Immunotherapy versus Targeted Therapy

Maysa Al-Hussaini, MD FRCPath Consultant Histopathologist, Cytopathologist

and Neuropathologist

Chair; Institutional Review Board King Hussein Cancer Center

Disclaimer

None

I know that most of the audience dislike

pathology, but I will try to change your minds

Outline

• What is targeted therapy – Tyrosine kinase receptor inhibitor

• What is immunotherapy – Immune checkpoint inhibitors

– T-cell mediated immunotherapy

– Vaccines

• Immunotherapy versus targeted therapy; similarities

• Immunotherapy versus targeted therapy; differences

Targeted Therapy

Target

Anything specifically fired at

Avoid collateral damage

Targeted Therapy

May 28, 2001

Revolutionary new

pills like GLEEVEC

combat cancer by

targeting only the

diseased cells. Is this

the breakthrough

e’ e bee aiti g for?

Differences with the more Traditional

Therapies

Traditional therapies

• Affect cells that are

doubling

• Not very specific

• Cytotoxic

Targeted therapies

• Drugs that inhibit a more

specific target in the cell

• Mixture of cytostatic and

cytotoxic

Mechanisms for Targeted Therapy

Actionable Mutations

• Actionable genomic events

• Potentially responsive to a targeted therapy

Companion Tests

Examples in Targeted Therapies and

Companion Tests

HER2/neu -- breast cancer Trastuzumab

KRAS/NRAS --colorectal cancer

Cetuximab and panitumumab

EGFR and ALK -- non-small cell lung cancer

Gefitinib/erlotinib and crizotinib

BRAF -- melanoma Vemurafenib

Ph Ch--chronic myelogenous leukaemia Imatinib

Example of Targeted Therapy

Trastuzumab

- HER2/neu-2 (also known as ErbB-

2) stands for "Human Epidermal

growth factor Receptor 2."

- A cell membrane surface-bound

tyrosine kinase receptor.

- Encoded by the ERBB2 gene, a

proto-oncogene located at the long

arm of human chromosome

17(17q21-q22).

- Normally involved in the signal

transduction pathways leading to

cell growth and differentiation.

Example of Targeted Therapy

Trastuzumab

30% of women with breast cancer have HER2 positive breast cancer

which is more aggressive than regular breast cancer

Example of Targeted Therapy

Trastuzumab

• HER2/neu is important as the target of the

monoclonal antibody trastuzumab (marketed

as Herceptin).

• Trastuzumab is effective only in breast cancer

where the HER2/neu receptor is

overexpressed.

Her-2/ Neu Companion Testing

IHC

Her-2/ Neu Companion Testing

IHC

FISH

Her-2/ Neu Companion Testing

IHC

FISH

Her-2/ Neu Companion Testing

IHC

FISH

Outline

• What is targeted therapy – Herceptin as an example

• What is immunotherapy – Immune checkpoint inhibitors

– T-cell mediated immunotherapy

– Vaccines

• Immunotherapy versus targeted therapy; similarities

• Immunotherapy versus targeted therapy; differences

Immunotherapy

April 1, 2016

What if your

immune system

could be taught

to kill cancer?

Immunotherapy

• In 1890 William Coley, a surgeon at Memorial Sloan Kettering noticed that cancer patients who suffered from infections after surgery often fared better than those who did not.

• His finding led to the development of Coley’s toxins, a cocktail of inactive bacteria injected into tumors that occasionally resulted in complete remission.

Immunotherapy

History of Cancer Immunotherapy

Immunotherapy

Harness immune system components

to enable the patient’s immune

system to specifically recognize and

kill cancer cells.

Targeted Therapy

Target

Anything specifically fired at.

Avoid collateral damage

Cancer Immunology

• Cancer cells are esse tially self —part of the

host.

• They often display unusual or inappropriate

proteins on their cell surface that allow the

i u e syste to ide tify the as non-self . • An antitumor immune response is often

mounted.

Cancer Immunology

• Cancer cells have evolved a number of

mechanisms to enable evasion of this immune

response and render it ineffective.

• A state of immune tolerance has been

established.

X

X

Immunotherapies

Immunotherapy

Immune checkpoint inhibitors

T-cell immunotherapy

Vaccines

Immune Checkpoint Inhibitors

• The programmed death 1 receptor, PD-1 (also

known as CD279) and its ligands programmed

death ligands, PD-L1 (B7-H1; CD274) and PD-L2

(B7-DC; CD273).

• Members of the CD28 and B7 families

• The PD-1 receptor is expressed on the surface of

activated T cells.

• PD-L1 and PD-L2 are expressed on the surface of

APCs such as dendritic cells or macrophages.

Immune Checkpoint Inhibitors

Activated T-lymphocytes

APC/ macrophages

Immune Checkpoint Inhibitors

• Play critical roles in T cell co-inhibition and

exhaustion.

– When the ligands bind to PD-1, an inhibitory

signal is transmitted into the T cell, which reduces

cytokine production and suppresses T-cell

proliferation.

• PD-L1 is the predominant ligand, while PD-L2

has a much more restricted expression pattern

Immune Checkpoint Inhibitors

Activated T-lymphocytes

APC/ macrophages

Immune response

Protective

mechanism

Mechanisms of Immune Evasion

Cancer cell exploit the PD-1 pathway to create an immunosuppressive environment

Allow cancer cells to thrive

T-cell exhaustion

Immune Checkpoint Inhibitors

Monoclonal antibodies blockading the PD-1/PD-L1

pathway will enhance T-cell function

PD-L1 as a Biomarker for Cancer

Immunotherapy

• PD-L1-positive cancers are associated with

poorer prognosis

• A correlation of PD-L1 expression and overall

response rate was demonstrated in patients

with the highest levels of PD-L1 expression

(IHC 3; defi ed as ≥ % PD-L1-positive tumor-

infiltrating immune cells)

PD-L1 Companion Testing by IHC

Cancers with Overexpression of PD-L1

• Melanoma

• Non-small-cell lung cancer (NSCLC)

• Renal cell carcinoma

• Bladder cancer

• Ovarian carcinoma

Nivolumab (BMS-936558)

• The first agent targeting the PD-1 pathway to

enter clinical testing

• It is a fully human IgG4 mAb

X

X

Combination of Immunotherapies

• Nivolumab is being evaluated in a phase I trial

in combination with the CTLA-4-targeting

agent ipilimumab (NCT01024231)

• Rapid and deep tumor regression observed in

many patients

X

X

Combination with Chemotherapy

• Nivolumab is combined with platinum-based

chemotherapy (gemcitabine/cisplatin,

pemetrexed/cisplatin, or

carboplatin/paclitaxel) in patients with

chemotherapy-naïve, advanced NSCLC

Side effects

• Autoimmune adverse events

– hepatitis, endocrinopathies, and dermatitis

– Rash, pruritus, fatigue, and diarrhea elevated

lipase levels

Immunotherapies

Immunotherapy

Immune checkpoint inhibitors

T-cell immunotherapy

Vaccines

T-cell Immunotherapy

• Adoptive immunotherapy (cell therapies or

living therapies)

– Passive transfer of immune cells, which may or

may not be modified / genetically altered to

express a desired set of traits and / or features.

• Chimeric antigen receptor (CAR) T-cell

• T-cell receptor (TCR)

• Tumor infiltrating lymphocyte (TIL) based therapies

Chimeric Antigen Receptor (CAR)

T-cells

T-cell Immunotherapy

• Some types of lymphoma; CLL

• Leukemia; refractory ALL and more recently

AML

Side Effects

• Tumor lysis

• Weakening of the immune system in the

recovery phase after fighti g the tu or like fighting an infection .

• Cytokine release syndrome; fever, myalgia and

severe hypotension.

• Neurotoxicity; ataxia, aphasia, confusion,

delirium and hallucination.

Immunotherapies

Immunotherapy

Immune checkpoint inhibitors

T-cell immunotherapy

Vaccines

Therapeutic Cancer Vaccines

Typ

es

of

can

cer

vacc

ine

s tumor cell type-based vaccines

Peptide vaccines

DNA- based

Vector-based

Dendritic cell-based

Therapeutic Cancer Vaccines

Tumor Cell-based Vaccines

Therapeutic Cancer Vaccines

Peptide Vaccines

Therapeutic Cancer Vaccines

DNA Vaccines

Therapeutic Cancer Vaccines

Vector-based Vaccines

Therapeutic Cancer Vaccines

Dendritic Cell-based Vaccines

Immunologic Memory

Immunotherapy

Immune checkpoint inhibitors

T-cell immunotherapy

Vaccines

Immunologic Memory

• A hall ark feature of adapti e i u e syste

• Can attack and thus prevent the re-appearance of antigically similar cancer cells

• Can help to keep the patient cancer free

• This is a lacking feature of other types of therapies

• Transferring the concept of cancer into a chronic disease .

Outline

• What is targeted therapy – Tyrosine kinase receptor inhibitor

• What is Immunotherapy – Immune checkpoint inhibitors

– T-cell mediated immunotherapy

– Vaccines

• Immunotherapy versus targeted therapy; similarities

• Immunotherapy versus targeted therapy; differences

Immunotherapy versus Targeted therapy

Similarities

• Both modalities can essentially be considered targeted therapies.

• Both modalities target tumor cells and avoid normal cells.

• Many of the targeted therapies are approved along with a specific molecular test or companion diagnostic kit, making the precision molecular diagnostics a mandatory prerequisite for the cost-effective use of targeted treatment.

Outline

• What is targeted therapy – Tyrosine kinase receptor inhibitor

• What is Immunotherapy – Immune checkpoint inhibitors

– T-cell mediated immunotherapy

– Vaccines

• Immunotherapy versus targeted therapy; similarities

• Immunotherapy versus targeted therapy; differences

• In targeted therapy, the cancer cells are directly targeted through trying to block actionable mutations in the cancer cells in one or more oncogenic drivers.

• Specific mutation

• Although targeted therapy offers a robust response rates in patients with a driver mutation resistance is often inevitable

• In immunotherapy, cancer is indirectly targeted, as it tries to effectively boost the body's own immune system to eliminate the cancer.

• No specific mutation

• Immunologic memory allowing for long term remissions or even cure

Immunotherapy versus Targeted therapy

Differences

An Additional Difference

Cost!

• In targeted therapy, the cancer cells are directly targeted through trying to block actionable mutations in the cancer cells in one or more oncogenic drivers.

• Specific mutation

• Although targeted therapy offers a robust response rates in patients with a driver mutation resistance is often inevitable

• Cheaper

• In immunotherapy, cancer is indirectly targeted, as it tries to effectively boost the body's own immune system to eliminate the cancer.

• No specific mutation

• Immunologic memory allowing for long term remissions or even cure

• More expensive

Immunotherapy versus Targeted therapy

Differences

Conclusions

• Immunotherapy and targeted therapy are essentially targeted therapy .

• Both modalities specifically target tumor cells and avoid normal cells.

• Targeted therapies act on actionable mutations in tumor cells.

• Immunotherapies act on enhancing the immune system of the host to fight the cancer cells.

• Immunologic memory is an important feature of immunotherapies associated with long remissions and potential cures.

• Cost remains an important determinant of the choice of treatment.

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Thank you!