Guillermo Lerzo Especialista en Oncología INTRODUCCIÓN A LA INMUNOTERAPIA

Guillermo LerzoEspecialista en Oncología

INTRODUCCIÓN A LA INMUNOTERAPIA

Tumor Immunology: Overview

Dendritic cell

TUMOR

perforingranzyme cytokines

Activated T cell

T cell clonal expansion

Resting T cell

LYMPH NODE

TCR CD28

MHCB7

Tumor antigen

Weiner LM. N Engl J Med. 2008;358:2664-2665.

Tumor-Derived Immune Suppression

• Tumors go to great lengths to evade the immune response.• Systematic studies have identified multiple mechanisms

cancers employ to defeat the immune response:– Immunosuppressive cytokines: TGF-β, IL-4, -6, -10.– Immunosuppressive immune cells: T-regs, macrophage.– Disruption of immune activation signaling: loss of MHC

receptor, IDO production.• Goal: therapy strategies that “liberate” underlying anticancer

immune responses.

Immunotherapeutic approaches to breast cancer

Mary L. (Nora) DisisUniversity of WashingtonFred Hutchinson Cancer Research CenterSeattle, [email protected]

Non-specificNo antigensNo memoryImmediateTransient

SpecificAntigensMemory

Slowly developingLifelong

Major categories of the immune system

drrajivdesaimd.com

Clinically effective anti-tumor immunity

Fridman et al, Nat Rev Ca, 2012Bindea et al, Curr Opin Immunol, 2010

High magnitude Type ICD4 (Tbet+), CD8 (GZB+)

MemoryLow levels of regulatory cells

Butt et al Oncogene, 2013

Increase effector T-cells Enhance existing immunity

TrastuzumabVaccines

Adoptive T-cell Therapy

Checkpoint inhibitorsCytokine Therapy (IL-15, IL-7)

Depletion Tregs, MDSCMoAB (X-IL-10, TGFb)

Modulate the tumor microenvironment

Approaches to optimizing a therapeutic immune response

Topalian et al, JCO,

ActivateStimulatory signals

SuppressInhibitory signals

What is the optimal receptor-ligand interaction to target?

Use early in treatment course in a subset of breast cancer: mutation status, high levels of TIL?

****

Butt et al Oncogene, 2013

Increase effector T-cells Enhance existing immunity

TrastuzumabVaccines

Adoptive T-cell Therapy

Checkpoint inhibitorsCytokine Therapy (IL-15, IL-7)

Depletion Tregs, MDSCMoAB (X-IL-10, TGFb)

Modulate the tumor microenvironment

Approaches to optimizing a therapeutic immune response

Naive Prior/Concurrent

Ba

selin

e I

FN

R

esp

on

se(c

SP

W/1

06 P

BM

C)

ICD ECD ICD ECD0

500

1000

1500

20002000

5000

< 0.0001

< 0.0001

p

p

n=97, Stage III/IV HER2+ Stanton et al, 2014

Trastuzumab induced Type I immunity

Ferris et al, JCO, 2010

IFN-g secretion

Disis et al, CCR Focus, 2013

Immunotherapeutic approaches to breast cancer

Tumor immune environment

•Level of TIL•Phenotype of TIL(Type I, II and regulatory)

Provide Type I immunityElicit Type I immunityRelease Type I immunity

Propagate immune response

Associate Professor Sherene Loi, MD, PhDConsultant Medical OncologistHead, Translational Breast Cancer Genomics and Therapeutics labPeter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Tumor Infiltrating Lymphocytes (TILs) in Breast Cancer

San Antonio Breast Cancer Symposium, December 9-13, 2014

This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.

What is the evidence that immunity is important in breast cancer?

• Breast cancer incidence increases in age

• Breast cancer in young women is more aggressive

• Immunosuppressed patients have worse outcomes from breast cancer

• TILs and immune-related gene signatures have been shown to have associations with prognosis in some breast cancer subtypes

• Objective responses to T cell checkpoint inhibitors have observed in breast cancer (data this meeting)


San Antonio Breast Cancer Symposium, December 9-13, 2014

Tumor infiltrating lymphocytes (TILs)- why evaluate TILs?

• First publication in EJC in 1992 Aaltomaa et al 1992

• Immune gene signatures are associated with prognosis in ER-negative breast cancer Desmedt et al, 2008; Teschendorff et al 2007; Alexe et al,2007; Rody et al 2009

• TILs represented a feasible way of evaluating the prognostic and predictive role of immunity in large cohorts of well annotated breast cancer samples (ultimate marker will depend on clinical utility)


Predefined parameters for TILs evaluation

intratumoral TILs =direct contact to tumor cells

stromal TILs = between the tumor cells

LPBC = Lymphocyte-predominant breast cancer„more lymphocytes than tumor cells“ (≥60% TILs /≥50% TILs )

TLS (tertiary lymphoid structures)= follicular aggregates outside of the tumor


Courtesy C Denkert

Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014

intratumoral TILs =direct contact to tumor cells

stromal TILs = between the tumor cells

LPBC = Lymphocyte-predominant breast cancer„more lymphocytes than tumor cells“


Courtesy C Denkert

Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014

Predefined parameters for TILs evaluation

Higher levels in HER2+ and TNBC

Loi et al, JCO 2013; Ann Oncol 2014This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.

Higher TILs=better survival in primary TNBC

P=0.01

MFS OS

Post-neoadjuvant setting in TNBC

Dieci et al, AoO 2014; Loi et al, JCO 2013; AoO 2014

Primary TNBC, prior to Chemo

TILs prognostic in HER2+ treated with anti-HER2 agents and CT


Unpublished data- NeoALTTO study

For every 1% increase in TILs, 3% decrease in risk of an event, independent of treatment arm (trastuzmab, lapatinib and combination).

Clinical implication of TILs

• Pre-existing host anti-tumor immune responses

• The more you have, the better outcome from 1. Primary HER2+ breast cancer treated with anti-HER2 agents and chemo2. Primary TNBC treated with adjuvant anthracycline-based chemo3. Probably also in metastatic disease

• Role in clinical decision making?• Role in predicting response to T cell checkpoint inhibitors and other

immunotherapies


Converting tumors from low TILs into high TILs

• Immunogenic chemotherapy- anthracyclines, metronomic chemo, gemcitabine

• Radiotherapy can drive a T cell response.– Dose and schedule

could be critical– Combinations with

immunotherapies could be beneficial

Verbrugge et al 2012; Dewan et al, 2009; Klug et al, 2013BOSTON-II study- NCT02303366

Conclusions

• TILs represent functional pre-existing Th1 immunity

• Why some breast cancers do and do not have varying levels of TILs remains to be elucidated

• Role of TILs in clinical decision making– Analytical validity of TILs biomarker ongoing– Clinical utility of TILs remains to be determined

• However prognostic associations of TILs supports the concept that immune approaches may improve outcome in HER2+ BC and TNBC– TNBC- combination therapy


Abstract S1-06: Edith A. Perez et al.

• Stromal tumor-infiltrating lymphocytes (Str-TILs): In the Alliance N9831 trial Str-TILs are associated with chemothetapy benefit but not associated with trastuzumab benefit.

N9831 Trial Incorporating Trastuzumab in Adjuvant Therapy.

• 945 patients with HER2 positive breast cancer.• 3 Arms: A. AC – T B. AC – T – H C. AC – T + H- Str-TILs defined as % tumor stromal that

contains lymphocytic infiltrate (LI).- Str-TILs measurements: > 60% classified as

“lymphocyte predominant breast cancer (LPBC).

Univariable Str-TILs Results (1)• Tumors with high Str-TILs were more likely to be hormone

receptro negative (p< 0.0001)• In Arm A (chemotherapy): - LPBC patients: 10ys RFS = 90.9%. - non-LPBC patients: 10ys RFS = 64.3%. - HR = 0.22; 95% CI 0.07 to 0.68, p=0.009. In Arm C (chemptherapy + trastuzumab): - LPBC patients: 10ys RFS = 80.0% - non-LPBC patients: 10ys RFS = 79.6%. - HR = 1.13;95% CI 0.45 to 2.84, p=0.79.

Univariable Str-TILs Results (2)

• In LPBC patients group (Str-TILs > 60%): - Arm A: 10ys RFS = 90.9%. - Arm C: 10ys FRS = 80.0%. - HR = 2.43%; 95% CI 0.58 to 10.22, p = 0.22.. In non-LPBC patients group (Str-TILs < 60%): - Arm A: 10ys RFS = 64.3%. - Arm C: 10ys RFS = 79.6%. - HR = 0.49; 95% CI 0.35 to 0.60, p<0.0001.

Str-TILs: Multivariable Results.• Variables: nodal status, HR status, tumor size, tumor grade, age.. Dichotomous cutoff of Str-TILs: LPBC status - associated with RFS in Arm A HR= 0.19;95% CI 0.66 to 0.61, p=0.005 - not associated with RFS in Arm C HR= 1.01; 0.95% CI 0.39 to 2.6, p=0.98. Increasing Str-TILs deciles - associated with RFS in Arm A (p<0.0001) - not associated with RFS in Arm C (p=0.13)

CONCLUSIONS• Provocative results: - increasing % Str-TILs correlates with benefit of chemotherapy in early stage HER2+ BC. - impact of adding adjuvant trastuzumab not as clear in patients with LPBC.. Plans: corroborate in a separate cohort. . Identify subtypes of Str-TILs. . Correlate Str-TILs with inmune gene profiles. . Determine whether changing the amount and type

of Str-TILs will improve patients outcome.

Str-TILs in Early Stage HER2+ BC:Conclusions.

• Increasing Str-TILs associated with increased RFS in pts treated with chemotherapy.

- not foun to be associated with increased RFS in pts treated with chemotherapy plus trastuzumab.

. Patients with non-LPBC had better RFS when treated with chemotherapy + trastuzumab compared to chemotherapy alone.

- but pts with LPBC did not have better RFS when treated with chemotherapy + trastuzumab than chemotherapy alone.

Checkpoint Protein Inhibition

2014 San Antonio Breast Cancer Symposium

San Antonio, TX December 9th, 2014

Jeffrey Weber M.D. Ph.D.Moffitt Cancer Center

Immune Checkpoint Pathways

CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1;PD-L1 = programmed death ligand 1; TCR = T-cell receptor.

31

Immunotherapy for breast cancer: Myth or Fact?

• Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1

• TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2

• PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3

• Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4

1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132

PD-1/PD-L1 blocking agents in development

• Pembrolizumab - humanized IgG4 anti PD-1 antibody, approved for second line therapy of melanoma

• Nivolumab, human IgG4 anti PD-1 antibody, approval for melanoma pending

• MPDL-3280A, humanized PD-L1 antibody

• MEDI 4736, human IgG1 PD-L1 antibody

• AMP 224, fusion of Fc and anti-PD-L1

Immunotherapy for breast cancer: Myth or Fact?

• Tumor infiltrating lymphocytes (TIL) in primary triple negative breast cancer after neo-adjuvant chemotherapy are associated with better RFS, DMFS, OS1

• TIL in stroma and tumor tissue are associated with RFS and OS after adjuvant chemotherapy2

• PD-L1 expression and TIL in primary breast cancer are associated with a better outcome3

• Myeloid derived suppressor cells are associated with high likelihood of nodal metastases in breast cancer4

1: Adams, S et al JCO 2014 2: Loi, Y et al JCO 2013 3: Schalper, K et al CCR 2014 4: Yu, J et al J Immunol 20132

PD-1 blockade: Myth or Fact?• PD-L1 staining is a predictive marker useful

for choosing melanoma patients for PD-1/PD-L1 blockade• There appears to be an association between ORR

and tumor PD-L1 positivity by IHC in most trials• Patients may still respond even if tumor PD-L1

staining is negative• Equivocal data on association of PD-L1 staining

with overall survival.

PD-L1 expression and response rate

N PDL1 + Positive

PDL1 - Negative

Nivolumab (Topalian, NEJM, 2012)

42 9/25 (36%) 0/17 (0%)

Nivolumab (Weber #9011)

44 8/12 (67%) 6/32 (19%)

MPDL3280A (Hamid #9010)

30 4/15 (27%) 3/15 (20%)

Nivolumab/ Ipilimumab (Callahan #3003)

27 4/10 (40%) 8/17 (47%)

Nivolumab (Grosso #3016)

34 7/16 (44%) 3/18 (17%)

Urba, W ASCO 2014

Efficacy Based on Tumor PD-L1 Expression (Central Review, RECIST v1.1)

Presented by: Richard Kefford, ASCO 2014

a1-sided P values calculated by logistic regression, adjusting for dose/schedule.PD-L1 positivity defined as staining in ≥1% of tumor cells.Analysis cut-off date: 18 October 2013.Daud A et al. Presented at: 2014 Annual AACR Meeting; April 5-9, 2014; San Diego, CA.

P = 0.0007a

8060402000

20

40

60

80

100

PFS,

%

Time, weeks

PD-L1+

PD-L1–P = 0.0051

8060402000

20

40

60

80

100

Time, weeks

OS,

%

PD-L1+

PD-L1–

P = 0.3165

Overall survival based on tumor PD-L1 expression by IHC does appear to favor PD-L1+ tumors

Ribas, A et al SMR 2014

Conclusions: Checkpoint protein inhibition for breast cancer

• Many different histologies now respond to checkpoint protein inhibitory drugs, including breast cancer!

• Slow regression, progression prior to regression are common in immuno-oncology and require new response criteria to accommodate irRC responses.

• Immune related adverse events are a new field for toxicity management and require a learning curve.

• Prolonged duration of response and plateauing of survival curves suggest that cures are possible.

• The Law of Unintended Consequences suggests that new and unexpected toxicities will occur.

Clinical Development of Inhibitors of PD-1 Immune Checkpoint

Target Antibody Molecule Development stage

PD-1

Nivolumab(BMS-936558) Fully human IgG4

Phase III multiple tumors (melanoma, RCC, NSCLCa,

HNSCC)

Pembrolizumab(MK-3475) Humanized IgG4 Phase I-II multiple tumors

Phase III NSCLC/melanoma

Pidilizumab(CT-011) Humanized IgG1 Phase II multiple tumors

PD-L1

MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors

MPDL-3280A Engineered human IgG1 Phase I-II multiple tumorsPhase III NSCLC

MSB0010718C Fully human IgG1 Phase I solid tumors

Abastract S1-09: Rita Nanda et al.• A phase IB study of pembrolizumab (MK-3475) in

patients with advanced triple-negative breast cancer. University of Chicago, IL.

• Pembrolizumab (MK-3475) is a humanized IgG4, High-Affinity, Anti-PD-1 Antibody:

- High affinity for the PD-1 receptor. - Dual ligand blockade of PD-L1 and PD-L2. - No cytotoxic activity. - PK supports dosingevery 2 weeks or every 3 weeks. - Demostrated clinical activity in multiple tumor types.

KEYNOTE-012: triple-negative breast cancer cohort.

• Recurrent or metastatic triple-negative BC.• ECOG PS 0 – 1.• PD-L1 tumor expression was assesed: 58% of all pts.• No systemic steroid therapy.• No autoimmune disease.• No active brain metastasis.• Response assesment every 8 weeks.• Treatment: Pembrolizumab 10 mg/kg iv Q2W.

Treatment-Related Adverse Events with Incidence >5%.

• Any grade: arthralgia 18.8% fatigue 18.8% myalgia 15.6% nausea 15.6% ALT/AST increased 6.3% diarrhea 6.3% erythema 6.3% headhache 6.3%

. Grade 3-4: headhache 3.1%

Best Overall Response (RECIST 1.1)• Overall response rate: 5 (18.5%)• Best overall response: - complete response 1 (3.7%) - partial response 4 (14.8%) - stable disease 7 (25.9%) - progressive disease 12 (44.4%) - no assesment 3 (11.1%)* 66% pts > 4 lines for metastatic disease.

Pembrolizumab: summary.• Pembrolizumab showed an acceptable safety and

tolerability profile in pts with heavily pretreated, PD-L1-positive. Advanced triple-negative breast cancer.

• Pembrolizumab was associated with an OOR of 18.5%.• Response was durable, with the median response

duration not reached (range, 15 to 40+ weeks) and 3 of 5 responders on treatment for >11 months.

• The acceptable safety and tolerability profile and promising antitumor activity support the further development of pembrolizumab in patients with advanced triple-negative breast cancer.

Documents

Guillermo Lerzo Especialista en Oncología INTRODUCCIÓN A LA INMUNOTERAPIA