Course 2.

3: Principles of Therapy and Treatment

Chairman: Prof. Dr. med. Christian Buske

Principles of Anticancer Immunotherapy

Lecturer: Dr. rer. nat. Sabine Stienen, M.Sc.

1.- Which statement is correct?

Select one:
A. CTLA-4 is upregulated on the plasma membrane early after T cell activation, to maintain
immunologic homeostasis by triggering upregulation of the B cell function. This happens by binding to
the molecule B7 on APC whereby preventing the costimulatory signal that can be induced through
CD28/B7 binding.
B. CTLA-4 is upregulated on the plasma membrane early after T cell activation, to maintain
immunologic homeostasis by triggering downregulation of the T cell function. This happens by binding to
the molecule CD28 on APC whereby preventing the costimulatory signal that can be induced through
CD28/B7 binding.
C. CTLA-4 is upregulated on the plasma membrane early after T cell activation, to maintain
immunologic homeostasis by triggering downregulation of the T cell function. This happens by
binding to the molecule B7 on APC whereby preventing the costimulatory signal that can be induced
through CD28/B7 binding.

Discussion:

Principles of tumor recognition by T cells

a) T cell activation require antigen presentation by dendritic cells, macrophages or tumor cells
b) Amplification of T cell response by activation APCs
c) Activated CD4+ T cells can proliferate, differentiate and activate effector cells such as cytotoxic
T cells via IL-2 secretion

ONCOLOGY MEETS IMMUNOLOGY

Cancer formation or oncogenesis
o Characterized through accumulation of genetic alteration and loos of normal cellular
regulation
o Associated with presentation and release of neoantigens
 Tumor-specific or tumor associated
 Differentiation antigens, cancer testis antigens and other
 Process of cancer immunoediting can be induced
o Loss of immune protection in the tumor microenvironment despite an otherwise
functional immune system
o Modified regulation of the cancer immunity
 Elimination :::¸equilibrium:::::: escape phase (cancer immune surveillance)
First clinically targeted immunology checkpoint: cytotoxic T lymphocyte-associated antigen 4
(CTLA-4)

 Upregulated on plasma membrane after T cell activation

 Downregulation of T cell function by binding to B7 on APC whereby preventing
costimulatory signal through CD28/B7 binding
 Exert activity mainly in lymph nodes
 Immnotherapeutics mABs; Ipilimumab and Tremelimumab:::: Binding to CTLA-4
proteins B7.1 and b7.2 ::::: blocking of dowregulation of Tcell activity:::: allows CTLs to
ccontinue destroying cancer cells

2.- Which statement is not correct?

Select one:
A. "Tumor-targeting” monoclonal antibodies selectively recognize tumor cells by binding to matching
tumor-associated antigens whereby inducing signaling interruption in oncogenic pathways, opsonizing of
tumor cells initiating antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis and stimulation of
adaptive immune responses.
B. Immunomodulating antibodies interact with soluble or cellular components of the immune
system to elicit novel or reinstate existing anticancer immune reactions by opsonizing tumor cells
leading to activation of co-stimmulatory receptors that are expressed on immune effector cells.
C. Improvement strategies for treatment with tumor-targeting monoclonal antibodies involves
conjugation of toxins to antibodies, conjugation of radioactive ligands to antibodies, generation of bispecific
antibodies targeting two distinct antigens and the concurrent administration of immune modulatory factors
together with the tumor-targeting antibody.

Discussion:

Tumor-targeting by monoclonal antibodies

Monoclonal antibodies (mAbs) can induce:

 Signaling interruption in oncogenic pathways

 Opsonizing tumor cells and initiation of antibody-dependent cellular cytotoxicity (ADCC)
or phagocytosis
 Stimulation of adaptive immune response

Improvement strategies

 Conjugation of toxins to antibodies

 Conjugation of radioactive ligands to antibodies
 Bispecific antibodies
 Concurrent administration of immune modulatory factors
Antitumor effects of monoclonal antibodies
I. Direct tumor killing
a. Receptor blockade or agonist activity
b. Induction of apoptosis
c. Or delivery of a drug or cytotoxic agent
II. Immune-mediated cell killing
a. Complement-dependent cytotoxicity (CDC)
b. Antibody-depend cellular cytotoxicity (ADCC)
c. And regulation of T cell function
III. Specific effect of an antibody on tumor vasculature and stroma
IV. Other antibodies exclusively employing immunomodulatory effects led to a
separation from de class of tumor targeting monoclonal antibodies

IMMUNOMODULATORY mAbs

 Interaction with soluble and cellular components of immune system to elicit novel o
reinstate existing anticancer immune reaction
 Inhibition of immunosuppressive receptors expressed on activated T cells (checkpoint
blockade): CTLA-4, PD-1 or by NK cells: KIR
 Inhibition of ligands of these receptors: PD-L1
 Activation of co-stimulatory receptors expressed on immune effectors cells: Ox40, 4-1BB,
GITR
 Neutralization of immunosuppressive factors released in tumor microenvironment: TGF1

3.-The concept of immunoediting involves

Select one:
A. Surveillance, adaptation, escape.
B. Inflammation, infiltration, proliferation.
C. Elimination, equilibrium and escape.

Discussion:

Immunoediting
Step 1: ELIMINATION
 Tumor antigens are recognized by a variety of immune-system cells of innate and adaptive
system. Elimination of tumor cells before they clinically visible-
 Increase expression and activity (Tumor immunity) : Perforin . IFN a/b/g, TRAIL, TBK a, FasL,
NKG2D, IL-1, IL-12
Step 2: EQUILIBRIUM
 Tumor in balanced status: New variants occur that eventually escape the immune system and
proliferate to for a tumor. Genetics instability/immune selection = Tumor cell variant, genetic
and epigenetic changes, resistance to immune detection.
 Tumor dormancy : Il-12, IFN g = IL-10, IL.23

Step 3: ESCAPE
 Failure of immune system: tumor outgrowth results in clinically evident disease
 Tumor progession: A2a/A2bR, CD39, CD73, PD-1, CTLA-4, Tim3, LAG-3, PD-L1, Gallectin-1/3/9,
Stat3, Cox2, PGE, IL-23, IL-10, TGFb, IDO, TDO, Arg1

The first checkpoint inhibitor for treatment of metastatic melanoma was

approved by the FDA in

Select one:
A. 2009.
B. 2011.
C. 2014.
D. 2001.

Discussion:

1986: INF-a approved as cancer immunotherapy

1991: fist tumor-associated antigen cloned (MAGE-1)
1992: IL-2 approved as cancer immunotherapy
1997: Rituximab approved as fist mAb for patient with NHL
2011: Ipilimumab as first checkpoint inhibitor approved for patient with mMelanoma
2014: Pembrolizumab as anti-PD-1 checkpoint inhibitor approved for patient with mMelanoma
/ Blinatumomab as firsts bispecific T cell engager approved for patient with rel/ref ALL

5.- The gut microbiome is involved in intestinal T cell development by killing

FOXP3-positive regulatory T cells.

Select one:
A. Incorrect.
B. Correct.