Immune checkpoint inhibitors: rational and mechanism of action

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Immune checkpoint inhibitors:

rationale and mechanism of action

John B.A.G. Haanen MD PhD

Naples May 12 2017

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My dysclosures

• I have provided consultation, attended advisory boards, and/or provided lectures for: Pfizer,

MSD, BMS, IPSEN, Roche/Genentech, NEON Therapeutics, Novartis for which NKI received honoraria

• Through my work NKI received grant support from BMS, MSD, Novartis

• I declare no conflict of interest

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Why should we use immune checkpoint inhibitors?

• How is T cell activation regulated?

• What is the role of immune checkpoint molecules?

• Why would blockade of immune checkpoint lead to anti-tumor immunity?

• Can response to immune checkpoint inhibitors be predicted?

• What are the risks of blocking immune checkpoint molecules?

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Why should we use immune checkpoint inhibitors?

• How is T cell activation regulated?

• What is the role of immune checkpoint molecules?

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T cell activation

Sharma & Allison Science 2015

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Upregulation of inhibitory molecules dampen or prevent T cell activation

Sharma et al., Nat Rev Cancer 2011

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PD-1/PD-L1 interaction with B7-1

Arlene Sharpe, ASCO 2013

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Why should we use immune checkpoint inhibitors?

• Why would blockade of immune checkpoint lead to anti-tumor immunity?

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Cytotoxic T-Lymphocyte Antigen-4

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CTLA4 plays a role during T cell priming

Ribas. N Engl J Med 2012

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Leach et al., Science 1996

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B7.1 negative coloncarcinoma model

Leach et al., Science 1996

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van Elsas et al., J Exp Med 1999

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Vaccine + anti-CTLA4 cures mice from agressive melanomas

van Elsas et al., J Exp Med 1999

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Ipilimumab

Hodi et al 2010 NEJM

1 Year 2 Year

Ipi + gp100 N=403 44% 22%

Ipi + pbo N=137 46% 24%

gp100 + pbo

N=136 25% 14%

1 Year 2 Year 3 Year Ipilimumab+

DTIC

N=250 47.3 28.5 20.8

Placebo+

DTIC N=252

36.3 17.9 12.2

Pre-treated-pts +/- gp100

HLA-A2 3mg/kg

Re-induction possible

Robert et al NEJM 2011 naive-pts

+ DTIC 10 mg/kg

Maintenance possible

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Treatment with anti-CTLA-4 mAb

Maker et al., Ann Surg Oncol 2005

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Freeman & Sharpe. Nat Immunol 2013

PD1 and PD-L1 checkpoint

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Programmed Death-1 receptor (PD1)

• Discovered in 1992 by Honjo and coworkers

– Upregulated gene in relation to apoptosis

• Member of the Ig superfamily

• Cytoplasmic domains with ITIM and ITSM

– Recruites phosphatases

– Inhibits PI3K and AKT activity

• Inducibly expressed by CD4 and CD8 T cells, NKT cells, B cells, monocytes and subtypes of DC

• Expressed by both effector and regulatory T cells

• PD1/PD-L1 interaction involved in tolerance and chronic inflammation

• PD1/PD-L1 contributes to functional T cell exhaustion during chronic infection and cancer

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PD-1 pathway inhibits T cell response directly downstream of the TCR

Freeman PNAS 2008

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PD-L1 on human tumor cells mediates T cell inhibition

Pardoll DM, Nat Rev Cancer 2012

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PD-L1 NSCLC Sample IHC staining

Negative Weak Positive (1%-49%)

PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive

Strong Positive (50%-100%)

Courtesy of N Rizvi

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PD-1 pathway is a good target for cancer immunotherapy

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PD1/PD-L1 play a role at the tumor/effector phase

Ribas. N Engl J Med 2012

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Anti-PD1 (nivolumab)

Topalian et al., NEJM 2012

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Phase I study with pembrolizumab in metastatoc

melanoma

Hamid et al., NEJM 2013

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Why should we use immune checkpoint inhibitors?

• Can response to immune checkpoint inhibitors be predicted?

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Cancer immunity cycle

Kim and Chen, Ann Oncol 2016

Anti-CTLA4

Anti-CTLA4 Anti-PD1/PDL1

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Cancer immunity cycle

Foreignness of tumor T cell repertoire

Capacity to infiltrate

Sensitivity of tumor for T cell killing

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Probability of respons to immunotherapy is correlated with mutational burden

Schumacher & Schreiber. Science 2015

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PD-1 Blockade in Mismatch Repair Deficient Cancer Independent of Tumor Histology

Presented By Lawrence Fong at 2016 ASCO Annual Meeting

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Slide 12

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Cancer immunity cycle

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Translational research on patients treated in the Phase II IMvigor 210 Study of Atezolizumab (anti-PD-L1) in Metastatic Urothelial Carcinoma

Presented By Samuel Funt at 2016 ASCO Annual Meeting Rosenberg et al., Lancet 2016

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Pretreatment T cell clonality in the blood inversely correlated with overall survival (n=29)

Presented By Samuel Funt at 2016 ASCO Annual Meeting

* Log-Rank

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Cancer immunity cycle

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Inflamed vs non-inflamed tumoren

Inflamed Non-inflamed

TILs

CD8+ T cells Foreignness PD-L1 expression

gene signature IFN-γ

Pre-existing immunity

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Tumors with β-catenine pathway activation in non-inflamed subset

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Loss of PTEN promotes resistance to T cell mediated immunotherapy

Peng et al., Cancer Disc 2015

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Cancer immunity cycle

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PD-L1 NSCLC Sample IHC staining

Negative Weak Positive (1%-49%)

PD-L1 = 0% positive PD-L1 = 2% positive PD-L1 = 100% positive

Strong Positive (50%-100%)

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OS in Checkmate-066 according to PDL1 expression

Atkinson et al. abstract 3774 SMR 2015

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Why should we use immune checkpoint inhibitors?

• What are the risks of blocking immune checkpoint molecules?

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Immune related adverse events occurring with immune checkpoint blockade

colitis hypophysitis

vitiligo dermatitis

Thyroiditis Hepatitis Pneumonitis Nephritis Meningitis etc.

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Summary

• Immune checkpoint inhibition allows T cell

responses against cancer to develop or to be re- activated

• Many cancers show sensitivity to immunotherapy

• This is defined by foreignness, broad T cell repertoire, capacity to infiltrate tumors and sensitivity of the tumor to T cell killing

• Side effect are the result of induction of an aspecific immune response