Download Engineering the Immune System to Recognize Myeloma Cells

The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Improving the Overall
Understanding of Immunotherapy
in Multiple Myeloma
Webinar 3, September 17, 2015
Engineering the Immune System
to Recognize Myeloma Cells
Speakers
Moderator:
• David Avigan, MD
Harvard Cancer Center
Boston, Massachusetts
Faculty:
• Ivan Marques Borrello, MD
Johns Hopkins Sidney Kimmel
Comprehensive Cancer Center
Baltimore, Maryland
• Edward A. Stadtmauer, MD
University of Pennsylvania
Abramson Cancer Center
Philadelphia, Pennsylvania
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
The Four Pillars of Cancer Therapy
•
•
•
•
Surgery
Radiation therapy
Chemotherapy
Immunotherapy
–
–
–
–
Monoclonal antibodies
Vaccines
Adoptive cell transfer
Checkpoint inhibitors
Immune System Basics
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
How the Immune System Works
• Defends you against
various “germs” or
foreign invaders that
cause infection,
illness, or disease
–
–
–
–
Bacteria
Viruses
Fungi
Parasites
How Does the Body Fight
Against Foreign Invaders?
Immunity
Innate
(natural)
• Defender
components are
always ready to
defend you
• Your first line of
defense against
invaders that get
into your body
Adaptive
(acquired or specific)
• The invader
awakens your
immune cells to
mount their defense
• Can have a longlasting effect against
future invaders
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Your Defense Team Lineup
Natural killer
cells
Macrophages
Dendritic
cells
T cells
Innate
B cells
Adaptive
NK, natural killer.
Immunotherapy
Directing the immune
system to fight cancer
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Why May Myeloma Cells Hide
From the Immune System?
• They look too much like normal cells and so
are not identified as foreign.
• Antigen presentation on myeloma cells in a
way that favors tolerance
• Myeloma may inactivate normal T cells
• Myeloma may increase presence immune
inhibiting cells in the tumor microenvironment
• Myeloma cells have increased activity of
immune inhibiting pathways
Cancer Immunotherapies
Already Available
Checkpoint
Inhibitors
mAbs
Vaccine
mAbs
1990s
2000s
• mAbs are used in a variety of solid and heme tumors—examples include
rituximab (Rituxan), trastuzumab (Herceptin), alemtuzumab (Campath)
• Vaccines are being used in prostate cancer—one example is sipuleucel-T
(Provenge)
• Checkpoint inhibitors are being used in melanoma—for example,
ipilimumab (Yervoy)
mAbs, monoclonal antibodies.
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Harnessing the Immune
System to Fight Myeloma
Types of Immunotherapy
Monoclonal
Antibodies
Vaccines
Chimeric Antigen
Receptor (CAR)
T Cells
Direct effects
1. Extract WBCs
from patient
Monoclonal antibody
2. Modify and
expand cells
in lab
Antigen
ADCC
Fc receptor
CDC
Myeloma cell
3. Infuse MM-targeted
cells back to
patient
C1q
MAC
Lysis
NK cell
Cell death
Webinar 1
Webinar 2
Webinar 3
Immune Cell Therapy
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Immune Cell Therapy
What is it?
How are the
T cells
directed to
MM cells?
How does it
work against
myeloma?
• It is an infusion of autologous
MM-directed T cells
In two main ways:
1. Patient’s T cells are harvested
and then engineered in a lab to
be able to identify specific
surface markers on MM cells
2. These engineering T cells are
then stimulated in a lab to make
them more active and to
proliferate and grow
• Infused, MM-directed T cells
directly kill MM cells and
stimulate T-cell immunity
Types of Immune Cell Therapy
• Chimeric antigen receptor (CAR) T cells
• T-Cell Receptor (TCR) engineered T cells
• Marrow-infiltrating lymphocytes (MILs)
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Engineered T Cell Therapy
TCR transgene
Myelomaspecific TCR
eg MAGE-A3 TCR
OR
Peripheral blood
T cells
Chimeric antigen
receptor (CAR)
transgene
Tumor-specific
CAR
(for example,
anti-CD19)
T cells kill
myeloma
cells
In vitro T cell expansion
Adoptive T cell therapy
CAR T Cell Therapy
in Multiple Myeloma
Myeloma patients with
disease progression
within 1 yr of prior ASCT
• CART T cell therapy: CTL019
• MM precursor cell surface
target: CD19
• Preliminary results of phase 1
study
Second ASCT
CTL019 infusion
Patient outcome
evaluated
– 10 patients treated
– 6 patients with ongoing
responses
– 1 patient (so far) attained
minimal residual disease
(MRD)-negative sCR for > 1
year
Garfall AL et al. N Engl J Med. 2015;373:1040.
sCR, stringent complete response
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Additional Studies of CAR T Cell
Therapy in Multiple Myeloma
Study
1
2
CAR T Cell
Therapy
MM Surface
Target
Kappa light
chains
CAR.
CART-138
CD138
Patient
Population
Results
Institution
Relapsed
• Infusion safe
• Modest antiBaylor
myeloma activity College of
(3 patients with
Medicine
stable disease)
Refractory
• Safe, feasible,
tolerable
• 4 of 5 patients
with stable
disease
China
1. Ramos CA et al. Presented at the American Society of Blood and Marrow Transplantation meeting.
February 2014. Grapevine, Texas. Abstract 6.
2. Guo B et al. J Cell Immunother. 2015; in press.
Marrow-Infiltrating Lymphocytes
(MILs)
• Features of MILs
2. Stimulate and
expand MILs
in lab
MILs
Stimulated
MILs
1. Extract MILs
from patient
– Broad antigenic
specificity
– Ability to traffic
to the BM
– Persistence over
time
3. Infuse stimulated
MILs back to
patient
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Marrow-Infiltrating Lymphocytes
(MILs)
Newly diagnosed or
relapsed myeloma
patients
MILs collection,
expansion, and activation
• Phase 1 study to
examine feasibility,
safety, and efficacy
– Results showed
Initial therapy
Autologous stem cell
transplant
Activated MILs reinfusion
Myeloma-specific
activity measures
• A strong correlation
between clinical
outcome and tumorspecific activity
• Achieving at least a
90% reduction in
disease burden
increased progressionfree survival
Noonan KA et al. Sci Transl Med. 2015;7:288ra78.
Questions & Answers
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Question
Are there any complications to the
patient with these engineered
T cell therapies?
Question
Are the engineered cells able to be
self sustaining? Or do you have to
use ongoing infusions to maintain
the effect?
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Question
What is the appropriate setting
for these therapies?
Question
How does a patient’s age impact
these therapies?
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Question
Are these therapies affordable and
accessible to patients?
We wish to thank the faculty
for their contributions
and Bristol-Myers Squibb
for providing an educational
grant in support of this activity.
Engineering the Immune System to Recognize Myeloma Cells
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The Multiple Myeloma Research Foundation Webinar Series Improving the Overall Understanding of
Immunotherapy in Multiple Myeloma
Additional Information
Speak to an MMRF Nurse Specialist
Call Monday – Friday, 9:00 AM – 7:00 PM EST
866-603-MMCT (6628)
Need information about clinical trials?
Go to: myelomatrials.org
Join the MMRF CoMMunity Gateway to
Share and Connect with other Members of
the Myeloma Community
Go to: mmrfcommunitygateway.org
Engineering the Immune System to Recognize Myeloma Cells
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