This document summarizes a presentation on opportunities for immunotherapy in breast cancer. It discusses how the immune system fights cancer, types of immunotherapy including checkpoint inhibitors and CAR T-cell therapy. Experience with immunotherapy in breast cancer has been underwhelming due to breast cancer typically having low numbers of immune cells, but responses have been seen in triple negative and HER2+ breast cancers. Future opportunities include increasing immune cells prior to standard treatments and engaging the immune system in the adjuvant setting to reduce recurrence risks.
1. Opportunities for Immunotherapy in
Breast Cancer
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Margaret Gatti-Mays, MD MPH
Co-Director, Clinical Trials Group
Lab of Tumor Immunology and Biology
2 May 2018
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Disclosures
§ I have no personal or professional conflicts of interests
§ I have no financial disclosures
§ I will discuss investigational, non-FDA approved treatment during my
presentation
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Breast Cancer, An Overview
How does the Immune System Fight Cancer?
What is Immunotherapy?
Experiences with Immunotherapy in Breast Cancer
Future of Immunotherapy in Breast Cancer
Topics to Cover
5. 5
Breast Cancer Statistics
§ Breast cancer occurs in women
and men
§ Most breast cancers are:
§ Invasive (80%) vs DCIS (20%)
§ Diagnosed in Early Stages*
§ Hormone Receptor Positive
§ Risk of breast cancer increases
with age
Women Men
New Cases 266,120 2470
Deaths 40,920 460
Lifetime Risk 1 in 8 women 1 in 1000 men
Seigel et al. 2018. Cancer Statistics, 2018. CA Cancer J Clin 2018;68:7-30
American Cancer Society. Breast Cancer Facts & Figures 2017-2018.
0
5
10
15
20
25
30
<40 40-49 50-59 60-69 70-79 80+
DCIS Invasive
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Breast Cancer Subtype and Prognosis
§ 4 Main Subtypes* but within each group, there are distinct subgroups
§ Luminal A (ER+/PR+/HER2-; good behaving)
§ Luminal B (ER+/PR+/HER2+ or ER+/PR+/HER2- but more aggressive)
§ HER2+ (ER-/PR-/HER2+)
§ Triple Negative Breast Cancer (ER-/PR-/HER2-)
§ The breast cancer subtype relates to response to therapy (endocrine,
chemotherapy, and immunotherapy) and prognosis
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Breast Cancer Multi-Disciplinary Team
§ Oncology – a branch of medicine that specializes in the diagnosis and
treatment of cancer
§ Treatment of the Breast (Local)
§ Surgery – lumpectomy, mastectomy, sentinel lymph node biopsy, axillary
lymph node dissection
§ Radiation – radiation to the breast, lymph nodes
§ Treatment of Cancer Outside the Breast (Systemic)
§ Medical Oncology – chemotherapy, endocrine therapy, immunotherapy
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Immune System is the First Line of Defense Against Cancer
§ Higher cancer risk in immunocompromised patients
§ Solid Organ and Bone Marrow Transplant Recipients
§ HIV
§ Immune Deficiencies Tumor cell
Normal cell
POW!
BOOM!
ZAP!
Abnormal Cells
Immune System
Normal Cells
Engles et al. 2011. JAMA; Shaprio et al. 2011. Am J Hematol
Grulich et al. 2007. Lancet; Kasiske et al. 2004. Am J Transplant
Le Mire et al. 2006. Br J Dermatol; Herrero et al. 2009. Clin Transplant
10. 10
👾 😴Immune cellTumor cell
YY
YSome tumor cells are smart. They “distract” the
immune cells, which fatigues the immune cells.
Thsi talk si intrresting → Thsi tlkkhio hodsio si
intrresting sfwqoihnsli whhulsoulobhaghl hipojw
Immune Equilibrium
Normally immune cells “proofread” cells
within the body and can correct errors
Thsi talk si intrresting → This talk is interesting
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Immune System: Summary
§ The immune system plays an important role in surveillance and
elimination of abnormal cells through a process called “immuno-
editing”
§ Tumor cells “insulate” themselves with various mechanisms that can
help them hide from or fatigue the immune system
§ Through natural selection, these tumor cells are able to persist and
grow
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What is Immunotherapy
§ Immunotherapy is a type of cancer treatment that
helps your immune system fight cancer
§ The immune system helps your body fight infections and other diseases.
It is made up of white blood cells and organs and tissues of the lymph
system
§ Certain immunotherapies can:
§ Mark cancer cells so it is easier for the immune system to find and destroy
them
§ Boost your immune system to work better against cancer
https://www.cancer.gov/about-cancer/treatment/types/immunotherapy
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Standard Chemotherapy vs Immunotherapy
Chemotherapy Immunotherapy
Target Tumor or the environment
around the tumor
Immune System
Limitations Side Effects
(nerve damage, heart failure, low
blood counts, etc)
Requires a working immune system
(tumor size, multiple prior therapies)
Tumor Evolution Resistance to therapy New target and responses
Onset of Effect Often immediate action Delayed (may get better over time)
Memory Response No Yes
Adapted from Gulley JL. 2013. ASCO Education Book
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Bilusic M, Madan RA, Gulley JL Clin Ca Res 2017
1) Generation of Immune Response 2) “Good” Immune Cells within the Tumor
Requirements for Effective Immunotherapy
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Urothelial: Atezolizumab. Powles T et al. Nature 2014
These long lasting responses are why
oncology is so interested in
immunotherapy…Can we change cancer
to a chronic condition?
23. 23
Morello A, Sadelain M, Adusumilli PS. Cancer Discov. 2016.
Li, J., Li, W., Huang, K. et al. J Hematol Oncol. 2018.
Ho-Yen CM, Jones JL, Kermorgant S. Breast Cancer Res. 2015.
Tumor Associated Antigens
(TAA)
• HER2 – amplification in 15%
of breast cancers
• CEA -50% of breast cancers
• cMET – amplification in
trastuzumab-resistant or
TNBC
• MSLN (mesothelin) – 20-30%
of breast (mostly TNBC)
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FDA Approved Therapeutic Cancer Vaccines
Indication and Clinical Benefit Date
Approved
Intravesical BCG
(TheraCys)
Non-muscle Invasive Bladder Cancer 1990
Sipuleucel-T
(Provenge)
Metastatic Prostate Cancer 2010
Talimogene laherparepvec
(T-Vec)
Melanoma 2015
Lamm et al. 1991. NEJM.
Kantoff et al. 2010. NEJM.
Andtbacka et al. 2015. JCO.
26. 26
Drug-Antibody Conjugate: T-DM1 (Kadcyla)
FDA approved for mHER2+ patients
who have previously received a
taxane and trastuzumab
Accessed 4/20/18: https://www.kadcyla.com/patient/her2-positive-breast-cancer/how-does-kadcyla-work.html
27. 27
Conventional Chemotherapy vs Immunotherapy
Chemotherapy Immunotherapy
Target Tumor or its microenvironment ü Immune System
Limitations Side Effects ü Requires a working immune system
(tumor size, multiple prior therapies)
Tumor Evolution/
New Mutations
Resistance to therapy ü New target and responses
Pharmacodynamics Often immediate action ü Delayed (may get better over time)
Memory Response No ü Yes
Gulley JL. 2013. ASCO Education Book
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A Brief Review of Experiences with
Immunotherapy in Breast Cancer
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Breast Cancer: A Cold Tumor
§ Low numbers of immune cells in breast
cancers
§ All breast cancer subtypes: 10%
median
§ TNBC median 20-25 %
§ HER2+ median 15-20%
§ ER+/PR+ median 5-10%
Loi S et al. 2013. JCO 31:860-7.; Adams S et al. 2014. JCO 32: 2959-66; Ibrahim EM, et al. 2014. Breast Cancer Res
Treat 148:467-76; Stanton SE et al, 2016. JAMA 2:1354-60; Garcia-Teijido P et al. 2016. Clin Med Insights Oncol
10: 31-9; Krishnamurti et al 2017 Human Pathology. ePub ahead of print; Image from Basu et al. 2014. SABCS
§ In TNBC and HER2+, patients with
more immune cells in their tumors do
better
§ For every 10% increase in immune
cells
§ Improved response to pre-surgery
chemotherapy
§ Decreased risk of relapse
§ Improved overall survival
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Breast Cancer: A Cold Tumor
• PD-1/PD-L1 Experiences
• Underwhelming results
• Unselected tumors: 2 to 10% ORR
• PD1+/PD-L1+ tumors: 15 to 20% ORR
• TNBC >HER2 > HR+
• PD-L1 expression seems to
correlate with ER-/PR-
Loi S et al. 2013. JCO 31:860-7.; Adams S et al. 2014. JCO 32: 2959-66; Ibrahim EM, et al. 2014. Breast Cancer Res Treat 148:467-
76; Stanton SE et al, 2016. JAMA 2:1354-60; Garcia-Teijido P et al. 2016. Clin Med Insights Oncol 10: 31-9;
Krishnamurti et al 2017 Human Pathology. ePub ahead of print; Image from Basu et al. 2014. SABCS
How do we get more immune cells
into a breast tumor?
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Checkpoints in Breast Cancer: Objective Response Rates
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
ObjectiveResponseRates
+ + + + + ++
+ PD-L1
ER+/PR+/HER2-
HER2+
TNBC
FDA approved,
Non-breast
Balar et al. 2017. Imvigor. Lancet; Le DT et al. 2015. KEYNOTE-164.JCO. Weber et al. 2015. CHECKMATE-037.
Lancet Oncol. Kaufman et al. 2018. JAVELIN. J Immunother Cancer. Dirix L et al, JAVELIN. 2015 SABCS; Rugo et al,
KEYNOTE-028. 2015 SABCS; Nanda et al, KEYNOTE-012 2016. JCO.; Adams et al. KEYNOTE-086. 2017 ASCO
Schmid et al. 2017 AACR.; Emens et al. 2015. AACR
+ + + +
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CAR T-Cell in Breast Cancer
§ Current CAR T-Cell TAAs:
§ Established targets: HER2, CEA, cMET, MSLN
§ Newer targets: CD133, ROR1, CD70, EpCAM
§ 15 Open Trials on clinicaltrials.gov
§ Only early pilot studies reported so far. Awaiting clinical response
results
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Heery C et al . 2015. JAMA Oncol.
Docetaxel 3.9 months
Docetaxel + PANVAC 7.9 months
PANVAC for Breast Cancer
CEA-MUC-1
Vaccines:
(rMVA-TAA-TRICOM)
(rF-TAA-TRICOM)
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A Durable Response Serves as an Inspiration
§ A 32 year old female was diagnosed with triple positive breast cancer
§ She had biopsy-confirmed metastatic disease in her liver shortly after lumpectomy
§ Treated with standard of care chemotherapy, had removal of her liver metastasis, then AI/Trastuzumab but
unfortunately had progression of her cancer
§ Continued on Trastuzumab and started treatment with PANVAC. No evidence of cancer at 10 years!
Mohebtash et al. 2011. Clin Cancer Res
Baseline 9 months 18 months
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Drug-Antibody Conjugate: Sacituzumab govitecan (IMMU-
132) in Triple Negative Breast Cancer
§ Chemotherapy: SN-38 is the active metabolite of irinotecan
§ Antibody targets “Trop-2” which has high expression on many cancers including TNBC
§ FDA gave sacituzumab govitecan breakthrough designation in 2016
110 participants Responses Standard of Care
Objective Response Rate 31% 10-15%
Median time of response 9.1 months 2 to 5 months
• 9 long-term responders who were progression free for >1 year
• 4 responders > 2 years
Good clinical activity as single agent in heavily
pretreated relapsed/refractory mTNBC
Bardia A. et al. SABCS 2017.
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Opportunities for Immunotherapy in Breast Cancer
§ Increasing immune cells prior to surgery, chemotherapy, radiation
§ In TNBC, HER2+ for every incremental increase in TILs: Improved response to
pre-surgery chemotherapy, decreased risk of relapse, improved overall
survival
§ Reducing risk of recurrence through engaging the immune system in the
adjuvant setting
§ Low tumor volume after surgery, chemotherapy, radiation
§ Can we create immune memory?
§ Re-sensitizing the tumor to chemotherapy in metastatic setting
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The Future: Combination Therapy
Emens LA. 2017. Europ J Can
§ Single Agent Therapy
§ Some benefit (10-20%)
§ Some benefit for a long time
§ Combination Therapy
§ Increased clinical benefit on an
individual and population basis
§ More side effects
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39
Can we make a “cold” tumor ”hot”?
Breast Cancer
Slide from J. Schlom
T-cells kill the
tumor
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Standard of Care Treatments for Breast Cancer
Therapy Tumor
Effects
“Good” Immune Effects Combination
Trials
Radiation Yes Yes Yes
Chemotherapy Yes Yes - Some do at normal or
lower than normal doses
Yes
Endocrine therapy Yes Yes - AIs, fulvestrant Yes
CDK 4/6 Inhibitors Yes Yes Yes
Trastuzumab Yes Yes Yes
Kadcyla Yes Yes Yes
Table adapted from Zitvogel et al, Nature Reviews Immunology 2008; Emens and Middleton.
Cancer Immunol Res 2015; Dieras et al. 2017. Lancet Onc 18:732-42.; Katz et al. 2017. JCO
35 (15 supp): e12512-e; Muller et al. 2015. Sci Transl Med 7. Junttila et al. 2011. Breast Cancer
Res Treat. 128:347-5;Bianchini and Gianni. 2014. Lancet Oncology 15:e58-68
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Future of Immunotherapy in Breast Cancer
§ Make breast cancer “hot?
§ How do we get more immune cells into a breast tumor?
§ More Combinations
§ Checkpoints +/- vaccine +/- chemotherapy +/- radiation
§ Move from the metastatic setting to adjuvant setting
§ Maybe even the neoadjuvant (presurgery) setting
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On-Going Immunotherapy + Chemotherapy Trials
§ Atzeolizumab + Abraxane in mTNBC (0 to 3 prior treatments)
§ Phase 3 trial IMPASSION-130 with 38% response rate in PD-L1+
§ Pembrolizumab + Eribulin in mTNBC (0 to 3 prior treatments)
§ Phase 1b/2 ENHANCE study with a 26% response rate in PD-L1+
§ Pembrolizumab + Trastuzumab in trastuzumab resistant mHER2+
§ Phase 1b/2 PANACEA is ongoing with a preliminary 15% response rate in PD-L1+
§ Pembrolizumab + Abemaciclib in mER+/PR+
§ Phase 1b study is ongoing with a preliminary 14% response rate, 75% control rate at 16
weeks
Adams S et al. 2016. ASCO; Tolaney S et al. 2017.; SABCS.;
Rugo HS et al. 2017.; SABCS. Loi S et al. 2017. SABCS.
Checkpoint Inhibitor Response
Rates in Breast Cancer
• TNBC: 10-20%
• PD-L1+: 15 to 20%
• HER2+: 4%
• ER+/PR+: 3-12%
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ü Breast Cancer, An Overview
ü How does the Immune System Fight Cancer?
ü What is Immunotherapy?
ü Experiences with Immunotherapy in Breast Cancer
ü Future of Immunotherapy in Breast Cancer
Topics to Cover
44. 44
Summary
§ Breast cancer is a “cold” tumor
§ Single immunotherapy drug treatments have not worked well in most*
breast cancers
§ Earlier treatment with immunotherapy agents may be better
§ Sequencing of immunotherapy and chemotherapy
§ Combinations of immunotherapy agents and/or standard of care agents
are the future
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Acknowledgments
§ Most importantly, patients, families, friends
§ Jeffrey Schlom PhD
§ James Gulley MD PhD
§ Julius Strauss MD
§ Darren Mays PhD MPH
§ Lab of Tumor Immunology and Biology
§ NCI Intramural Program
46. Thank you for your attention
Margaret.gatti-mays@nih.gov
NIH Referral Office: 866-611-6310