The basics of tumour immunology

Austin Duffy, Consultant Medical Oncologist, The Mater

Hospital
Associate Professor of Translational Oncology, UCD
36 yr old firefighter with duodenal cancer

Baseline 12wks

Le...(Duffy AG) et al. Science 2017

77 yr old lady with refractory endometrial cancer

Baseline 12wks (Tx: pembrolizumab)

Le...(Duffy) et al. Science 2017

America’s hospital
America’s hospital

Cell-based therapies
- Tumor-infiltrating lymphocytes (TIL)
- Engineered T-cell receptor (TCR)
- Chimeric Antigen Receptor (CAR)

Steve Rosenberg
T-cell

Cancer cell
William Coley
 Coley’s toxins

Cancer Research Institute/Proceedings of the Royal Society of Medicine 01/1910/3 (Surg Sect): 1-48
Helen Coley Nauts
T-cell

Cancer cell
America’s hospital

Steve Rosenberg
TIL Therapy
Proof of principle

Tran et al. Science 2014

Regulating T-cell activity

APC T-cell

APC, antigen-presenting cell; TCR, T-cell receptor. Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.
Regulating T-cell activity

APC T-cell

MHC T-cell receptor

APC, antigen-presenting cell; TCR, T-cell receptor. Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.
Regulating T-cell activity
(Tumour-derived) antigen
APC T-cell - Processed antigen
- Peptides, 9-12 monomers
- Expressed on cell surface in context of
MHC
- ‘Neo’ ie truly foreign (not previously
passed through thymic selection)
- Arise from non-synonymous genetic
MHC T-cell receptor alteration or virally associated

APC, antigen-presenting cell; TCR, T-cell receptor. Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.
Regulating T-cell activity

APC T-cell Nothing happens!

TCR engagement, no costimulation

APC, antigen-presenting cell; TCR, T-cell receptor. Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.
Regulating T-cell activity

APC T-cell

T-cell proliferation, differentiation,

survival

CD28 costimulation

Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.

N Engl J Med. 2006
Regulating T-cell activity

APC T-cell

Down-regulation,
functional inactivation

CTLA-4 upregulation

Adapted from Sharpe AH, et al. N Eng J Med. 2006;355:973–5.

 Wild-type CTLA4-/-

heart

pancreas

Tivol et al. Immunity 1995

Enhancement of anti-tumour immunity by CTLA-4 blockade

‘These results suggest that

blockade of the inhibitory
effects of CTLA-4 can
allow for, and potentiate,
effective immune responses
against tumor cells.’

Leach, Krummel and Allison. Science 1996

Improved survival with ipilimumab in metastatic melanoma

Hodi, F. S. et al. N. Engl. J. Med. 2010

 CTLA-4 PD-1
Adapted from Ledford H, et al. Nature. 2018;562:20–21.
 CTLA-4 PD-1
Adapted from Ledford H, et al. Nature. 2018;562:20–21.
 CTLA-4 PD-1
Adapted from Ledford H, et al. Nature. 2018;562:20–21.
The PD-1 checkpoint and cancer

Ligation of T-cell PD-1 by tumour B7-H1 results in the downregulation of T-cell effector functions that destroy tumour tissue. MHC, major histocompatibility
complex. Adapted from Sznol M, Lieping C. Clin Cancer Res. 2013;19:1021–34.
PD-L1 expression: adaptive expression (2o to IFN)

Chen et al. JITC. 2019 Taube et al. Sci Transl Med. 2012
 Complimentary areas of action for anti-CTLA-4, anti-PD-1
Tumour-draining node

CTLA4
T-cell activation

Ipilimumab, tremelimumab

PD1/PDL1
Regulation of T-cell
function in periphery
Pembrolizumab, nivolumab, etc

Adapted from Pardoll DM. Nat Rev Cancer. 2016;12:252–64.

 Complimentary areas of action for anti-CTLA-4, anti-PD-1

CTLA4
T-cell activation

Ipilimumab, tremelimumab

PD1/PDL1
Regulation of T-cell
function in periphery
Pembrolizumab, nivolumab, etc

Periphery/tumour site
Adapted from Pardoll DM. Nat Rev Cancer. 2016;12:252–64.
Combined CTLA4/PD-1 blockade in metastatic melanoma

Ipi/nivo

nivo

Ipi
But remember this all happens in a suffocating microenvironment….
Suppressive mechanisms

MDSC
- Secretion of arginase, ROS
- Suppress T-cell function

Macrophage
- M2 differentiation
- Defective Ag presentation
- Impaired tumor killing

Treg
- Secrete immunesuppressive
cytokines (IL10, TGFb)
- Impair T-cell activation

Dendritic cell
- Immature
- Defective Ag presentation

Adapted from Kerkar and Restifo. Cancer Research 2012

+hypoxia
Immunesuppressive
+VEGF etc mechanisms

MDSC
- Secretion of arginase, ROS
- Suppress T-cell function

Macrophage
- M2 differentiation
- Defective Ag presentation
- Impaired tumor killing

Treg
- Secrete immunesuppressive
cytokines (IL10, TGFb)
- Impair T-cell activation

Dendritic cell
- Immature
- Defective Ag presentation

Adapted from Kerkar and Restifo. Cancer Research 2012

+hypoxia
Immunesuppressive
+VEGF etc mechanisms

MDSC
- Secretion of arginase, ROS
- Suppress T-cell function

Macrophage
- M2 differentiation
- Defective Ag presentation
- Impaired tumor killing

Treg
- Secrete immunesuppressive
cytokines (IL10, TGFb)
- Impair T-cell activation

Dendritic cell
- Immature
- Defective Ag presentation

Adapted from Kerkar and Restifo. Cancer Research 2012

MDSC elevated in peripheral blood of patients with advanced cancer

fresh PBMC
frozen PBMC
whole blood
40
CD14+HLA-DRlo/- (%)

30

20

10

0
Patient Healthy

Duffy AG et al. Cancer Immunol. Immunother 2013

 inhibition of Regulates
dendritic cell leukocyte
maturation recruitment

directly

↑VEGF
inhibits CTL
accumulation trafficking,
of MDSC proliferation,
and effector
function

directly ↑expression
induce T reg of PD1 on
proliferation TILs
 lenvatinib plus pembrolizumab (HCC)
Anti-VEGF Anti-PD1

Finn et al. J Clin Oncol 2020

immunotherapy
‘Immunotherapy’
• Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1…LAG-3, TIM-3)1–3
• T-cell agonists (Ox40)4
• Vaccines (peptide, autologous)5
• Oncolytic viruses6
• Targeted therapies (AKTi, CDk4/6i  lymphocyte infiltration)7
• Standard therapies
• Immunogenic chemotherapy or radiotherapy,8,9 TACE, ablation
• STING pathway activators10
• Cell-based approaches (CAR-T, TCR)11,12
• Microbiome manipulation
……etc, etc, etc!!!!
1. Seidel JA, et al. Front Oncol. 2018;8:86; 2. Long L, et al. Genes Cancer. 2018;9:176–89; 3. He Y, et al. Onco Targets Ther. 2018;11:7005–9; 4. Croft M, et al. Immunol Rev. 2009;229:173–91; 5. Guo C, et al.
Adv Cancer Res. 2013;119:421–75; 6. Raja J, et al. J Immunotherapy Cancer. 2018;6:140; 7. Lheureux S, et al. Eur J Nucl Med Mol Imaging. 2017;44:41–54; 8. Wu J, Waxman DJ. Cancer Lett. 2018;419:210–
21; 9. Golden EB, Apetoh L. Semin Radiat Oncol. 2015;25:11–7; 10. Bai J, Liu F. Diabetes. 2019;68:1099–108; 11. Miliotou AN, Papadopoulou LC. Curr Pharm Biotechnol. 2018;19:5–18; 12. Zhang J, Wang L.
Technol Cancer Res Treat. 2019;18:1–13; Elinav E, et al. Nat Rev Cancer. 2019;19:371–6.
 Normal T Cell CAR T Cell

TCR
Signalling domain
CD80/CD28
Ag recognition domain
Processed
antigen Extracellular target

MHC
Emily Whitehead

• Diagnosed with ALL at 5 years old

• Relapsed 16m post-chemo; hospice advised
• Attended U.Penn
• First child to receive CAR-T

Read this article! (type in ‘lisa rosenbaum nejm car t’)

Emily Whitehead
Adapted from Kolata, G. (April 2018) ‘Desperation Oncology’: When Patients Are Dying, Some Cancer Doctors Turn to Immunotherapy. New York Times. Available at:
https://www.nytimes.com/2018/04/26/health/doctors-cancer-immunotherapy.html (Accessed November 2019)
Conclusions: The basics of tumour immunology

• PD-1, CTLA-4 stories illustrate power, specificity and memory of the immune
system

• Importance of basic science discoveries

• The immunology is accessible and understanding it will help you follow the story
and understand efficacy/resistance/toxicity….. and it’s just more interesting that
way
Conclusions: The basics of tumour immunology

• PD-1, CTLA-4 stories illustrate power, specificity and memory of the immune
system

• Importance of basic science discoveries

• The immunology is accessible and understanding it will help you follow the story
and understand efficacy/resistance/toxicity….. and it’s just more interesting that
way

Thank you for your attention!