2.7 Immunotherapy / Vaccines / Biological Response Modifiers - Shah

what is considered to be the fourth modality of cancer treatment?

immunotherapy

immunotherapy is based on…

utilizing the patients immune system to fight cancer

when normal tissue becomes a tumor or cancerous tissue, ____ develop on their surface

antigens

when normal tissue becomes a tumor or cancerous tissue, antigens develop on their surface. These antigens send a signal to immune cells which leads to ________ or ______

direct killing of the tumor cells or releasing substances that can bring about will lead to tumor cell death

an abundance of ________ correlates with a favorable prognosis

infiltrating lymphocytes

early malignant tissue antigens are transported to the lymphoid organs by _____

dendritic cells

Myeloid suppressor cells inhibit T-lymphocyte function through ____ and ______

direct cell contact and immunosuppressive mediators

Classic Treg markers include:

CD4⁺, CD25⁺, FOXP3⁺.

innate immune system:

1. mediated by

2. when is it activated

3. memory development

1. granulocytes and macrophages

2. first response to antigen

3. no change with repeated exposure

adaptive immune response:

1. mediated by

2. when is it activated

3. memory development

1. T cells

2. when specific antigens are there

3. develops memory!

name 4 tumor related reasons that T cells might not be responsive to tumors (escape mechanisms)

• Secretion of immunosuppressive factors (e.g., TGF-β)

• Expression of Fas ligand → T-cell apoptosis

• Down-regulation of MHC expression

• Defective antigen processing and presentation

name 4 T cell related reasons that T cells might not be responsive to tumors (escape mechanisms)

• Dysfunctional CD3 zeta chain

• Lack of co-stimulation

• Lack of adhesion molecules

• Low-affinity TCR binding

What is negative selection?

Deletion of T cells that react strongly to self peptide/MHC complexes in the thymus.

Why may T cells fail to respond to tumor self-antigens?

Weak immunogenicity

T cells that survive negative selection interact weakly with self-antigens and fail to become activated.

How do we break tolerance and activate T cells against tumors?

Checkpoint inhibition (PD-1, PD-L1, CTLA-4 blockade)

Immunotherapy can be defined as

the ability to activate the immune system to destroy cancer cells

immunotherapy can be classified as…

specific or nonspecific

active or passive

Specific and Active Immunotherapy

Vaccines (induce long-lasting anti-tumor immunity and memory)

Specific and Passive Immunotherapy

Monoclonal antibodies and T cell-based therapy

Non-specific and Active Immunotherapy

Bacterial products and Biological Response Modifiers (cytokines)

Non-specific and Passive immunotherapy

LAK (lymphokine-activated killer cells) and TIL (Tumor Infiltrating Lymphocytes)

Immune checkpoint inhibitors MOA

block immune checkpoints so immune cells can respond more strongly to cancer.

T-cell transfer therapy MOA

T cells are taken from a patient’s tumor, selected or modified, expanded in the lab, and returned to the patient to attack cancer.

T-cell transfer therapy is also called…

adoptive cell therapy / adoptive immunotherapy.

Monoclonal antibodies are…

therapeutic antibodies used to target cancer

cancer treatment vaccines function

boost the immune system’s response to cancer cells

cancer vaxs enhance the ____ against cancer

immune response

cancer vax are different than traditional vax bc they…

do not provide immunity to cancer

Dendritic cells MOA

capture and processing antigens

Present antigens to T cells to initiate an immune response

5 main types of cancer vaccines

1. Tumor cell vaccines

2. Dendritic cell vaccines

3. Antigen vaccines

4. Peptide vaccines

5. DNA (genetic) vaccines

what are the two types of tumor cell vaxs

Autologous

Allogeneic

Autologous Tumor cell vax are made using..

pts own cells

Allogeneic Tumor cell vax are made using..

other persons cells

Whole Tumor Cell Vaccines:

1. what does it use

2. types

3. purpose / goal / function

1. whole tumor cells rendered safe by irradiation

2. allogenic and autologous

3. injection initiates specific immune response so that the immune system attacks similar tumor cells in the body

PROVENGE is a form of _____ immunotherapy

autologous cellular

PROVENGE MOA

targets PAP antigen (which is in most prostate cancers)

induces immune response against PAP

Dendritic Cell Vaccines:

1. description

2. process

3. results

1. dendritic cells are generated outside of the body and are modified to recognize tumor antigens

2. dendritic cells are taken from the patient, exposed to the tumor antigens, then are returned to the patient

3. dendritic cells present the tumor antigens to the T cells to activate them

tumor antigen vaccines:

1. description

2. purpose

1. Vaccines that use specific tumor antigens to stimulate an immune response.

2. Direct the immune system to recognize specific tumor proteins and trigger targeted immune responses against tumor cells

what is injected in peptide antigen vaccines?

one specific epitope

What is the concept behind anti-idiotype vaccines?

Antibodies can act as antigens and trigger an immune response.

1. How do anti-idiotype vaccines work?

2. what do they mimic?

3. primary target

1. Antibodies that resemble cancer cells are injected to stimulate an immune response.

2. Cancer cell antigens.

3. lymphoma

What is introduced in DNA cancer vaccines?

Tumor genes instead of tumor antigens.

What happens after DNA is injected in DNA vaccines?

Body cells take up the DNA and produce tumor antigens.

DNA/Genetic vaccines:

1. description

2. MOA

3. goal

1. Provide a continuous supply of antigens to maintain an immune response against cancer.

2. host cells express the tumor antigen, the antigen presentation stimulates the immune response

3. generate T cell mediated immunity against tumor cells

What type of immunotherapy are monoclonal antibodies?

Specific, passive immunotherapy

Monoclonal antibodies approved for clinical use include…

• Herceptin (trastuzumab) – anti-HER2/neu

• MabThera (rituximab) – anti-CD20

trastuzumab (Herceptin)

1. targets

2. indication

1. HER2/neu; tumor cells for NK cell destruction

2. used for HER2 positive breast cancer

Target of rituximab (MabThera/Rituxan)

CD20

Cancer target of Panorex (edrecolomab)

colorectal cancer

Cancer treated with Herceptin

Breast cancer

Target of Avastin (Bevacizumab)

VEGF receptor

Target of Erbitux (Cetuximab)

Epidermal Growth Factor Receptor (EGFR)

Major classes of immunosuppressants (3)

• Glucocorticoids

• Cytotoxic drugs

• Drugs acting on immunophilins

What are immunostimulants/ biologics?

Biologic therapies that improve how the immune system fights disease

What are monoclonal antibodies?

Proteins produced in the laboratory from a single clone of a B cell.

Strategy #1 of monoclonal antibody cancer therapy

Antibodies bind tumor antigens on cancer cells, marking them for immune destruction.

Strategy #2 of monoclonal antibody cancer therapy

Antibodies block cytokines or proteins needed for cancer cell growth by binding to cytokine receptors on tumor cells

Strategy #3 of monoclonal antibody cancer therapy

Conjugated antibodies deliver toxic substances (e.g., radioactive isotopes) to destroy tumor cells.

trastuzumab

1. description

2. most common cancer treated

1. humanized monoclonal antibody

2. breast cancer

What are cytokines? and when are they released?

Proteins released by immune cells when activated or stimulated.

What is aldesleukin?

Interleukin-2 (IL-2)

aldesleukin (IL-2)

1. class

2. MOA

3. indications

4. common ADE

5. severe ADE

1. Biologic response modifier (BRM)

2. Promotes development of T cells that fight cancer.

3. metastatic renal cell carcinoma and metastatic melanoma

4. flu like symps, loss of appetite, skin rash

5. cardiac arrhythmias, GI disturbs, neurologic effects

What type of drug targets IL-6 in cancer therapy?

Anti-IL-6 chimeric monoclonal antibody

What are interferons?

Natural cytokines produced by leukocytes, T-lymphocytes, and fibroblasts in response to infection or biological stimuli

Goal of interferon therapy in cancer

Activate tumor-specific cytotoxic T-lymphocytes to destroy tumor cells.

How do interferons work at the cellular level?

Bind specific receptors on cell membranes and modify enzyme activity, cell proliferation, and macrophage/T-cell activity.

Which interferon type is mainly used in cancer therapy?

alpha interferons

Cancers treated with alpha interferons (3)

• Hairy cell leukemia

• Malignant melanoma

• Kaposi’s sarcoma

Common side effects of interferons (4)

• Flu-like symptoms (fever, chills, fatigue, headache)

• Muscle aches

• Nausea and vomiting

• Loss of appetite

Neurologic side effects of interferons (4)

Confusion

Trouble thinking/focusing

Depression

Numbness or tingling of fingers

How are flu-like symptoms from interferons sometimes managed?

APAP before each dose

What are Biological Response Modifiers (BRMs)?

Drugs that modify the body’s biologic response to tumor cells

What type of molecules commonly act as BRMs?

Cytokines

What is the role of cytokines in immunotherapy?

Enhance the immune system after immune cell activation

Examples of cytokine BRMs

Interleukins and interferons

Another class of drugs included in immunotherapy BRMs

Immune checkpoint inhibitors

Common side effects of biological response modifiers

• Inflammatory reactions

• Peripheral neuropathy

• Skin rashes

• Depression

What is Interleukin-2 (IL-2)?

T-cell growth factor that promotes T-cell proliferation

Which cells produce IL-2?

T cells (and some B cells)

What is Interleukin-12 (IL-12)?

and what is it produced by?

Cytokine produced by macrophages and B cells

Immune effects of IL-12

• Activates NK cells

• Promotes CD4 T-cell differentiation to TH1-like cells

What is Interferon-gamma?

and what is it produced by?

Cytokine produced by T cells and NK cells

Main immune effect of Interferon-gamma

Activates macrophages

What is G-CSF?

Granulocyte-Colony Stimulating Factor

Drug example of G-CSF

Filgrastim (Neupogen)

Which cells normally produce G-CSF?

Fibroblasts and monocytes

Main pharmacologic effect of G-CSF

Stimulates neutrophil development and differentiation

What is GM-CSF?

Granulocyte-Macrophage Colony Stimulating Factor

Drug example of GM-CSF

Sargramostim (Leukine)

Which cells produce GM-CSF?

Macrophages and T cells

Main pharmacologic effect of GM-CSF

Stimulates growth and differentiation of the myelomonocytic lineage

Proleukin (aldesleukin) — what endogenous cytokine does it mimic?

recombinant IL-2

Primary pharmacologic action of aldesleukin (Proleukin)

Enhances lymphocyte proliferation (mitogenesis)

What immune cells are activated by aldesleukin (IL-2 therapy)?

Natural killer (NK) cells and lymphokine-activated killer (LAK) cells

Aldesleukin stimulates production of which cytokine?

Interferon-γ (IFN-γ)

Aldesleukin produces immunologic effects in what type of manner?

Dose-dependent

Key hematologic effects seen with aldesleukin therapy

Lymphocytosis, eosinophilia, thrombocytopenia

Aldesleukin induces production of which inflammatory cytokines?

TNF-α, IL-1, and IFN-γ

Primary site of metabolism for aldesleukin

Kidneys

How is aldesleukin cleared from circulation?

Glomerular filtration and peritubular extraction in the kidney