Manipulation of Immune Response

Question 1

Immunity by antibodies is what kind of immunity?

Answer 1

passive immunity

provides immediate protection but not long lasting

Question 2

Protection from intestinal infection by mother’s milk is what type of immunity?

Describe difference between passive and active immunity.

Answer 2

passive immunity

Active Immunization (Acquired)

• • activation of immune response
• • immunological memory

Passive Immunization

• • direct transfer of protective antibodies
• • no immunological memory

Active immunization
– introducing an AG to activate an immune response

Passive immunization: commonly used in emergency situations

• • e.g., antitoxins
• • antibodies raised in animals against toxins and venoms

Question 3

What composes the DTaP vaccine?

How does presence of the bacteria stimulate an improved response to the toxins?

Answer 3

Mixture of diphtheria toxoid (a soluble protein) tetanus toxoid (another soluble protein - adjuvant) and killed a cellular Bordetella pertussis bacteria.

The presence of the bacteria stimulates an improved response to the toxins (presumably by upregulating B7 expression by antigen presenting cells). It also produces more inflammation and discomfort at the site of injection.

Question 4

What type of vaccine is DTaP?

Answer 4

DTaP : Inactivated or “killed” vaccine

Question 5

What are 4 antigen sources for vaccines?

Answer 5

Killed/inactivated pathogen
Toxoid
Viral subunits
Live attenuated virus

Question 6

What type of immunity would you use for intracellular infections?

Answer 6

cell mediated immunity for intracellular infections

Generate memory cells

Question 7

What type of immunity for fungal infections?

Answer 7

IL17

Generate memory cells

Question 8

What type of immunity for toxins and organisms that resist phagocytosis?

Answer 8

B cell response for toxins and organisms that resist phagocytosis

Generate memory cells

Question 9

What type of immunity for viruses?

Answer 9

T & B responses for viruses

Generate memory cells

Question 10

Tumor antigens are usually self-proteins modified or selectively over expressed by a tumour. What are specific cell types for :

melanoma
B cell lymphoma
AML
prostate cancer

Answer 10

melanoma - MART-1, tyrosinase , Gp-100 (essentially melanocyte specific)


B cell lymphoma - CD20 (essentially B cell specific)

AML - CD33 (essentially myeloid specific)

Prostate cancer – PSA (prostrate specific antigen)

Question 11

In what types of cancers are the following expressed?

MAGE-3
Carcinoembryonic antigen (CEA)
HER2/neu

Answer 11

MAGE-3 (various tumors, e.g. melanoma)

Carcinoembryonic antigen (CEA) (colon and rectal)

HER2/neu (over expressed in breast cancer)

Question 12

In regards to active immunotherapy to boost ‘ineffective’ T cell responses, a range of tumor-specific antigens have now been defined and the best prospects are those that are widely expressed in tumors.

What are the synthetic peptide fragments to target?

What are the recombinant proteins to target?

What DNA/RNA could be targeted?

Answer 12

• synthetic peptide fragments (Gp100 AA 209-217)
• recombinant proteins (Gp100 AA 209-217)
• DNA/RNA (nucleotides encoding Gp100 AA 209-217)

Question 13

What is the FDA approved adjuvant?

Answer 13

alum

Question 14

What are delivery vectors for specific antigen vaccines?

Answer 14

• ’conventional’ adjuvants (alum-FDA approved, experimental adjuvants)
• viral delivery (retroviral)
• dendritic cells

Question 15

In designing whole tumor vaccines, tumor cells are poorly immunogenic so immunogenicity must be increased. How?

Answer 15

• addition of adjuvants
• use of gene-engineered tumour cells –cytokines
• costimulatory molecules B7

Question 16

What drug can be used to treat Non-Hodgkins lymphoma. Describe how it works

Answer 16

Passive (adoptive) immunotherapy

Rituxan (anti-CD20)
High response rate in B cell lymphoma (more than 70%).
Synergy with chemotherapy CHOP or XRT.
Recognizes B cell marker regulating B cell activation.
Induces growth arrest/apoptosis in vitro.

Question 17

How does Herceptin work?

Answer 17

(anti-HER2…growth receptor found on breast cancer cells) Synergy with chemo (60%) or XRT.
Recognizes EGF-like receptor regulating cellular proliferation (ERBB2).
Induces growth arrest/apoptosis in vitro

Trastuzumab - anti HER2 antibody

Question 18

In what case might TIL be most effective?

Answer 18

Passive (adoptive) immunotherapy

Patient’s own T cells are activated in vitro and retransferred

-provides an exogenous source of anti-tumour T cells

• most effective for highly immunogenic tumours
• melanoma

-may be boosted by concurrent immunization with tumor associated antigen

Question 19

What type of therapy is CAR? Describe how to make it. When might it be used?

Answer 19

Another excellent example of cellular adoptive therapy of tumors is passive transfer of chimeric antigen receptor transduced lymphocytes,

take monoclonal antibody specific for particular tumor associated antigen. take VL and VH and put on chimeric protein (VL and VH, TM CD8 region and signal component of CD3 zeta) so now capacity to recognize tumor associated antigen- antibody component and then have signaling molecules inside the cell… retroviral vector and engineer that component into a cell population

take leukaphersis, take out cells, w retroviral vector transduce their cell population, expand cell populations in vitro, then re-inject modified T cell populations back into the individual (Slide 30)

now T cells reactive against tumor associated antigen

Question 20

How do tumors evade immune system?

Answer 20

under normal immune conditions, with response to infectious agent, immune system responds and you know B7 and CD28 v important in that process. to not allow immune system to overrespond, CTLA4 is prod. and PD1 (these are checkpoints) checks on system so it doesn’t overreact… tumor cells have co-opted those checkpoints.

Question 21

What type of cell displays CTLA-4? How does it work?

Answer 21

CTLA-4 is found on the surface of T cells, and acts as an “off” switch when bound to B7 on the surface of antigen presenting cells.

CTLA-4 transmits an inhibitory signal in T cells, (whereas CD28 transmits a stimulatory signal).

T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, which inhibits an overly active immune response.

Several monoclonals are available to inhibit the interaction of B7 with CTLA-4.

Question 22

What is ipilimumab? What does it do?

Answer 22

Ipilimumab blocks CTLA-4

Blocking Antibodies to CTLA-4 Allow Positive Signaling from Costimulatory Molecules to T Cells, 
Boosting the Tumor Immune Response

immue checkpoint blockade as physician- antibodies directed at CTLA4 - when do that… can then allow T cells that were turned off by tumor cell to carry out their effector function

Question 23

Would upregulating PD1 promote or inhibit tumor cell growth?

Answer 23

PD-1 functions as an immune checkpoint, playing an important role in down regulating the immune response by preventing the activation of T-cells and by promoting apoptosis (programmed cell death) in antigen specific T-cells.

Normal homeostasis, PD-1 reduces autoimmunity and promotes self tolerance.

However, tumors can upregulate PD L1/2 on their surface, neutralizing cytotoxic T cell tumor attack.

PD-1 (cell receptor) is overexpressed on tumor-infiltrating T cells, which are functionally exhausted.

Blocking the PD-1 or PDL-1 pathway would restore/promote the function of chronically exhausted tumor-specific T cells and decrease tumor-induced immune suppression

Question 24

What cell type displays PD-L1?

Answer 24

tumor cell

PD1 is on T cell

Question 25

How does Nivolumab/Opdivo work?

Answer 25

Mechanism of action of PD-1 blocking antibody Opdivo (Nivolumab): After binding the PD-1 receptor, this blocking antibody prevents the inactivation of the immune system. PD1 receptor on the surface of T lymphocytes is blocked by Opdivo (Nivolumab, red), which prevents its binding to PD-L1 ligand on the surface of the tumor cell.

Question 26

What is a toxoid?

Answer 26

soluble protein