Personalized approaches, non-virus approaches, RNA engineering, epigenetic engineering,

Personalized medicine is
emerging as the paradigm of the development of cancer prevention and treatments
(Jackson). The efficacy of targeted therapies in tumors suggests future
treatments will be based on tumor molecular abnormalities instead of the
current system of tissue type (Jackson). In personalized medicine, an
individual’s characteristics (including their genetic profile) guide clinical
decisions (Jackson). Personalized medicine can also be utilized in the
recognition of prognostic biomarkers; for example, identifying cancer
predisposition genes can aid in the modulation of risk-modification behaviours (Jackson).
There are numerous strategies for eliciting anti-tumor activity, such as inducing
T cell responses against cancer using dendritic cell-targeted vaccines
(Kastenmuller). Immunotherapies are growing immensely as the newest wave of
biotechnology for cancer (Mount). Cell therapies are a diverse group of therapies in early stages of
development with the potential to play a vital role in commercial clinical
contexts (Mount). They can be classified by the following ways: the disorder
they undertake, whether they’re autologous or allogenic, or the cell type (Mount).
Therapies may be most accurately classified by therapeutic indication because
mechanisms tend to be similar among different cell types (Mount). Different
types of technologies include genome editing, cell plasticity,
three-dimensional, somatic cells, cell immortalization, and ex vivo
modification (Mount). The reason why most of these treatments are in early
stages of development is because they are the newest wave of biotechnology, and
their efficacy and safety have yet to be fully proven (Mount). There are
numerous translational challenges to consider, but there are patterns across
cell therapies, regardless of classification (Mount). The first use of immunotherapy for cancer is
accredited to Coley in 1890 who observed the regression of sarcoma following
severe bacterial infections (Dai).

Lymphocyte therapies are a classification of therapy for cancer and
inflammatory diseases (June). They have the potential to harness humans’
natural immune response and strengthen immunity toward the purpose of obviating
illness (June). Lymphocyte therapy involves the transfusion of genetically
modified lymphocytes (June). It can be conducted with allogenic (donor) or
autologous (adoptive transfer) infusion (June). Both allogenic and autologous
lymphocytes have been tested for antitumor activity (June). For example,
antitumor effects were observed upon the infusion of allogenic T lymphocytes (June).
However, the modification of autologous lymphocytes potentially has a larger
therapeutic window than allogenic lymphocytes (June). Lymphocytes can also be
used for preventative and diagnostic purposes; in 1990 a study was conducted in
which T cells were genetically altered to behave as biomarkers to measure the
extent of tumor infiltration (June). The study successfully demonstrated
minimal toxicity, but most of the transferred cells disappeared relatively
quickly (June). Tools for overcoming challenges such is persistence presented
by lymphocyte therapies include virus-vector approaches, non-virus approaches,
RNA engineering, epigenetic engineering, and protein transduction (June). Lymphocytes
may also be modified as TCRs, CARs, y? T cells, and natural killer cells (June).
The in vitro transfusion of lymphocytes has reached clinical trial because its
toxicities are minimal and more predictable than those of in vivo transfusion (June).
It has been observed that in lymphocyte therapies toxicities most often occur
due to transgene specificity or vector integration into the genome (June). Adoptive
cell therapy is a subset of personalized medicine in which antitumor cells are
transfused to a cancer-bearing host (Rosenberg). Using lymphocytes in
immunotherapy has shown to be effective in showing regression in cancers such
as melanoma (Rosenberg). Regarding T cell activation for transfusion, in vitro
activation has proven to be effective in avoiding inhibitory factors in vivo
(Rosenberg). A limitation of ACT is the identification of cells that can target
tumor cell-surface antigens and not healthy tissue antigens (Rosenberg).
Careful selection must also be made of suitable targets for attack (Rosenberg).
Although ACT is promising, its ability to treat solid tumors (such as in
epithelial cancers) is severely limited by a lack of tumor-surface targets (Rosenberg).
There has also been clinically observed toxicity when targeting antigens shared
by tumors and normal tissue (Rosenberg). T cells expressed with chimeric
antigen receptors (CARs), an extension of adoptive cell transfer therapy, have
been shown to be successfully applied to the treatment of hematologic
malignancies (Rosenberg). The application of CARs for cancer treatment involves
removing a patient’s T cells to be genetically modified to express CARs, which
aid in specificity and augment anti-tumor activity (Zhao).

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a. CAR’s functions include binding tumor cell-surface antigens
and activating T cells (Sadelain).  The
transgenic modification of T cells with chimeric antigen receptors allow T
cells to recognize tumor cells (Dai). CARs are engineered by fusing the
antigen-binding region of a monoclonal antibody (mAb) or other to
membrane-spanning and intracellular binding domains (Dai). The CARs most
popularly tested are CD19 directed autologous T cells (Dai). They have
demonstrated significant efficacy in B-cell leukaemias, sarcomas, and
neuroblastomas. CARs utilize cell effector mechanisms using human leukocyte
antigen (HLA) independent recognition (Dai). They have demonstrated regression
most sufficiently in B cell malignancies, neuroblastoma, and sarcoma (Dai).
Unlike TCRs, and of clinical benefit, CARs recognize antigens independently of
MHCs (Dai). This means they can avoid mechanisms in place used by tumors to
avoid recognition (Dai). They can also bind both cell surface proteins and
carbohydrates, thereby providing more opportune targets (Dai). CARs are sought
after for their opportune targeting techniques as in principle, any cell surface
molecule can be targeted by CARs(Sadelain). Theoretically, CARs initiate T cell
activation, and modulate T cell expansion and persistence in the tumor
microenvironment(Sadelain). Upon the expression of CARs, tumor-targeted T cells
are generated(Sadelain). Stable gene transfer is required to enable sustained
CAR expression in clonally expanding and persisting T cells(Sadelain).

 

b. Clinical advantages and disadvantages(Sadelain). For example,
TCR strength is limited by its affinity for antigen(Sadelain). However, CARs
are limited by cell surface molecules, whereas TCRs target both surface
molecules and intracellular proteins(Sadelain). An advantage of CARs is that they
don’t require antigen processing and presenting by HLA, therefore they can
recognize antigen on any HLA background(Sadelain).

T cell
immunotherapy can be used to recognize malignant tumor cells, but is limited by
the ability to expand T cells restricted to tumor-associated antigens (Kalos). CARs
may overcome tumor tolerance for immunity by allowing T cells to respond to
cell surface antigens (Kalos). However, CARs on their own have demonstrated
minimal in vivo expansion and antitumor effects (Kalos). Clinically, CARs can
trigger T cell activation but its in vivo proliferation is limited (Kalos). Another
challenge of CAR immunity is that T cells rapidly disappear after infusion and
their medicinal effect is not long-lasting (Kalos).

c. To
augment their function and improve longevity, they may be combined with
costimulatory ligands, chimeric costimulatory receptors, or cytokines (Sadelain).
“CARs are an
application of this approach that combines an antigen recognition domain of a
specific antibody with an intracellular domain of the CD3-zeta chain or FcyRI
protein.” With the production of second generation CARs, T cell expansion has
shown to be improved (Kalos).Costimulatory
CARs may improve persistence of CD19 T cells (Zhao). CAR T cell action is
augmented by the production of second generation CARs (Zhao). This helps
redirect cytotoxicity and reprogram T cell function and endurance via.
costimulatory domains (Zhao). These second-generation CARs send T cell activating
and costimulatory signals, resulting in improved proliferation (Zhao). This
ensures immediate and long-term effects (Zhao). An example of successful
application of CARs in their use in CD19 against B cell malignancies (Zhao).
Studies have demonstrate complete remissions (Zhao). CAR T cells can also be
engineered to different levels of potency (Zhao). T cells may also activate the
IRF7/IFN? pathway which further contributes to anti-tumor activity (Zhao).
Tests have been conducted with CD28 or 4-1BB costimulatory signalling domains
(Zhao).

d. In terms of their toxicity profile, the lysis
of tumor cells may lead to dangerously high levels of cytokines (Kalos). However
this can be resolved with preventative medicine Kalos).Adverse effects of autologous lymphocytes consist mainly of
excessive cytokine release which can be prevented with medication prior to
transfusion (June). It has been observed that in lymphocyte therapies
toxicities most often occur due to transgene specificity or vector integration
into the genome (June). Regarding the safety and efficacy of CARs, preclinical studies
are conducted mostly in animals with little genetic diversity as is found in
humans (Fox). While assumptions have been made, and findings have demonstrated
toxicities (of??) as a result of CAR therapies, a common limitation of studies
thus far is that there is not yet a fully reliable assessment of in vivo potential
toxicity (Fox). Adverse effects of autologous lymphocytes consist mainly of
excessive cytokine release which can be prevented with medication prior to
transfusion (June).

 

One of the major concerns regarding lymphocyte therapies for cancer
include worries of impracticality and cost (June). However, arguments remain
that if a therapy is effective in the long-term it will be commercially
cost-effective (June).