cellular and molecular pharmacology - presentation

Cellular and molecular
pharmacology
(MPL 104T)
Unit 4: IMMUNOTHERAPEUTICS
PRESENTED BY : VERMA SIMRAN
M.Pharm (pharmacology)
Supervisor : Dr. snigdha das mandal

What is immunotherapeutic
 A type of therapy that uses substances to
stimulate or suppress the immune system to help
the body fight cancer, infection, and other
diseases.

INTRODUCTION
 Immunotherapy, also called biological therapy, biotherapy or biological
response modifying therapy (BRM therapy), is a set of treatment
techniques that boost the body’s natural defenses'-the immune system
to fight cancer and certain infections.
 Some immunotherapy treatments boost the immune system over all,
while others try to teach it to attack specific types of cells found in
tumors.
 Treatments include the administration of vaccines, creams, tablets and
the use of monoclonal antibodies (these are a type of protein that can
attach to cancer cells in the body).

HISTORY
 William Coley, MD, a New York surgeon, first noted that getting an infection after surgery
seemed to help some cancer patients.
 In the late 1800s, he began treating cancer patients by infecting them with certain kinds
of bacteria, which came to be known as coley toxins.
 Although he had some success, his technique was overshadowed when other forms of
cancer treatment, such as radiation therapy, came into use.
 Not only is Coley known as the "Father of Immunotherapy," he also became the model
for the present-day clinician-scientist.
 First he had inspiration: He was deeply moved by the death of his very first patients due
to widespread metastatic bone sarcoma.
 Second, motivated by this inspiration, he combed the literature to find ideas about what
might be an effective treatment for cancer. Some reports suggested that having an
infection might cause tumor regression.
 Third, following his study of the literature, he developed a theory for treatment. He began
to inject patients with bacteria and bacterial products and noticed that some tumors
disappeared.
 Finally, he regularly published his work.

What is immunotherapy used for?
 Immunotherapy is used to strengthen the immune system
to help it fight cancer and side effects of cancer
treatments.
 It can also be used to combat allergies.
 Allergy shots, also known as subcutaneous
immunotherapy can alter the immune system and prevent
the development of new allergies.

What does immunotherapy involve?
 Treatment uses substances produced by living organisms or
substances made in a laboratory.
 It can be administered in several ways :
 Intravenous (IV): An injection is administered directly into a vein.
 Oral: In capsule or tablet form to ingest.
 Topical: Application of a cream on the skin to fight cancer in its initial
stages.
 Intravesical: This is an injection administered directly into the bladder to
help tackle bladder cancer.

How long does treatment last?
 This can depend on a number of factors, including : The
type of cancer and how advanced it is.
 The type of immunotherapy taken.
 How the patient reacts to the treatment.

Side effects of immunotherapy
 Some of the most common side effects associated with
immunotherapy treatment may include : chills,
constipation, coughing, decreased appetite, diarrhea, fever
and flu-like symptoms, headache, infusion-related reaction
or injection site pain, itching, localized rashes.

TYPES OF IMMUNOTHERAPEUTIC AGENTS IN
CLINICAL USE :
1. Monoclonal antibodies
2. Fusion proteins
3. Soluble cytokine receptors
4. Recombinant cytokines
5. Small-molecule mimetics
6. Cellular therapies

1. MONOCLONAL
 Monoclonal antibodies (mAbs) are manufactured in vitro to
recognize specific targeted antigens (Ags); they are used to treat
solid and hematopoietic tumors, inflammatory disorders, and
infections. Most mAbs in clinical use target a single Ag, but a few
are engineered to be bispecific.
 The monoclonal antibodies that are currently in clinical use
include:
a. Murine
b. Chimeric
c. Humanized
d. Fully human

MURINE MONOCLONAL ANTIBODIES
 Murine monoclonal antibodies are produced by injecting a
mouse with an antigen, harvesting its spleen to obtain B cells
that are producing antibody specific to that antigen, fusing those
cells with immortal mouse myeloma cells, growing these
hybridoma cells (eg, in cell culture), and harvesting the antibody.
 Although mouse antibodies are similar to human antibodies,
clinical use of murine monoclonal antibodies is limited because
they induce human anti-mouse antibody production, can cause
immune complex serum sickness (a type III hypersensitivity
reaction), and are rapidly cleared.

Chimeric monoclonal antibodies activate antigen
Chimeric monoclonal antibodies activate antigen-presenting
cells (APCs) and
T- cells more effectively than murine monoclonal antibodies
but can still induce production of human anti-chimeric
antibodies.

Humanized monoclonal antibodies
 Humanized monoclonal antibodies against various antigens
are available for the treatment of colorectal cancer, breast
cancer, leukaemia, allergy, autoimmune disease, transplant
rejection, and respiratory syncytial virus infection.

Fully human monoclonal antibodies
 Fully human monoclonal antibodies are produced using transgenic
mice that contain human immunoglobulin genes or using phage
display (ie, a bacteriophage-based cloning method) of
immunoglobulin genes isolated from human B cells.
 Fully human monoclonal antibodies have decreased
immunogenicity and therefore may have fewer adverse effects in
patients.

Different between
Chimeric antigen
receptors and T-
cell receptor

2.FUSION PROTEINS
 These hybrid proteins are created by linking together the gene
sequences encoding all or part of 2 different proteins to generate a
chimeric polypeptide that incorporates desirable attributes from the
parent molecules (eg, a cell-targeting component combined with a
cell toxin). The circulating half-life of therapeutic proteins can also
often be improved by fusing them to another protein that naturally
has a longer serum half-life (eg, the Fc region of IgG).

3.SOLUBLE CYTOKINE RECEPTORS
 Soluble versions of cytokine receptors are used as therapeutic
reagents. They can block the action of cytokines by binding with them
before they attach to their normal cell surface receptor.
 Etanercept, a fusion protein, consists of 2 identical chains from the
CD120b receptor for tumour necrosis factor (TNF)-alpha. This agent
thus blocks TNF-alpha and is used to treat rheumatoid arthritis,
polyarticular juvenile idiopathic arthritis, ankylosing spondylitis,
psoriatic arthritis, and plaque psoriasis. Soluble interleukin (IL)
receptors (eg, those for IL-1, IL-2, IL-4, IL-5, and IL-6) are being
developed for treatment of inflammatory and allergic disorders and
cancer.

4.RECOMBINANT CYTOKINES
 Recombinant cytokines Colony-stimulating factors (CSF), such as erythropoietin,
granulocyte CSF (G-CSF), and granulocyte-macrophage CSF (GM-CSF), are used in
patients undergoing chemotherapy or transplantation for hematologic disorders and
cancers and in patients with severe chronic neutropenia (see table Some
Immunotherapeutic Agents in Clinical Use).
 Interferon-alpha (IFN-alpha) and IFN-gamma are used to treat cancer,
immunodeficiency disorders, and viral infections; IFN-beta is used to treat relapsing
multiple sclerosis.
 Many other cytokines are being studied.
 Anakinra, used to treat rheumatoid arthritis, is a recombinant, slightly modified form of
the naturally occurring IL-1R antagonist; this drug attaches to the IL-1 receptor and
thus prevents binding of IL-1, but unlike IL-1, it does not activate the receptor. Cells
expressing cytokine receptors can be targeted by modified versions of the relevant
cytokine which is a fusion protein containing sequences from IL-2 and from diphtheria
toxin).

5.SMALL-MOLECULE MOMETICS
Small-molecule mimetics Small linear peptides, cyclized
peptides, and small organic molecules are being developed
as agonists or antagonists for various applications. Screening
libraries of peptides and organic compounds can identify
potential mimetics (e.g., agonists for receptors for
erythropoietin, thrombopoietin, and G-CSF).

6. CELLULAR THERAPIES
Cellular therapies Immune system cells are harvested (eg, by
leukapheresis) and activated in vitro before they are returned to the
patient.
The aim is to amplify the normally inadequate natural immune response
to cancer.
Methods of activating immune cells include using cytokines to stimulate
and increase numbers of antitumor cytotoxic T cells and using pulsed
exposure to antigen-presenting cells such as dendritic cells with tumor
antigens.
Before being returned to the patient, T cells can be genetically
engineered to express chimeric antigen receptors (CAR) or T cell
receptors (TCR) capable of recognizing tumor antigens, an approach
that has shown efficacy in patients with leukemia and lymphoma.

REFERENCES
1) Roliński J, Grywalska E, Pyzik A, Dzik M, Opoka-Winiarska V, Surdacka A, Maj M, Burdan F, Pirożyński M, Grabarczyk P,
Starosławska E. Interferon alpha as antiviral therapy in chronic active Epstein-Barr virus disease with interstitial pneumonia - case
report. BMC Infect Dis. 2018 Apr 20;18(1):190. [PMC free article] [PubMed]
2) Verhoeven D, Stoppelenburg AJ, Meyer-Wentrup F, Boes M. Increased risk of hematologic malignancies in primary
immunodeficiency disorders: opportunities for immunotherapy. Clin Immunol. 2018 May;190:22-31. [PubMed]
3) Guo LL, Wang GC, Li PJ, Wang CM, Liu LB. Recombinant adenovirus expressing a dendritic cell-targeted melanoma surface
antigen for tumor-specific immunotherapy in melanoma mice model. Exp Ther Med. 2018 Jun;15(6):5394-5402. [PMC free article]
[PubMed]
4) Thangamathesvaran L, Shah R, Verma R, Mahmoud O. Immune checkpoint inhibitors and radiotherapy-concept and review of
current literature. Ann Transl Med. 2018 Apr;6(8):155. [PMC free article] [PubMed].
5) Karkhah A, Javanian M, Ebrahimpour S. The role of regulatory T cells in immunopathogenesis and immunotherapy of viral
infections. Infect Genet Evol. 2018 Apr;59:32-37. [PubMed].
6) Querido S, Weigert A, Adragão T, Henriques J, Birne R, Matias P, Jorge C, Nascimento C, Bruges M, Machado D. Intravenous
Immunoglobulin and Rituximab in HLA Highly Sensitized Kidney Transplant Recipients. Transplant Proc. 2018 Apr;50(3):723-727.
[PubMed]
7) Martínez T, Garcia-Robledo JE, Plata I, Urbano MA, Posso-Osorio I, Rios-Serna LJ, Barrera MC, Tobón GJ. Mechanisms of action
and historical facts on the use of intravenous immunoglobulins in systemic lupus erythematosus. Autoimmun Rev. 2019
Mar;18(3):279-286. [PubMed]
8) Apte S, Navarro-Puerto J, Damodar S, Ramanan V, John J, Kato G, Ross C, Shah C, Torres M, Fu C', Rucker K, Pinciaro P,
Barrera G, Aragonés ME, Ayguasanosa J. Safety and efficacy of intravenous immunoglobulin (Flebogamma® 10% DIF) in patients
with immune thrombocytopenic purpura. Immunotherapy. 2019 Feb;11(2):81-89. [PubMed]
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hepatitis B virus-specific transfer factor]. Nan Fang Yi Ke Da Xue Xue Bao. 2013 Dec;33(12):1827-30. [PubMed]
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(TF) prevents genital or labial herpes relapses. Biotherapy. 1996;9(1-3):67-72

Newer release :
Clinical trials present a new approach using immunotherapy
combinations for bladder cancer treatment.
After 40 years of treating metastatic bladder cancer with chemotherapy
as a primary treatment, scientists now present a new approach using
immunotherapy combinations. The results of two studies have been
presented at the European Society for Medical Oncology (ESMO)
conference in Madrid. The outcomes of these studies could
revolutionize the landscape of bladder cancer treatment.
PHILADELPHIA – A broad new strategy could hold hope for treating
virtually all blood cancers with CAR T cell therapy, which is currently
approved for five subtypes of blood cancer. Scientists in the Perelman
School of Medicine at the University of Pennsylvania have
demonstrated the potential efficacy of this approach in preclinical tests.

QUESTIONES
Is immunotherapy right for me?
How do I get immunotherapy?
Will immunotherapy work?
How long will it take to work?
How is immunotherapy given?
What if I have an autoimmune disease?
What if I have had an organ transplant?
What side effects will I have?
How will I know whether immunotherapy is working?

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cellular and molecular pharmacology - presentation