daniel s. chen md phd€¦ · atezolizumab+chemo 1l small cell lung impassion130 os 1l tnbc pdl1...

The Next Era of Cancer Therapeutics: Defining Biologic Problems and Engineering Solutions in Cancer Immunotherapy

PEGS Virtual MeetingWednesday June 3rd, 2020

Daniel S. Chen MD PhDChief Medical OfficerIGM Biosciences

DISCLOSURES

I am an employee of IGM Biosciences

The information presented is solely intended to foster the exchange of scientific and medical information.

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)

Powles et. al. Lancet 2018

Chen DS PEGS Virtual 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)

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?

A COMPLEX SET OF TUMOUR, HOST AND ENVIRONMENTAL FACTORS GOVERN STRENGTH, AND TIMING, OF ANTI-CANCER IMMUNE RESPONSES

Adapted from Chen and Mellman. Immunity 2013; Chen and Mellman. Nature 2017

∫(Fstim) - ∫(Finhib) ≥ 1/ n=1, y (TCRaffinity x frequency)Cancer immune set point:


Cancer immune set pointCancer immunity cycle

TUMOR IMMUNITY CONTINUUM

IMMUNE DESERTCD8+ T cells are

absent from tumor and its

periphery

IMMUNE EXCLUDEDCD8+ T cells

accumulated but have not efficiently

infiltrated

INFLAMEDImmune cells

infiltrated, but inhibited

Inflamed Non-inflamed

Mechanisms associated with immune escape to PD-L1/PD-1 inhibition

Mutational Load, Endogenous retrovirus

TGF signalReactive stroma, MDSCs, Angiogenesis, Low MHC I

Respond favorably to PD-L1/PD-1 inhibition

IFNg signalPD-L1 expression, B-cells, TILs,

Intact Ag presentation

Fatty acid metabolismNeuroendocrine features

Wnt/b-cateninKi67hi,, Low MHC I

Adapted from Hegde et al., Clin Cancer Res, 2016.Hegde and Chen, Immunity 2020 Chen DS PEGS Virtual 2020

PROBLEM STATEMENT FOR CANCER IMMUNOTHERAPY

• Complex system: Immune system is highly complex with many positive and negative regulators comprising many cell types, circulating factors and compartments, all with spatial and temporal considerations

• Balance between anti-cancer immunity and autoimmunity: Simple systemic manipulation of immunity is often limited by stimulation of autoimmunity

• Cancer heterogeneity: Human cancer can be broadly separated into three phenotypes that feature three distinct mechanisms of immune escape with each likely driven by specific dominant biology


HOW CAN ENGINEERED THERAPEUTICS HELP ADDRESS THESE CHALLENGES IN IMMUNOTHERAPY?


1. ALLEVIATE IMMUNOSUPPRESSION

KILLCANCERCELLSInflamed

INFLAMEDCD8+ T

cells infiltrated,

but areinhibited

Sources: Modified from Chen DS, Mellman I. Immunity. 2013; Herbst et. al. Nature 2014; Hegde, Karanikas, Evers. Clin Cancer Res 2016


ECHO-301/KEYNOTE-252: IDO INHIBITOR + PD1 INHIBITOR PHASE III STUDY

Long GV et al. ASCO 2018

MelanomaN~600

Epcadostat + pembrolizumab

Placebo + pembrolizumab

OS HR 1.13


Community map of cancer immunity: A multitude of suppressive factors in Inflamed Cancer

https://cancer-immunity.nature.com/pages/map

Chen and Mellman. Nature 2017

• How many of the suppressive factors are important?

• How will we target multiple suppressive factors at once?


2. AGONIZE AND ACTIVATE T CELLS ONLY IN THE TME


ACTIVATE Non‐inflamed

IMMUNE DESERT

Immune cells are absent from tumor

and its periphery


IMMUNE DESERTS: A PROFOUND ABSENCE OF T CELLS AND OTHER IMMUNE CELLS IN THE TUMOR MICROENVIRONMENT

Passive:Potential lack of immunogenic antigens Lack of Antigen PresentationLack of appropriate co-stimulationImmune Hostile TMELack of immune attractive chemokines

Active:Repulsive Chemokines

Mutational Load , Endogenous retrovirus

Fatty acid metabolismNeuroendocrine features

Wnt/b-cateninKi67hi

Low MHC I

IMMUNE DESERTImmune cells are

absent from tumor and its

periphery

Adapted from Hegde et al., Clin Cancer Res, 2016.Hegde and Chen, Immunity 2019 publication pending

Possible MOAs?


3. TARGETING IMMUNE EXCLUSION

RECRUIT/INFILTRATE

Excluded

EXCLUDED

CD8+ T cells present but

have not efficiently infiltrated



One of TGF’s functions is to trigger the formation of collagen fibers that can trap T cells:Will inhibiting TGF relieve this immune inhibition?

Bladder “excluded” phenotype: CD8/Collagen

Mariathasan, et al. Nature 2018

15


M7824:Anti-PDL1/TGFb Trap

Strauss, et al. CCR 2018

TARGETING DOMINANT IMMUNE BIOLOGY IN THE TME


ALTERNATIVE: BYPASS REGULATION OF ENDOGENOUS IMMUNITY

EXCLUDED

CD8+ T cells present but

have not efficiently infiltrated

INFLAMED

CD8+ T cells infiltrated,

but areinhibited

IMMUNE DESERT

Immune cells are absent from tumor

and its periphery


Synthetic Immunity Inflamed and Non‐Inflamed


SYNTHETIC IMMUNITYEnable a potent “synthetic” anti‐cancer immune response targeted at tumor‐associated antigens (TAA)

Scott et. al. 2017

CAR-T

Anti-CD3

Anti-TAA

T cell engagerEnables immune-mediated elimination of cancer cells even when pMHC

machinery is lost or downregulated

Hegde and Chen, Immunity 2019 publication pending Chen DS PEGS Virtual 2020

SYNTHETIC IMMUNITY AND THE CANCER IMMUNITY CYCLE

Adapted from Chen and Mellman, Immunity 2013Hegde and Chen, Immunity 2020 Chen DS PEGS Virtual 2020

NEW DATA FROM AMERICAN SOCIETY OF HEMATOLOGY (ASH19): BCMA-TARGETED T CELL ENGAGERS AND CAR-T

Patients treated at 10mg (n=9): ORR 89%, 44% sCR/CR (MRD negative); CRS ~100%1 patient with Gr3/Gr5 CRS

6→10 mg and 10 mg

CC-932692:1 BCMAxCD3

(BMS)

Costa, et. al. ASH 2019 Berdeja, et. al. ASH 2019

Patients treated at 150x106 cells (n=12): ORR 83%, 33% sCR/CR (MRD negative); CRS ~67%, Neurotox 25%; 1 patient with Gr5 CRS at 450x106 cells

bb21217BCMA CAR-T

(BlueBird/BMS)

SYNTHETIC IMMUNITY: CHALLENGES FOR CART

• Homing of infused cells to TME

• Infiltration into TME

• Killing of target cells• Target Expression• Suppression

• CART cell survival• CART cell proliferation• CRS

• Cell preparation/logistics• Patient selection

• Promote endogenous immunity

Adapted from Chen and Mellman, Immunity 2013Hegde and Chen, Immunity 2020 Chen DS PEGS Virtual 2020

SYNTHETIC IMMUNITY: CHALLENGES FOR T CELL ENGAGERS

Adapted from Chen and Mellman, Immunity 2013Hegde and Chen, Immunity 2020

• Killing of target cells• Target Expression• Suppression

• CRS management and limitations to optimal dosing

• Adequate host T cells

• Promote endogenous immunity


T CELL ENGAGERS: ACTIVATION AND FUNCTION


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 T CELL ENGAGERS COMES FROM ANTI-CD3 COATED PLATES



YYYY

YYYY YY YYYY


Plate Bound T Cell Activation

T cell




T Cell Signaling and Activation


YYYY

YYYY YY YYYY


T cellT cell dependent

cytotoxicity

+++

Generalized cytokine release




T Cell Signaling and Activation


YYYY

YYYY YY YYYY


T cellT cell dependent

cytotoxicity

+++

Generalized cytokine release


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)


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


IGM CD20xCD3 binds very strongly to Ramos lymphoma cells at 37°C

HIGH AFFINITY HIGH AVIDITY IGM-BASED CD20XCD3 (IGM-2323) T CELL ENGAGER: BINDING

Keyu Li, Dean Ng, Ramesh Baliga

Koff for IGM-2323: unmeasurable

IgM CD20xCD3

IgG CD20xCD3

Anti-CD20

Anti-CD3

Anti-CD20

Anti-CD3


IGM CD20xCD3 is significantly more potent against rituximab-resistantRamos Lymphoma cells expressing low levels of CD20

HIGH AFFINITY HIGH AVIDITY IGM-BASED CD20XCD3 T CELL ENGAGER: T CELL DEPENDENT CYTOTOXICITY

Antibody (pM)

IgM CD20xCD3IgG CD20xCD3

Rituximab

Marigold Manlusoc, Keyu Li, Ramesh Baliga, Bruce Keyt Chen DS PEGS Virtual 2020

IGM: DISSOCIATION OF CYTOTOXICITY AND “CYTOKINE RELEASE”

Dissociation of cytotoxicity and lack of cytokine release replicated in human, murine and non-human primate studies; Phase I study FPI late 2019, target complete dose escalation 2020

Keyt PEGS 2017

Lower cytokine release profile in vitro compared to IgG CD20 x CD3 bispecific antibody

IL-6 IL-2

IFNγ TNFα


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

NHP dosed up to 25mg/kg of CD20 x CD3 IgM: no identified clinical or pathologic AEs/Tox Chen DS PEGS Virtual 2020

BIOPHYSICAL PROPERTIES OF ENGINEERED CANCER IMMUNOTHERAPY CAN BE MODIFIED TO OPTIMIZE EFFECTS

Deeg et al. Nano Lett 2013

Zal, Zal & Gascoigne

Miguel Otero Ritter et al.

Modified fromCalvo and Izquierdo 2018 other modification

physical characteristics of a T cell engager

• Shape• Size• Rigidity• Flex regions• Polarization• Charge• Coating/


TCR SIGNALING: CYTOTOXICITY VS CYTOKINE RELEASE

Faroudi et al. PNAS 2003;100:24:14145-14150

Cytotoxicity as a function of antigenic stimulus

Functional T cell signaling is not dichotomous Two different activation thresholds in CTLs, with lytic threshold being more sensitive


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 PEGS Virtual 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, compartment control•Temporal (prolonged vs pulsatile modulation)

• eg stability of signals, cellular context, limit overstimulation

EXAMPLE PLATFORM TECHNOLOGY: ENGINEERED IGM AND IGA Focus on Control of:


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

Problem Statement for Pandemic Respiratory VirusPrevent infection, inhibit viral spread, modulate immunity

• Challenges for Antibody Engineering:

• How to irreversibly neutralize virus?• How to block viral variants?• How to provide appropriate access to viral sites of infection?• How to limit inflammation but enhance anti-viral immunity?• How to reduce Antibody Dependent Enhancement risk?

• Immunity is highly complex, requiring optimal immunotherapy to deliver tuned and orchestrated biologic modulation within specific compartments and to specific cells- at just the right amount

• Advances in antibody engineering may readily enable therapies that can provide such modulation in a convenient and accessible format

• Such approaches are well suited to cancer immunotherapy, but may also be applied to many other medical applications

CONCLUSIONS

Illustrative

Hegde and Chen, manuscript in preparation

Inno

vatio

n

57 years 46 years 49 years 16 years

Surgery(1846)

Radiotherapy(1903)

Chemotherapy(1949)

Targeted therapy(1998)

Cancer Immunotherapy(2014)

Amplitude

Wavelength (l)

Time

Synthetic immunity (CAR-T, etc)(2017)


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 PEGS Virtual 2020

daniel s. chen md phd€¦ · atezolizumab+chemo 1l small cell lung impassion130 os 1l tnbc pdl1...

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