daratumumab: uncovering a novel mechanism of …...daratumumab was approved for treatment of...
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Dr. Kate Sasser, PhD
Corporate VP, Translational Research
December 14th, 2017
Daratumumab: Uncovering a novel mechanism of action for an approved antibody therapy
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CD38 is ubiquitously expressed in Myeloma(on plasma cells and also other immune cells)
MM cell
CD38
• Transmembrane receptor with enzymatic activity: produces cADPR and NAADP
• Regulates cellular calcium signaling
• Contributes to leukocyte “rolling” along endothelium: CD31 is the ligand for CD38
• Highly expressed in myeloma and other heme malignancies good target antigen
CD38 expression
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Tumor specific Mechanisms of Action of Daratumumab in the Bone Marrow Microenvironment
Adapted from Laubach JP, et al. Expert Opin Investig Drugs. 2014;23(4):445-452.
• Human IgG1K monoclonal antibody
– Complement-dependent cytotoxicity
(CDC)
– Antibody-dependent cell-mediated
cytotoxicity (ADCC)
– Antibody-dependent cell-mediated
phagocytosis (ADCP)
– Induction of apoptosis
– Modulation of cellular enzymatic
activities associated with calcium
mobilization and signaling
• Combination of these activities leads to
elimination of plasma cells from bone
marrow in MM patients
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Daratumumab was approved for treatment of relapsed/refractory myeloma, based on ph2 study
NK cells are reduced with Daratumumab treatment. Would an NK–sparing dose
or schedule be more efficacious?
Lokhorst, et al. NEJM. 2015.
Patients with a clinical response
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Daratumumab + SOC significantly improves PFS above SOC alone in relapsed myeloma (ph3 studies CASTOR and POLLUX)
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Daratumumab added to SOC results in > 4 fold increase in minimal residual disease negative (MRD-) rates(CASTOR and POLLUX ph3 trials)
Avet-Loiseau et al, ASH 2016.
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Evaluating the mechanism of action (MOA) in the clinic
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SIRIUS Clinical study GEN501p2 Clinical study
Krejcik, et al. Blood. 2016.
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Daratumumab treatment increases CD8+ T cells in the periphery and the bone marrow
Krejcik, et al. Blood. 2016.
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Dara reduces CD38+Tregs in periphery and marrow
Tregs (CD3+CD4+CD25+CD127dim)
Pre-treatment
Post-1st Dara infusion
%C
D3
8+
Tre
gs/C
D3
+ p
op
ula
tio
nCD38+ Treg
CD38+ Tregs are highly immune suppressive compared to CD38- Tregs
Krejcik, et al. Blood. 2016.
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Dara also depletes CD38+ MDSC and regulatory B cells
Krejcik, et al. Blood. 2016.
Pre
-tre
atm
ent
Post-
1stD
ara
infu
sio
n
CD38+ MDSCs
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11 Immunity, Volume 42, Issue 4, 2015, 607–612Front. Oncol., 26 June 2013 Front. Immunol., 19 June 2013
Regulation of immune responses by different immunosuppressive cell populations
Myeloid Derived Suppressor Cells Regulatory T Cells Regulatory B Cells
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Dara monotherapy treatment increased T-cell clonality(evaluated by TCR sequencing)
(n=22 patients with pre/post samples)
Responders (R) (≥PR) had increased clonality
compared to Non-responders (NR)
Krejcik, et al. Blood. 2016.
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T cell clonality significantly increased with DRd, but not with Rd
• Significant increase in clonality in DRd treatment arm (P = 3.00-12)
• No significant increase in clonality in Rd arm (P = 0.665)
Chiu C, et al. ASH 2016.
• Significant increases in clonality in patients treated with DRd compared
to Rd alone (P = 3.26-10)
– Median of TCRβ clonality score was 0.166 at baseline and
increased to 0.263 at Cycle 3 in DRd arm
Suggests T cell modulation specific to Daratumumab
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Baseline T cell richness (diversity) correlates with PFS in DRd arm, but not Rd arm
Chiu C, et al. ASH 2016.
Previous studies suggest T cell diversity a surrogate measure of “immune responsiveness”
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Deep immune phenotype characterization: CyTOF (cytometry by time-of-flight)
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Clinical trials samples have been collected for relapsed patients on monotherapy
and combination treatments (SIRIUS, CASTOR, POLLUX). (peripheral)
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CyTOF demonstrates changes in immune cell populations with Dara treatment
Adams, et al. ASH 2016.
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Daratumumab mediated T cell expansion is accompanied by increased Granzyme B production
Adams, et al. ASH 2016.
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Daratumumab reduced CD38+ immune suppressive cells, increased CD8+ T cell counts and T cell clonality
Krejcik, et al. Blood. 2016.
Could
targeting
CD38+
immune
suppressive
cells be a
therapeutic
approach in
solid tumors?
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Daratumumab as an IO agent?
Hypothesis: Malignancies (including solid tumors) with high levels of CD38high immunosuppressive cells will be responsive to the combination of daratumumab with IO therapeutics and lead to improved clinical responses.
Effector T CellsTumor Cell
PD-1Tumor specific
cytotoxicity
T-Regs MDSCs
CD38
Daratumumab
CD38
Daratumumab
B-Regs
Anti-PD1
PD-L1
Anti-PDL1
PDL-1
CD38
Daratumumab
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Emerging Data indicates CD38 could be a target in solid tumors
• Regulatory T cells, Regulatory B cells, MDSC are known to contribute to solid tumor progression
and are therapeutic targets of interest for immunotherapy
• Recent data published or presented in meetings:
• CD38 may be a target in NSCLC since it is expressed in ~20% of tumors and is increased in PD1 resistance.
• In NSCLC mouse models, CD38 inhibition alone was able to reduce lung tumor growth, and combinations of
CD38 and PDL1 inhibition were synergistic
• In CLL, Daratumumab Decreases Treg-Mediated Immunosuppression and Potentiates CD8+ T-Cell-Induced
Killing of Chronic Lymphocytic Leukemia (CLL) Cells Ex Vivo
• Current clinical trials testing whether Daratumumab could improve clinical response in solid tumors
• Janssen NSCLC trial: Daratumumab in combination with Pembro in NSCLC
• BMS mixed solid tumor trial: Daratumumab in combination with Nivolumab in solid tumors
Chen, Abstract #79, ASCO-SITC 2017
Manna, et al, Abstract #1736. ASH 2017.
Maj, et al. Nature Immunology. Oct 2017
Chatterjee, et al. Cell Metabolism. Nov 2017
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The role of Translational Research…..
• Confirms proposed mechanism of action, evaluates novel mechanisms of action in clinical setting
• Identifies potential pharmacodynamic (PD) biomarkers to help select appropriate clinical dose
• Identifies potential predictive biomarkers
• Develops complementary and companion diagnostics
• Evaluates potential novel therapeutic combinations
• Determines resistance mechanisms
Translational Research
Discovery Research Clinical Research
Translational Research spans drug development and can contribute novel scientific understanding of the therapy
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Acknowledgements
• Genmab team• Jeroen Lammerts van Bueren
• Paul Parren
• Marije Overdijk
• Janssen team• Tahi Ahmadi
• Chris Chiu
• Homer Adams
• Tineke Casneuf
• Amy Axel
• Jordan Schecter
• VUMC collaborators• Jakub Krejcik
• Tuna Mutis
• Henk Lokhorst
• Niels van de Donk
• Patients and their families!
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