The document discusses current strategies for cancer immunotherapy, including monoclonal antibodies and cell-based immunotherapy. Monoclonal antibodies can target cancer cells directly via mechanisms like antibody-dependent cellular cytotoxicity. They can also be conjugated to toxins or radioactive particles for targeted delivery. Immune checkpoint blockers are a type of monoclonal antibody that blocks inhibitory receptors on T-cells to prolong anti-tumor responses. Cell-based immunotherapy includes adoptive T-cell therapy using tumor-infiltrating lymphocytes or chimeric antigen receptor T-cells that are genetically modified to target specific tumor antigens. Immunotherapy has advantages over other treatments in that it can target cancers throughout the body, is highly specific to cancer cells, and may provide durable, long-

1. CANCER IMMUNOTHERAPY
Done by:
Abdallah M. Youssof

2. CONTENTS
 3. Cancer Immunotherapy: Today Strategies and Agents;
 3.1. Monoclonal Antibodies
 3.5. Cell-based Immunotherapy
 4. Advantages of Immunotherapy over alternatives.
 5. Challenges and Limitations of Immunotherapy.
ABDALLAH M. YOUSSOF 2

3. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): Structure
• During the past 20 years, mAbs have been a
major treatment for diverse cancers, including
breast, lymphoma, and CRC malignancies.
• The mAbs are artificial versions of large proteins
produced by a particular B-cell clone, which have
unique antigen specificity that allows them to
bind to epitopes on the cancer cell or in its
plasma.
• Therapeutic mAbs are typically of the
immunoglobulin G (Ig G) class.
• mAbs can be “naked,” meaning it is not
combined with any other drug, or conjugated;
joined with chemotherapy drugs, radioactive
particles, or toxins in order to lead them into
cancer cells.
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4. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs):
Mechanisms of ActionA- Naked mAbs:
• Primary mechanisms:
1. Antibody-dependent cellular cytotoxicity (ADCC)
2. Complement-dependent cytotoxicity (CDC)
ADCC: the antibody binds to a specific antigen expressed on the surface
cancer cell via Fv part. Then, via the Fc, it binds to specific receptors
expressed on immune-effector cells (such as macrophages and NK cells)
resulting in activation of the immune-effector cells to lyze the target cells.
CDC: when the C1 complex binds the antibody–antigen complex, activates a
cascade of complement proteins to form a complex that attacks the
membrane. This results in lysis of the target cell.
dependent on
immune
effector mechanisms
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5. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs):
Mechanisms of ActionA- Naked mAbs:
• Additional mechanisms:
1. Triggering direct cell death (apoptosis)
2. Inhibition of cell signaling (mAbs bind to ligand or receptor that
is expressed on the cell surface and block the target signaling
pathway).
3. Inhibition of angiogenesis
4. Blocking of immune checkpoints
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6. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs):
Mechanisms of Action
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7. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs):
Mechanisms of ActionB- Conjugated mAbs:
• Serve as drug delivery carriers that can be conjugated as:
1. mAb–toxin conjugates,
2. mAb–radionuclide conjugates,
3. mAb–nanoparticles conjugates,
4. mAb–liposome conjugates, or
5. mAb–biodegradable polymers conjugates
• The antitumor efficacy of these mAb conjugates is no longer mediated by
ADCC and CDC actions, but by the radionuclides, toxins, or other anticancer
agents that are specifically targeted toward the tumor or malignant cells.
The advantage of these conjugates
over conventional drugs is that
cytotoxic agents can be delivered
directly and at higher local
concentrations to tumor tissues,
without causing damage to normal
cells.
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8. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): FDA
Approved mAbs
• In 1997, Rituximab (Rituxan, Genentech) became the first mAb approved for
clinical use, indicated in patients with select B-cell malignancies.
• Trastuzumab, Alemtuzumab, Ibritumomab tiuxetan, Cetuximab,
Bevacizumab, Panitumumab, Ofatumumab, Ipilimumab, Brentuximab
vedotin, Nivolumab, and Pembrolizumab.
• Many other mAbs are undergoing regulatory review at the FDA or are in
phase 3 clinical trials.
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9. 3. CURRENT STRATEGIES AND AGENTS
3.1. Monoclonal Antibodies (mAbs): Immune
Checkpoint Blockers (ICBs)
• Immunomodulatory mAbs that block IC receptors; (Checkpoint
ligand/receptor interactions)
• As noted earlier, tumors can utilize immunosuppressive checkpoints to
impede T-cell activity and evade the body’s immune system.
• ICBs overcome this mechanism by blocking the checkpoint receptors on T-
cells that act as brakes to the immune response; this results in prolonged
antitumor responses.
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10. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): MOA of
ICBs Checkpoint ligand/receptor interactions can
be stopped by:
A. Blocking IC receptors such as
[Cytotoxic T-Lymphocyte
Associated Antigen 4 (CTLA-4) and
Programmed Death-1 (PD-1)] , or
B. Blocking IC ligands of tumor cells,
such as Programmed Death
Ligand-1& 2 (PD-L1and PD-L2).
R
L
CD28
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11. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): A. CTLA4
blockade CTLA-4, the first IC receptor to be clinically targeted, is expressed
exclusively on the surface of T-cells, where its main function is to regulate
the early-stage T-cell activation.
 Due to its higher affinity for CD80 and CD86 than CD28 antigen on T-cells,
CTLA-4 competes for binding to CD80 and CD86 resulting in inhibition of
T-cell activation by delivering inhibitory signals.
 The mechanism of action for CTLA-4 ICBs involves both enhancement of
T-cell activity and inhibition or elimination of Tregs activity (Tregs achieve
their suppressive action by controlling both the antitumor immune response
and autoimmunity).
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12. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): B. PD1
Blockade
 PD-1 receptor, present on activated T cells and on non-T lymphocyte
subsets, including B cells and NK cells, is more broadly expressed within the
body than CTLA-4.
 The main role of PD-1 is to limit T-cell activity in peripheral tissues in
order to prevent autoimmunity during an inflammatory response to
infection.
 The binding of PD-1 to PD-L1 or PD-L2 Ligands on tumor cells leads to
inhibition of T-cell proliferation and cytokines production.
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14. 3. CURRENT STRATEGIES AND
AGENTS
3.1. Monoclonal Antibodies (mAbs): B. PD1
Blockade PD-1 blockade with ICBs:
I. induces T-cell activation and expansion,
II. enhances antitumor responses by diminishing the
number and/or suppressive activity of Tregs,
III. enhances NK activity in tumors and tissues, and
IV. enhances antibody production as well.
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15. 3. CURRENT STRATEGIES AND AGENTS
3.1. Monoclonal Antibodies (mAbs): ICBs as
promising immuno- therapeutic agents
 ICBs can provide durable, long-term survival benefits and
are well tolerated.
 A notable case is the success of the ICB drug
pembrolizumab, which, combined with surgery and radiation,
has reportedly eradicated all evidence of advanced melanoma
in former President Jimmy Carter even though it had
metastasized to his liver and brain.
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16. 3. CURRENT STRATEGIES AND
AGENTS:
3.1. Monoclonal Antibodies (mAbs): FDA
approved ICBs
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17. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy: (Adoptive T-
cell therapy)Rather than provoking an immune response, cell-based immunotherapies
contain intrinsic antitumor properties.
 Adoptive T-cell Therapy (ACT) is the transfer of natural or genetically
modified T cells that have been expanded ex vivo into patients to treat
metastatic cancers.
 The infused cells can be allogenic (obtained from a donor whose human
leukocyte antigens (HLA) are acceptable and match to the patient) or
autologous (obtained from the same individual).
 With allogenic cells, an immune response is triggered based on allogeneic
differences in the expression of peptide/HLA (human leukocyte antigen)
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18. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy: Types of ACT
I. Tumor-Infiltrating lymphocytes (TILs): are white blood cells that have left
the bloodstream and migrated towards a tumor.
 TILs react to epitopes and to shared antigens and neoantigens created by
tumor-specific mutations.
 However, identification of the tumor antigen is not required for TIL cell-
based treatment because the TILs infiltrating a tumor are already antigen-
specific T cells.
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19. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy: TILs Process
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20. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy: Types of ACTII. Chimeric Antigen Receptor “CAR” Therapy:
 The development of CAR therapy is one of the most promising genetic
engineering approaches to cell-based immunotherapy.
 In this method, CARs are introduced by genetic engineering into
autologous T cells ex vivo to enhance their activity and specificity against
antigens expressed on the tumor cell surface.
 The TCR is modified so that its antigen binding portion is conjugated to an
artificial signaling molecule that sends activation signals to T cells when it
binds to the antigen/MHC “major histocompatibility complex” complex.
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21. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy:
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22. 3. CURRENT STRATEGIES AND
AGENTS
3.5. Cell-Based Immunotherapy:
 CAR-based adoptive cell therapy approaches are insensitive to tumor
escape mechanisms arising from HLA molecule loss (non-HLA-restricted).
 Currently, the major limitation to CAR treatment is the lack of sufficiently
specific tumor surface antigens.
 In 2018, FDA has given marketing approval for both Gilead’s Yescarta and
Novartis’s Kymriah for treatment of patients with various forms of blood
cancer.
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23. 4. ADVANTAGES OF
IMMUNOTHERAPY
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The excitement surrounding immunotherapy arises from its
tremendous therapeutic promise and its multiple potential
advantages compared to traditional front-line treatments.

24. 4. ADVANTAGES OF
IMMUNOTHERAPY
 General advantages of immunotherapy include:
1. Targeting: Immunotherapies have the potential to
generate powerful immune responses that target
tumors throughout the body, including tumors that
may be inaccessible to surgery or radiation.
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25. 4. ADVANTAGES OF
IMMUNOTHERAPY
 General advantages of immunotherapy
include:
2. Specificity: Many immunotherapies train the
immune system to recognize and target only
cancer cells.
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26. 4. ADVANTAGES OF
IMMUNOTHERAPY
 General advantages of immunotherapy include:
3. Durability: Immunotherapies can induce immune
memory, meaning protection is lasting and effective
against subsequent tumors.
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27. 4. ADVANTAGES OF
IMMUNOTHERAPY
 General advantages of immunotherapy include:
4. Universality: Some immunotherapies boost the
patient’s own cancer-specific immune responses,
meaning they have the potential to work for a wide
variety of cancers.
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28. 5. CHALLENGES AND LIMITATIONS OF
IMMUNOTHERAPY
 General advantages of immunotherapy include:
4. Universality: Some immunotherapies boost the
patient’s own cancer-specific immune responses,
meaning they have the potential to work for a wide
variety of cancers.
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29. 5. CHALLENGES AND LIMITATIONS OF
IMMUNOTHERAPY
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30. 5. CHALLENGES AND LIMITATIONS OF
IMMUNOTHERAPY
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31. REFERENCES:
1. Ventola, C.L., 2017. Cancer immunotherapy, part 2: efficacy, safety, and other
clinical considerations. Pharmacy and Therapeutics, 42(7), p.452.
2. Ventola, C.L., 2017. Cancer immunotherapy, part 1: current strategies and agents.
Pharmacy and Therapeutics, 42(6), p.375.
3. Ventola, C.L., 2017. Cancer immunotherapy, part 3: Challenges and future trends.
Pharmacy and Therapeutics, 42(8), p.514.
4. Immunology and Cancer Immunotherapy Research Program at NCCC
cancer.dartmouth.edu/res/immunology-cancer.htmlL.
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