...

1. Cancer Immunology and Immunotherapy in
Treatment of High Grade Glial Tumors1

2. 2

3. 3

4. 4

5. 5

6. Tumor Immunotherapy by Exogenous Production
and Autologous Reinfusion of Cytotoxic T Cells6

7. Cancer Immunotherapy by Depletion of
Immunosuppressive Treg Cells (CD4+CD25+)7

8. Genetic Production and propagation of T cell clones carrying
tumor-antigen specific T-cell receptors (TCR’s)
Isolate TIL’s (Tumor Infiltrating Lymphocytes) → Isolate T-cells with
strongest avidity to autologous tumor cells → Clone their TCR’s and
load into viral vectors → Transduce T cells and achieve their clonal
propagation in cell culture → Infuse to the patient
8

9. (From Deducing Mutant
Sequences) Determine
Antigenic Cancer
Peptides In Silico →
Clone TCR’s Selective To
Those Antigens via In
Vitro and In Vivo
Approaches → Virally
Transduce and Propagate
T cells With Most
Reactive TCR’s → Check
Their Activity By Co-
culturing with
Autologous Tumor Cells
→ Infuse to the Patient
9

10. Vaccination Approaches in Cancer
Immunotherapy
Peptide Based Vaccines – Personalized Peptide
Vaccine Strategy
Dendritic Cell Vaccines
Peptide Based Vaccines + Dendritic Cell Vaccines
Autologous / Whole Tumor Cell Vaccines
Allogeneic Tumor Cell Vaccines
DNA Vaccines
10

11. Peptide Based Vaccines
 Isolate PBMC’s from Cancer Patients → Screen Their
Reactivity To Each Peptide → Vaccine Specifically With
Peptides Causing Strongest Reactivity
 Short Peptides Are Safe, Easier To Produce and Easier to be
Loaded on MHC-1 Molecules To Activate Cytotoxic T Cells;
but:
 THEY ARE NOT IMMUNOGENIC ENOUGH !
 Longer Peptides May Not Directly Bind to MHC’s, so They
Need to be Taken Up and Presented by Dendritic Cells;
 However, They Are Presented by Longer Periods Causing
Higher Clonal Expansion of Specific CD4 and CD8 T
Lymphocytes
 23 Pancreas Cancer Patients Vaccinated With Long Peptides
After Surgical Resection → 4 Patients Surviving For 10 Years
!!! (Weden S, et al. Int J Cancer, 2011)
11

12. Autologous / Whole Tumor Cell Vaccines
Potent Vehicles: They Express All Relevant Antigens,
Both Known and Unidentified ! Thus They Can Induce
Robust Immunity and Prominent Clinical Responses
Disadvantages:
Not all tumor cells could not be isolated for culturing
If isolated: Length of procedure, risk of
bacterial/mycobacterial contamination
12

13. Rintatolimod (poly I:
poly C12U – tradename:
Ampligen) is an
experimental immuno-
modulatory double
stranded RNA drug.
Necrotic tumor cells
can be safer antigenic
sources, since
intracellular organelles
could provoke robust
innate immunity via
TLR’s. Low dose
hypochlorous acid
(HOCL) can be used for
this purpose.
13

14. Allogeneic Tumor Cell Vaccines (With
Established Cell Lines)
There is no necessity to obtain tumor cells via surgery.
They can be cloned easily, while proteolytic enzyme
treatment to establish primary tumor cell cultures decrease
the chances to obtain viable cells.
Risk of contamination is much less.
No need to isolate specific tumor associated antigens and
HLA typing, since their antigens can be presented by
autologous dendritic cells.
Either killed cells can be injected or they can be injected
after irradiating at specific radiation doses, which block their
proliferative capacity without inducing cell kill.
14

15. Allogeneic Tumor Cell Vaccines (With Established
Cell Lines)
The efficacy of both autologous and
allogeneic tumor cell vaccines can
be improved genetically via
transducing tumor cells to produce
immunostimulating cytokines (eg.
GM-CSF) and injecting non-
clonogenic irradiated cells to
provide sustained immune
stimulation !!
Disadvantage: Usage of fetal calf serum causes concerns for
clinical application. Culture conditions shall be optimized
15

16. Neolithic Age: BC 8000?
16

17. 17
GOBEKLİTEPE: BC
8000-9500
10 to 115. THOUSAND
YEARS OLD
Excavator: Klaus Schmidt

18. 18

19. 19

20. 20
17’th Dec 1903, Wright Brothers
1946, Supersonic Flight
2014, X-47B,
Unmanned
Warcraft
Reaching
subsonic speed

21. Multiple Ways to Augment
Antitumor
Immunity:
Adoptive T cells Therapy
Anti-CTLA-4 (ipilimumab),
Anti-PD-1(nivolumab),
IL-2 (Augmenting NK
Activity and T cell
Proliferation),
COX-2 inhibitors and All-
Trans Retinoic Acid
(Blocking Myeloid Derived
Suppressor Cells)
Anti-VEGF
IDO inhibition
(1-Methyl D-Tryptophan)
21

22. Antiangiogenic Agents and Radiation Therapy Also Increase Potency
of Cancer Vaccines via Enhancing Dendritic Cell Activation
22

23. DNA Vaccines Can Lead Prolonged Exposure To
Cancer Antigens.23

24. 24

25. 25

26. DNA Vaccines
Can Also
Contain
Molecules With
Structures of
PAMPs
(Pathogen
Associated
Molecular
Pattern)
The Cell
Damage At the
Injection
Site Would Also
Release
DAMPs
26

27. Transfection of
Dendritic or
Stromal Cells with
Plasmid DNA
Induces Their
Release of IFNγ via
Activating STING-
TBK1-IKKε
Signaling Pathway
and
Subsequent
Binding of IRF-3
Transcription
Factor to the IFNγ
Promoter
27