Anukritti Mehra

Department of Biotechnology ,
Isabella Thoburn College ,
Lucknow

Abstract-

The latest addition to tumor therapy is the use of dendritic cell (DC) vaccine
therapy. Dendritic cell vaccines are a combination of a vaccine and cell
therapy. These dendritic cells are like the factories of the immune system,
producing other molecules that activate key parts of the innate and adaptive
immune systems. DCs are important coordinators in the induction of
antitumor immunity due to their ability to present antigens. Chimeric
antigen receptor (CAR) T-cell therapy is a cancer-fighting immune system
that uses immune cells called T cells (a type of white blood cell) that are
engineered in the lab to find and destroy cancer cells. This is a method
of acquiring cells. CAR T cell therapy is sometimes referred to as a type
of cell-based gene therapy because it modifies the genes of T cells to help
them fight cancer.

Dendritic cell therapy and its role in Cancer –

An innovative and promising anti-cancer therapy invented recently is immunotherapy.

This therapy strengthens the body's natural defenses, or immunity, to destroy, kill, and
control cancer cells. Dendritic cell therapy is a widely used immunotherapy in India. It
has proven to be highly effective in treating tumors in advanced stages. It is known that
dendritic cell therapy has been used for many years to fight and control cancer
progression. Dendritic cell therapy is used to treat many types of cancer, including
glioma, melanoma, sarcoma, prostate cancer, breast cancer, ovarian cancer, and
pancreatic cancer.
In India, this treatment is always used in combination with other treatments such as
radiation therapy and chemotherapy to make it more effective and efficient.
Dendritic cell therapy in India is considered more effective, better tolerated by
patients, and has fewer side effects. dendritic cells
Dendritic cells are the most important protective substances in all human bodies. They
are present in the skin, blood, and mucous membranes. Dendritic cells form an
active defense system in the body when pathogens of any kind arise in the body,
such as viruses, bacteria, and cancer cells.
As part of this treatment, progenitor cells are harvested from the patient's blood.
These cells find, absorb, and recognize pathogens. These cells activate the body's immune
system by connecting with other defense cells and attracting them to the source of
infection. Dendritic cells also promote the formation of B cells and T cells, the foot
soldiers and special forces of the human body's immune system. Dendritic cell
therapy trains dendritic cells to recognize, absorb, and attack pathogens. This
activates the overall immune system in the body. However, over time, this treatment
successfully controls the growth and spread of cancer cells and tissues.

Dendritic Cell Vaccine (DCV) –

DCV is an important component of dendritic cell therapy. This vaccine is produced in

the following way.
• A blood sample is taken from the patient along with some cancerous tissue.
• Immature progenitor cells are cultured in the laboratory.
• Dendritic cells and cancer tissue grow together. This allows dendritic cells to better
recognize cancerous tissue.
• After about 2-3 weeks, the dendritic cells are ready to build a stronger
immune system in the body and the vaccine is ready to fight cancer. Results can be
seen within 3 months of administering the vaccine while the therapy takes around 6 to 9
months in order to detect the full effect of the vaccine given.
DCV is used for the treatment of the following types of Cancers-
Dendritic Cell Therapy is popularly, extensively, and effectively used for treatment of a
variety of cancers.In combination with other treatments ,this therapy provides miraculous
results. Around 4500 people in India are successfully treated with Dendritic Cell therapy and
other countries that were suffering from Uterine cancer, Pancreatic Cancer ,Breast Cancer,
Prostate Cancer, Colorectal Cancer,Liver Cancer,Melanoma, Intestinal Cancer, Glioblastoma,
Oesophageal Cancer, Renal Cancer, Sarcoma,Mesothelioma .

Dendritic Cell Cancer Therapy: Vaccinating the Right Patient at the Right Time-

The evolving field of immune checkpoint inhibition-

Currently, the clinical application of immunotherapy is mainly defined by ICI. ICI target
immune checkpoint molecules such as CTLA-4, PD-L1, and PD-1. These checkpoint molecules
have immune response which inhibit functions and are involved in the prevention of
autoimmunity and maintain peripheral tolerance. It is known that tumor cells upregulate
the expression of checkpoint molecules, which can lead to anergy of cytotoxic T cells in
the tumor microenvironment. CTLA-4, PD-L1, and PD-1 have different functions. CTLA-4
exerts an inhibitory function on early T cell activation, whereas PD-1 and PD-L1 play
a role in inhibiting the effector function of her T cells. ICIs aim to antagonize these
molecules and thereby strengthen immune defenses against cancer responses. In
2010, ipilimumab (a monoclonal antibody against CTLA-4) became the first
immunotherapy to provide clinical benefit in cancer patients, extending median overall
survival (OS) to 10 months (gp100 peptide vaccine (compared to 6.4 months in the
control group used). For metastatic melanoma. With an ORR (Overall Response Rate) of
approximately 10% to 20%, ipilimumab showed a remarkable improvement compared
to the then-standard treatment, but although a significant proportion of patients
responded, some melanoma patients showed no clinical benefit.
After these groundbreaking studies, ICI research accelerated. With the addition of the
PD-L1-targeted drugs avelumab, atezolimumab, and durvalumab, the ICI portfolio now
includes six FDA- and EMA-approved monoclonal antibodies (mAbs). Most of these ICIs
are approved for the treatment of multiple malignancies. These mAbs are currently
being tested in a variety of other malignancies, so the number of approved
indications is expected to rise..
In addition to PD-1, PD-L1, and CTLA-4, other checkpoint molecules (such as TIM-3 and
LAG-3) have also been shown to inhibit the immune response against cancer. Several
mAbs targeting these alternative checkpoint molecules are in various stages of clinical
research. Therefore, the number of clinically available mAbs is expected to continue
to increase. In addition to treating metastatic disease, the study aims to use her ICI
in adjuvant cancer therapy. For example, adjuvant ipilimumab, nivolumab, and
pembrolizumab were recently shown to improve progression-free survival (PFS) after
surgically resected stage III melanoma, and in the case of adjuvant ipilimumab,
prolonged OS was observed.

CAR (Chimeric Antigen Receptor) – T cells and their role in

immunotherapy –
Chimeric antigen receptors (CARs) are typically are artificial fusion molecules encoded by
genes that can do have the following effects-
Reprograms the specificity of peripheral blood polyclonal T cells for selected cell surface
targets. CARs are engineered receptors that combine the specific binding domain of a
tumor-targeting antibody with a T-cell signaling domain to enable targeted antibody-
redirected T-cell activation. Design of chimeric antigen receptor –
The overall structure of CAR consists of four domains connected in series.
In other words:
(i) Antigen recognition
Domain (per target),
(il) Hinge/Spacer
(iii) transmembrane elements;
(iv) Signaling endodomain

1) THE TARGETING MOIETY-

o The CAR ectodomain determines target specificity and contains elements most
commonly derived from MAbs (Monoclonal Antibodies) Co-expresses both the variable
heavy chain (VH) and light chain of the antibody (VL) into two separate polypeptide
chains to create a single-chain variable fragment (seFv).

2) THE HINGE/SPACER AND TRANS-MEMBRANE

HDOMAIN-

It plays a primarily structural role in the Central African Republic. Several reports
suggest that different hinge regions may critically control surface expression levels,
engineering stability, and antigen binding affinity, which directly impact the efficiency of
CAR-redirected effector functions. suggests that it is possible.

3) THE CAR SIGNALLING DOMAIN-

First generation CAR T cells contain a single T cell activation domain, mostly derived
from the zeta chain of the TCR/CD3 complex. CD3z alone guarantees a powerful effect
“Signal 1” from three immunoreceptor tyrosine-based activation motifs (ITAMs) replaces
the global signal provided by the entire CD3 complex. Second and third generation Chimeric
Antigen Receptors have been developed, with one and two co-stimulatory domains
connected in series with CD3z, respectively. Specifically, CD28 encompasses as a co-
stimulatory domain because it provides an early second signal and promotes high
stimulation.
IL-2 secretion level. Resistance to apoptosis.
Purpose of CAR-T cell development –

Escaping the mechanisms of tumor surveillance

o Low immunogenicity
o Antigen regulation
o Immunosuppression by tumor cells T
regulatory cells
o Induction of lymphocyte apoptosis
o Defects in the MHC-I production machinery can cause cancer cells to become
“invisible” to CD8 cells.

CAR-T cell therapy: “living medicine”

CAR-T cells are equivalent to "giving a patient a living drug," Renier J. Kennedy
explained. Brentjens, MD, of Memorial Sloan Kettering Cancer Center in New York, is
another early frontrunner in the CAR-T cell field.
As the name suggests, T cells, which help coordinate immune responses and directly
kill cells infected with pathogens, are the backbone of CAR T cell therapy.
Currently available CAR T cell therapies are personalized for each individual patient. These
are made by collecting her T cells from a patient and remanipulating them in the
laboratory to produce proteins called chimeric antigen receptors (CARs) on their
surfaces. CARs recognize and bind to specific proteins or antigens present on the surface
of cancer cells. Dealing with side effects of CAR T cell therapy
Like all cancer treatments, CAR T-cell therapy can cause serious side effects, including
mass death of antibody-producing B cells and infections. One of the most common and
serious side effects is cytokine release syndrome (CRS). T cells release cytokines as a part of
their Immune related job, chemical messengers that help stimulate and control immune
responses. In the case of CRS, the infused T cells rush the bloodstream with cytokines,
causing serious side effects such as dangerously high fever and a sudden drop in
blood pressure. In some cases, severe CRS can be lethal.

The majority of this treatment is a drug called tocilizumab (Actemra). The drug was
originally used to treat inflammatory diseases such as juvenile arthritis and blocks the
activity of IL-6, a cytokine that is mostly secreted in ample amounts by T cells and
macrophages.
Another side effect of particular concern with CAR T cell therapy is neurological effects,
such as severe confusion, seizure-like activity, and language impairment. The exact
cause of these neurological side effects (also known as immune effector cell-associated
neurotoxicity syndrome or ICANS) is still unknown.
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