daniel s. chen md phd · 2020. 5. 30. · pembrolizumab (keynote-001)3 baseline day 90 cd8 cd8 4...
TRANSCRIPT
Our Age of Acceleration: Intersections in Immunity, Engineering and Human Health
MIT TIM TalkSaturday May 30th, 2020
Daniel S. Chen MD PhDChief Medical OfficerIGM Biosciences
What does a paradigm shift actually look like?
Chen DS, MIT TIM Talk 2020
Long intervals between disruptive therapies in oncology
Hegde and Chen, Immunity 2020
Inno
vatio
n
57 years 46 years 49 years
Surgery(1846)
Radiotherapy(1903)
Chemotherapy(1949)
Targeted therapy(1998)
Amplitude
16 years
ImmunoTherapy(2014)
Wavelength (l)
Time
Chen DS, MIT TIM Talk 2020
Courtesy of Genentech Cancer Immunology Chen DS, MIT TIM Talk 2020
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Chen DS, MIT TIM Talk 2020
Immune Biology
A complex set of tumor, host and environmental factors govern strength, and timing of anti-cancer immune responses
The Cancer-Immunity CycleChen and Mellman. Immunity 2013
The Cancer-Immune Set PointChen and Mellman. Nature 2017
6
∫ (Fstim) ‐ ∫ (Finhib) ≥ 1/ n=1, y (TCRaffinity x frequency)
Chen DS, MIT TIM Talk 2020
Cancer Immunotherapy Shows Tranformative Promise
1. Chaft, et al. WCLC 2015; 2. McDermott, et al. J Clin Oncol 2015; 3. Hamid, et al. N Engl J Med 2013
Baseline
Post C2 (Week 6)
Patient with NSCLC treated with atezolizumab (FIR study)1
Patient with RCC treated with nivolumab (NCT00730639)2
Baseline
23 months
Patient with melanoma treated with pembrolizumab (KEYNOTE-001)3
Baseline
Day 90
CD8
CD8
4
Chen DS, MIT TIM Talk 2020
CANCER IMMUNOTHERAPY IS A BREAKTHROUGH
Checkmate 214 OS(Ipi+Nivo 1L Int/Poor risk RCC)
Escudier, et al. ESMO 2017
Keynote 189 OS (CarboPem+Pembrolizumab 1L NSCLC)
Gandhi et al. NEJM 2018
PACIFIC PFS (Durvalumab Stage IIIB NSCLC)
Antonia, et al. N Engl J Med 2017
Horn et. al. NEJM 2018
IMpower133 OS Atezolizumab+chemo
1L Small Cell Lung
IMpassion130 OSAtezolizumab+chemo1L TNBC PDL1≥1%
IMpower150 PFSAtezolizumab+Avastin+chemo
1L NSCLC
HR, 0.617 P < 0.0001
Reck, et al. ESMO IO 2017
IMbrave150 OSAtezolizumab+Avastin
1L HCCHR, 0.58 P <0.001
Finn, et al. NEJM 2020Keynote 24 OS
(Pembrolizumab 1L TPS≥50% NSCLC)
Reck, et al. N Engl J Med 2016
HR, 0.70 P =0.0069
HR, 0.62 (95% CI 0.45-0.86)
Chen DS, MIT TIM Talk 2020
Powles et. al. Lancet 2018
Publication Covers and Nobel9
Chen DS, MIT TIM Talk 2020
IMbrave150 OSAtezolizumab+Avastin
1L HCCHR, 0.58 P <0.001
Finn, et al. NEJM 2020
CANCER IMMUNOTHERAPY IS A BREAKTHROUGH
Checkmate 214 OS(Ipi+Nivo 1L Int/Poor risk RCC)
Escudier, et al. ESMO 2017
Keynote 189 OS (CarboPem+Pembrolizumab 1L NSCLC)
Gandhi et al. NEJM 2018
PACIFIC PFS (Durvalumab Stage IIIB NSCLC)
Antonia, et al. N Engl J Med 2017
Horn et. al. NEJM 2018
IMpower133 OS Atezolizumab+chemo
1L Small Cell Lung
IMpassion130 OSAtezolizumab+chemo1L TNBC PDL1≥1%
IMpower150 PFSAtezolizumab+Avastin+chemo
1L NSCLC
HR, 0.617 P < 0.0001
Reck, et al. ESMO IO 2017
Keynote 24 OS(Pembrolizumab 1L TPS≥50% NSCLC)
Reck, et al. N Engl J Med 2016
HR, 0.70 P =0.0069
HR, 0.62 (95% CI 0.45-0.86)
Powles et. al. Lancet 2018
Cancer immunotherapy is life altering… for some cancer patients
SO WHAT IS THE PROBLEM?
WHY CAN’T CANCER IMMUNOTHERAPY CURE CANCER MORE BROADLY?
Chen DS, MIT TIM Talk 2020
The T-Cell Army
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
Chen DS, MIT TIM Talk 2020
The T-Cell Army: Armed and Ready
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
Chen DS, MIT TIM Talk 2020
The T-Cell Army: Armed and Ready
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
Cancer
T-cell Army
Chen DS, MIT TIM Talk 2020
The T-Cell Army: Armed and Ready
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
PD-L1 CD8
Baseline
Cancer
T-cell Army
Herbst et al. Nature 2014
Chen DS, MIT TIM Talk 2020
The T-Cell Army: Armed and Ready
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
Cancer
T-cell Army
PD-L1 CD8
On-Tx
Herbst et al. Nature 2014
Chen DS, MIT TIM Talk 2020
The T Cell Army: Armed and Ready
So in some patients, the T cell army is armed and ready…
…but in others, not so much.
Chen DS, MIT TIM Talk 2020
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
Molinero, et al. unpublished data on file
CD8 PDL1
Cancer
No T-cell Army
The T Cell Army: Sometimes No One is at Home
Chen DS, MIT TIM Talk 2020
The T Cell Army: or can’t cross the “river”
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
T-cell Army
Cancer
CD8 PDL1
Herbst et al. Nature 2014
Chen DS, MIT TIM Talk 2020
The T Cell Army: or is unarmed
The T-cell army by Jerome GroupmanThe New Yorker, April 23rd, 2012
T-cell Tourists
CD8 PDL1Herbst et al. Nature 2014
Chen DS, MIT TIM Talk 2020
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Chen DS, MIT TIM Talk 2020
We’ve moved from figuring out how to design a violin, to how do we put together an orchestra.
Chen DS, MIT TIM Talk 2020
SYNTHETIC IMMUNITY AND THE CANCER IMMUNITY CYCLE
Adapted from Chen and Mellman, Immunity 2013Hegde and Chen, Immunity 2020 Chen DS, MIT TIM Talk 2020
SYNTHETIC IMMUNITY: ACTIVATION AND FUNCTION
Chen DS, MIT TIM Talk 2020
YYYY YY YY YYYYYY YY YYYY YYYYYYYYYY YY YY
YYYY
YYYY YY YYYY
Plates coated with anti-CD3 antibodies
MOST OF WHAT WE THINK WE KNOW ABOUT SYNTHETIC IMMUNITY COMES FROM ANTI-CD3 COATED PLATES
Chen DS, MIT TIM Talk 2020
YYYY YY YY YYYYYY YY YYYY YYYYYYYYYY YY YY
YYYY
YYYY YY YYYY
Plates coated with anti-CD3 antibodies
Plate Bound T Cell Activation
T cell
MOST OF WHAT WE THINK WE KNOW ABOUT SYNTHETIC IMMUNITY COMES FROM ANTI-CD3 COATED PLATES
Chen DS, MIT TIM Talk 2020
Plates coated with anti-CD3 antibodies
T Cell Signaling and Activation
YYYY YY YY YYYYYY YY YYYY YYYYYYYYYY YY YY
YYYY
YYYY YY YYYY
Plate Bound T Cell Activation
T cellT cell dependent
cytotoxicity
+++
Generalized cytokine release
MOST OF WHAT WE THINK WE KNOW ABOUT SYNTHETIC IMMUNITY COMES FROM ANTI-CD3 COATED PLATES
Chen DS, MIT TIM Talk 2020
Plates coated with anti-CD3 antibodies
T Cell Signaling and Activation
YYYY YY YY YYYYYY YY YYYY YYYYYYYYYY YY YY
YYYY
YYYY YY YYYY
Plate Bound T Cell Activation
T cellT cell dependent
cytotoxicity
+++
Generalized cytokine release
MOST OF WHAT WE THINK WE KNOW ABOUT SYNTHETIC IMMUNITY COMES FROM ANTI-CD3 COATED PLATES
A highly artificial system to have based our understanding of underlying T cell biology on; Easy studies to perform, but likely does not represent actual physiologic conditions (eg TCR engagement density and level of cross linking super physiologic)
Chen DS, MIT TIM Talk 2020
BIOPHYSICAL PROPERTIES OF ENGINEERED CANCER IMMUNOTHERAPY CAN BE MODIFIED TO OPTIMIZE EFFECTS
Zal, Zal & Gascoigne
Chen DS, MIT TIM Talk 2020
•Stoichiometry (interaction strength vs two targets/cells)
• eg Stronger binding to cancer cells, more physiologic signaling to T cells•Spatial (biophysical effects, signal strength)
• eg multimeric clustering, engagement density•Temporal (prolonged vs pulsatile modulation)
• eg stability of signals, cellular context, limit overstimulation
ENGINEERED PLATFORM TECHNOLOGY:
Focus on Control of:
Tim
eChen DS, MIT TIM Talk 2020
EXAMPLE OF A NEXT GENERATION PLATFORM:ENGINEERED IGM ANTIBODIES
High AvidityEnhanced binding, binding to difficult and/or rare targetsEnabled for modification with high specificity, high affinity binding domains Enables affinity-avidity matching
“Auto” forms engineered bispecificAccelerates innovation by enabling rapid therapeutic generationExtended range of ratios between binding and engaging moieties
Czajkowsky et al.
Conformational change upon bindingEnables specialized properties upon binding
Can be designed to drive forceful agonistic properties
Rigid and polarized disc shape confers biophysical
propertiesEnhanced control of T cell engagement
Altered kinetics and compartmentalizationFurther engineering for control
Example: Engineered IgM Antibody
Platform for multi-specific molecules and additional
engineering Enables construction of protein
based ”nano-machines”
Naturally occurring formatMay be important in minimizing immunogenicity
Chen DS, MIT TIM Talk 2020
SYNTHETIC IMMUNITY: T CELL SIGNALING AND FUNCTION CAN DIFFER
CD3T cell
Cancer Cell
Bispecific T cell : Target Engager
IgG
Bispecific T cell :Target Engager
Single Chain Units
CD20
CAR-T
T cell
Cancer Cell
CD20
CAR
T cell
Cancer Cell
T cell receptor : MHC Engagement
TCR
MHC
CD3T cell
Cancer Cell
Bispecific T cell : Target Engager IgM
CD3
CD20
CAR-T, Chimeric antigen receptor-T cellMHC, Major histocompatibility complex plus peptide TCR, T cell receptor
Co-stimulatory domain
~3-10 TCR-pMHC
interactions required for CD8 T cell mediated killing of a
cancer cell†
† Purbhoo et al. Nature Immunology 2004 Chen DS, MIT TIM Talk 2020
CD20XCD3 IGM BISPECIFIC T CELL ENGAGER: IN VIVO NON-HUMAN PRIMATE (NHP) EFFICACY AND SAFETY
Immunohistochemistry in vivo to detect CD19 and CD20 positive B cells in non-human primate spleen and mesenteric lymph nodes from NHP treated with a CD20 x CD3 IgM
IL-6 IL-2
IFNγ TNFα
Peak plasma inflammatory cytokine levels in a NHP dose study following treatment with CD20 x CD3 IgM
Chen DS, MIT TIM Talk 2020Dissociation of cytotoxicity and lack of cytokine release replicated in human, murine and non-human primate studies;
Phase I clinical study started late 2019, target complete dose escalation 2020
WE ARE IN THE MIDST OF A GLOBAL PANDEMIC UNLIKE ANYTHING MOST OF US HAVE EVER SEEN IN OUR LIVES…
The need for advancements in virology, immunology and therapeutics could not be greater
ENGINEERING COVID-19 THERAPEUTICS: TISSUE COMPARTMENTS, INTERACTIONS AND SARS-COV-2 INFECTION
Sites of SARS-CoV-2 infection1. Lung2. Heart/blood vessels3. Brain4. Eyes5. Nose/upper respiratory tract6. Liver7. Kidneys8. Intestines M
MM
M
M includes mucosal compartment
Wadman et al. Science 2020 Chen DS, MIT TIM Talk 2020
~100-150 nmSARS-CoV-2
Therapeutic IgG in bloodLeMessurier et al. 2020Mucosal barrier
Roitt et al., Immunology 5th ed
High affinity and avidity for SARS-CoV-2 spike protein
HOW TO SOLVE FOR AN ENEMY THAT EXHIBITS VARIABILITY AND MUTATION?
Steric hinderance
Emerging spike protein variants
Korber et al., 2020
Chen DS, MIT TIM Talk 2020
THE AGE OF ACCELERATIONS
Time
Mother Nature (global warming)
Moore’s Law(technology)
The Market (globalization)
Tom Friedman
2016
Chen DS, MIT TIM Talk 2020
NO DOUBT ABOUT IT… THIS IS OUR AGE OF ACCELERATIONS
Time
Immunology(biology)
Therapeutics(technology)
Disease(need)
Tom Friedman
2016
In a world that is rapidly changing, take a moment to stop and reflect on where we are.
Chen DS, MIT TIM Talk 2020
Appendix
ACKNOWLEDGEMENTS
• Angus Sinclair• Beatrice Wang• Tasnim Kothambawala• Ling Wang• Manal Amoury• Steve Carroll• Maya Leabman• Maya Kotturi• Marvin Peterson• Avneesh Saini• Madeline Tran
IGM Biosciences• Bruce Keyt• Kathy Miller• Paul Hinton• Dean Ng• Keyu Li• Kevin Carlin• Sachi Rahman• Yasinee Ng• Marigold Boe
• Wayne Godfrey• Eric Humke• Genevieve Hernandez• Iris Sison• Rachel Mejia
• Ramesh Baliga
• Fred Schwarzer • Misbah Tahir
Genentech/Roche• Pablo Umana• Ira Mellman• Priti Hegde• CITC
325 East Middlefield Road Mountain View, CA 94043 Chen DS, MIT TIM Talk 2020