or with tumor vaccines. The second
event that is required for active immunotherapy is the use of
potent immunostimulatory agents to evoke an effective
immune response against tumor antigens. It has previously
been confirmed that combination therapy with an anti-T reg
cell antibody and several different fusion proteins is an
effective method of reactivating the immune system to tumor
[14-17]. By comparison, when these reagents are used alone,
they produce only partial responses compared to untreated
controls [18,19]. For example, B7-CD28 co-stimulation
(second signal) is an important and vital step in the activation
of T cells [20]. Interestingly, it has been also demonstrated
that B7-CD28 co-stimulation can activate both the Th1 and
Th2 differentiation pathways and that the latter is dependent
on the induction of interleukin 4 (IL-4). Used systemically,
however, this approach can induce unwanted autoimmune
side effects such as those seen with anti-CTLA-4 antibody
treatment, which affects immunologically privileged sites in
the host [21]. These toxic side effects may be substantially
decreased if co-stimulation is targeted to the tumor site and
not distributed systemically [22].
Despite numerous in vitro and in vivo studies demon-
strating the stimulatory effects of various cytokines to
induce active leukocyte responses against tumor cells, favor-
able and consistent responses have remained elusive in the
actual treatment of human disease. The limitation in clinical
efficacy is partly due to the toxic effects observed with
traditional administration methods as well as the inability to
recreate the microenvironmental conditions required for the
generation of specific antitumor immune responses using
these reagents [23]. Systemic infusion produces elevated
cytokine levels that lead to a nonspecific activation of
immune cells. Since cytokines are meant to be released at
local sites of infection or tissue perturbation, systemic
infusion often leads to dysfunctional immune activation
with significant dose-limiting and potentially fatal toxicities
[24]. Additionally, treatment protocols which fail to localize
these bioactive reagents may not only be unsuccessful in the
generation of specific immune activity, but may predispose
19.2 IMMUNOTHERAPEUTIC STRATEGY FOR
CANCER: FUSION PROTEINS
Harnessing the immune system to treat tumor-bearing hosts
is a major goal of immunotherapy, which has been used for
over a century [6]. Effective cancer immunotherapy requires
the establishment of an immune response to reject cancer in
patients. However, impediments to this goal include host
failure to identify tumor antigens by the generation of
tolerance to self and negative immunoregulatory mecha-
nisms. As part of the malignant phenotype, tumors have
evolved to overcome innate and adaptive immune responses
of the host in order to grow and metastasize [6]. Historically,
investigators have been of the opinion that the immune
response against tumors is inherently weak and has insuffi-
cient T effector cells to destroy large, established lesions. As
evidenced by recent research, however, cancer immuno-
therapy may have sufficient therapeutic potential to treat
and cure deep-seated malignancies if properly invoked [7].
Search WWH ::




Custom Search