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LPBC = Lymphocyte-predominant breast cancer

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LPBC = Lymphocyte-predominant breast cancer
INTRODUCCIÓN A LA INMUNOTERAPIA
Guillermo Lerzo
Especialista en Oncología
Tumor Immunology: Overview
perforin
granzyme
cytokines
Resting T cell
Activated T cell
TUMOR
LYMPH
NODE
T cell
clonal expansion
Tumor antigen
TCR
MHC
B7
Dendritic cell
CD28
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.
Weiner LM. N Engl J Med. 2008;358:2664-2665.
Immunotherapeutic approaches to breast cancer
Mary L. (Nora) Disis
University of Washington
Fred Hutchinson Cancer Research Center
Seattle, WA
[email protected]
Major categories of the immune system
Non-specific
No antigens
No memory
Immediate
Transient
Specific
Antigens
Memory
Slowly developing
Lifelong
drrajivdesaimd.com
Clinically effective anti-tumor immunity
Fridman et al, Nat Rev Ca, 2012
Bindea et al, Curr Opin Immunol, 2010
High magnitude Type I
CD4 (Tbet+), CD8 (GZB+)
Memory
Low levels of regulatory cells
Approaches to optimizing a
therapeutic immune response
Butt et al Oncogene, 2013
Increase effector T-cells
Enhance existing immunity
Modulate the tumor microenvironment
Trastuzumab
Vaccines
Adoptive T-cell Therapy
Checkpoint inhibitors
Cytokine Therapy (IL-15, IL-7)
Depletion Tregs, MDSC
MoAB (X-IL-10, TGFb)
What is the optimal receptor-ligand
interaction to target?
Activate
Stimulatory signals
Suppress
Inhibitory signals
****
Topalian et al, JCO,
Use early in treatment course in a subset of breast cancer: mutation status, high levels of TIL?
Approaches to optimizing a therapeutic
immune response
Butt et al Oncogene, 2013
Increase effector T-cells
Enhance existing immunity
Modulate the tumor microenvironment
Trastuzumab
Vaccines
Adoptive T-cell Therapy
Checkpoint inhibitors
Cytokine Therapy (IL-15, IL-7)
Depletion Tregs, MDSC
MoAB (X-IL-10, TGFb)
Trastuzumab induced Type I immunity
IFN-g secretion
Baseline IFN Response
(cSPW/106 PBMC)
Ferris et al, JCO, 2010
5000
2000
2000
p < 0.0001
1500
p < 0.0001
1000
500
0
ICD
ECD
Naive
n=97, Stage III/IV HER2+
ICD
ECD
Prior/Concurrent
Stanton et al, 2014
Immunotherapeutic approaches to
breast cancer
Tumor immune
environment
• Level of TIL
• Phenotype of TIL
(Type I, II and regulatory)
Provide Type I immunity
Elicit Type I immunity
Release Type I immunity
Disis et al, CCR Focus, 2013
Propagate immune response
San Antonio Breast Cancer Symposium, December 9-13, 2014
Tumor Infiltrating Lymphocytes
(TILs) in Breast Cancer
Associate Professor Sherene Loi, MD, PhD
Consultant Medical Oncologist
Head, Translational Breast Cancer Genomics and Therapeutics lab
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
San Antonio Breast Cancer Symposium, December 9-13, 2014
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)
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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)
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Predefined parameters for TILs evaluation
intratumoral TILs =
direct contact to tumor
cells
stromal TILs =
between the tumor cells
LPBC = Lymphocytepredominant breast
cancer
„more lymphocytes than
tumor cells“
(≥60% TILs /≥50% TILs )
TLS (tertiary lymphoid
structures)= follicular
aggregates outside of the
tumor
Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Courtesy C Denkert
Predefined parameters for TILs evaluation
intratumoral TILs =
direct contact to tumor
cells
stromal TILs =
between the tumor cells
LPBC = Lymphocytepredominant breast
cancer
„more lymphocytes than
tumor cells“
Salgado, Denkert et al, Guidelines for TILs Evaluation in Breast Cancer- Annals of Oncology 2014
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Courtesy C Denkert
Higher levels in HER2+ and TNBC
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Loi et al, JCO 2013; Ann Oncol 2014
Higher TILs=better survival in primary TNBC
1.0
Primary TNBC, prior to Chemo
0.9
0.5
OS
No. At Risk
LPBC<30
LPBC>=30
0.7
0.6
0.5
0
No. At Risk
LPBC<30
LPBC>=30
0
MFS
0.8
Recurrence−free survival
0.8
0.7
P=0.01
0.6
Recurrence−free survival
0.9
1.0
LPBC<30
LPBC>=30
LPBC<30
LPBC>=30
95
39
1
88
37
95
39
1
88
37
2
74
37
2
74
37
3
Years
69
37
3
Years
69
37
4
62
35
4
62
35
5
6
39
19
18
9
5
39
19
6
18
9
Post-neoadjuvant setting in TNBC
Dieci et al, AoO 2014; Loi et al, JCO 2013; AoO 2014
TILs prognostic in HER2+ treated with antiHER2 agents and CT
For every 1% increase in TILs, 3% decrease in risk of an event, independent of
treatment arm (trastuzmab, lapatinib and combination).
Unpublished data- NeoALTTO study
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Clinical implication of TILs
• Pre-existing host anti-tumor immune responses
• The more you have, the better outcome from
1.
2.
3.
Primary HER2+ breast cancer treated with anti-HER2 agents and chemo
Primary TNBC treated with adjuvant anthracycline-based chemo
Probably also in metastatic disease
• Role in clinical decision making?
• Role in predicting response to T cell checkpoint inhibitors and other
immunotherapies
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
Converting tumors from low TILs into high TILs
• Immunogenic
chemotherapyanthracyclines,
metronomic chemo,
gemcitabine
• Radiotherapy can drive a
T cell response.
– Dose and schedule
could be critical
– Combinations with
immunotherapies could
be beneficial
BOSTON-II study- NCT02303366
Verbrugge et al 2012; Dewan et al, 2009; Klug et al, 2013
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
This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
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:
PD-1/PD-L1 blocking agents in
development
• Pembrolizumab - humanized IgG4 anti PD1 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:
PD-1 blockade: Myth or Fact?
• PD-L1 staining is a predictive marker useful
for choosing melanoma patients for PD1/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)
100
P = 0.0007a
PFS, %
80
60
PD-L1+
40
20
P = 0.0051
PD-L1–
0
0
20
40
60
80
Time, weeks
100
PD-L1+
OS, %
80
60
PD-L1–
40
P = 0.3165
20
0
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.
Presented by: Richard Kefford, ASCO 2014
0
20
40
60
Time, weeks
80
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
PD-1
PD-L1
Antibody
Molecule
Development stage
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
MEDI-4736
Engineered human IgG1
Phase I-II multiple tumors
MPDL-3280A
Engineered human IgG1
Phase I-II multiple tumors
Phase 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
fatigue
myalgia
nausea
ALT/AST increased
diarrhea
erythema
headhache
. Grade 3-4: headhache
18.8%
18.8%
15.6%
15.6%
6.3%
6.3%
6.3%
6.3%
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, PDL1-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.
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