Fattori predittivi di risposta alla immunoterapia

Fattori predittivi di risposta alla Immunoterapia

Claudio Doglioni

University Vita-Salute San Raffaele IRCCS San Raffaele Hospital

Milan

PD-1/PD-L1

• Immuno-oncology scenario

– Tumor Immune Micro-Environment TIME

• PD1-PD-L1 immune-checkpoint and determinants of Immune Checkpoints Inhibitors–ICI- response

- Mechanisms of PD-L1 expression and control

- Interplay between immune response and genomic landscape in cancer

Immune Checkpoint Inhibitors A new paradigm in

Cancer

Immunotherapy

Chimeric Antigen Receptor-T cells

CAR-T

Chen & Mellman Nature 2017

Octopus: T cells

Blue water: cold tumors

Red water: hot tumors

Yellow sea anemones:

MDSC

Crabs: tumor cells

Immune poor Immune rich

CD20 CD3 CD163

Binnewies et al Nat Med 2018

CRC: Consensus Molecular Subtypes 1-4

Immunity 2018 48, 812-830.e14DOI: (10.1016/j.immuni.2018.03.023) Copyright © 2018 The AuthorsTerms and Conditions

Immune landscape of Cancer

• C1 Wound healing

• C2 IFN-gamma dominant

• C3 Inflammatory

• C4 Lymphocyte depleted

• C5 Immunologically quiet

• C6 TGF-beta dominant

Nature 2018

Timing of clinical development of anti–CTLA-4, anti–PD-1, and anti–PD-L1 antibodies, from first administration to humans to FDA approval.

Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355

Published by AAAS

PD-L1 Expression in Non–Small-Cell Lung Cancers.

Garon EB et al. N Engl J Med 2015;372:2018-2028

22C3 Mab

TPS >50%

Inhibitory signals in Serous Ovarian Ca

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

LAG3 TIM3

PD1

0 0,5 1 1,5 2 2,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

PD-L1

TIM3 +++ TIM3 +

LAG3 +++

LAG3 +++ PD1 +++

MM: PD-L1,LAG3, VISTA,TIM3

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

LAG3

VISTA TIM3

0 0,5 1 1,5 2 2,5 3 3,5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

PD-L1

LAG3 MM

TIM3 MM

PD-L1 MM

VISTA MM

Cellsignal 2018

PD1(CD279)/PD-L1 (CD274) axis

• PD-1 is a negative costimulatory receptor

expressed by T cells, NK cells and some B cells.

• It is involved in the later stages of the immune response, regulating the activation of T cells in peripheral tissues.

• PD-1 has two ligands, PD-L1 (also known as B7- H1 or CD274) and PD-L2 (B7-DC or CD273).

• These ligands are expressed on a wide range of immune effector cells, antigen-presenting cells, and Tumor Cells.

PD1(CD279)/PD-L1 (CD274) axis

• The binding of PD-1 to one of its ligands, PD- L1 or PD-L2, can inhibit a cytotoxic T-cell

response.

• Tumors can coopt this pathway to escape T-cell–

induced antitumor activity.

• PD-L1 expression may also be induced by

interferon gamma, which is produced by T-

helper 1 cells as part of a host inflammatory

response

Mechanism regulating

PD-L1 expression

ICI in PD1-PD-L1 axis

▪ Patients respond to anti–PD-1 or anti–PD-L1 therapy because of a preexisting antitumor T cell response.

▪ The infiltrating T cells engage their TCR through recognition of a tumor antigen

▪ triggering expression of PD-1 on T cells

▪ release of IFN-gamma

▪ reactive expression of PD-L1 by cancer- cells

▪ Tumor cells disarm specific T cells through PD-L1 expression:

adaptive immune resistance / noli me tangere

▪ It is reversible by blocking the PD-1–PD-L1 interaction

Mechanism of action of PD-1–blockade therapy.

Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355

Published by AAAS

Ivashkiv L. Nature Review Immunology 2018

Interferon  and Cancer Immunotherapy

ICB: Immune Checkpoint Blockade

Cancer Cell 2016

CMTM6 a transmembrane protein maintains the expression of PD-L1 and regulates anti-tumour immunity.

Tonsil DAPI

PD-L1

CMTM6 merge

NSCLC ADCA CMTM6

NSCLC SQCC PD-L1

NSCLC SQCC CMTM6

❖Colorectal tumors downregulate interferon receptor IFNAR1

❖ Loss of IFNAR1 promotes generation of immune privileged niche

❖ IFNAR1 regulates viability of cytotoxic lymphocytes and efficacy of immunotherapies

IFNAR1+ IFNAR1-

PD-L1 IHC as marker of ICI response

• The predictive utility of PD-L1 IHC for

response to ICIs have yielded mixed results

• Response to treatment does not strictly

correlate with PD- L1 tumor expression in all

patients

The equivocal utility of PD-L1 as a predictive biomarker

• Why:

1. Heterogeneity of PD-L1 expression within the tumor microenvironment,

2. Different performance characteristics of IHC assay methods and reagents,

3. Lack of definition of critical cutoffs for PD-L1 staining associated with clinical outcomes,

4. Limited number of binding sites on the hydrophobic PD-L1 molecule

5. Denaturing effects of formalin fixation 6. Glicosylation of PD-L1

How to predict response to ICB?

• PD-L1 expression by IHC

• TMB

• Interferon 

• T lymphocyte status

• Exosomal PD-L1

Science 2015

Higher mutation burden in tumors, higher neoantigen burden, and DNA repair pathway mutations was associated with improved objective response, durable clinical benefit, and progression-free survival.

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

by Diana Miao, Claire A. Margolis, Wenhua Gao, Martin H. Voss, Wei Li, Dylan J.

Martini, Craig Norton, Dominick Bossé, Stephanie M. Wankowicz, Dana Cullen, Christine Horak, Megan Wind-Rotolo, Adam Tracy, Marios Giannakis, Frank Stephen Hodi, Charles G. Drake, Mark W. Ball, Mohamad E. Allaf, Alexandra Snyder, Matthew

D. Hellmann, Thai Ho, Robert J. Motzer, Sabina Signoretti, William G. Kaelin, Toni K.

Choueiri, and Eliezer M. Van Allen

Science

Volume 359(6377):801-806 February 16, 2018

Published by AAAS

PBRM1 LOF mutations correlate with clinical benefit in a validation cohort of ccRCC patients treated with immune checkpoint inhibitors.

Diana Miao et al. Science 2018;359:801-806

Published by AAAS

Nature Med May 2018

Science 2018

18-gene T cell–inflamed GEP that predicted response to pembrolizumab across multiple solid tumors.

❖The IFNγ⁺ mRNA signature (IFNγ⁺ , CD274, LAG3, CXCL9) may assist in identifying patients with improved outcomes with durvalumab, independent of PD-L1 assessed by IHC.

❖The baseline signature was associated with TMB but not survival

Dormant TIL: high CD3+/low GZB/low Ki-67 associated with:

•survival benefit to immune checkpoint blockers

•independent from the tumor mutational load and PD-L1 expression.

Tumor Immune Dysfunction and Exclusion (TIDE) Gene signature to model the tumor immune escape

as a reliable surrogate biomarker to predict ICB response.

The web application at http://tide.dfci.harvard.edu.

Tumor specific CD8 are CD39+

Bystander CD8 are CD39-

Nature 2018

Nature 2018

Exosomal PD-L1

Circulating exosomal PD-L1 may reflect distinct states of anti-tumour immunity^.

• Prior to pembrolizumab treatment

– PD-L1 level may correlate with a role of exosomal PD-L1 in immune dysfunction

– High levels of exosomal PD-L1 may reflect the ‘exhaustion’ of T cells to a stage at which they can no longer be reinvigorated by anti-PD-1 treatment.

• In on-treatment patients^,

– an increase in the level of exosomal PD-L1, following and correlating positively with T cell reinvigoration, would reflect the presence of a successful anti-tumour immunity elicited by the anti-PD-1 therapy

Determinants of response to Immune-checkpoint inhibitors

MMR/MSI INF gamma

Nature Medicine 2018

Cancer Cell 2018

Predicting response to ICIs

➢A single biomarker is not sufficient to select patients.

➢A combination of studies are necessary in baseline tumor biopsies

➢DNA analyses for tumor mutational load and

absence of deleterious mutations in key immune signaling pathways

➢RNA analyses to detect the presence or absence of IFN- signaling and a favorable tumor phenotype

➢PD-L1 expression in tumor cells and CD8+T cells expressing PD-1 in the TME

Precision guesswork

Pathologist

Someone who does precision guesswork based on unreliable data

provided by those

of questionable knowledge

See also Magician, Wizard

Grazie!