and Engineering Solutions in Cancer What Need Now?Checkmate 214 OS (Ipi+Nivo 1L Int/Poor risk RCC) Escudier, et al. ESMO 2017 Keynote 189 OS (CarboPem+Pembrolizumab 1L NSCLC) Gandhi

Clinical Challenges and Engineering Solutions in Cancer Immunotherapy: What Do We Need Now?

PEGS Europe Meeting

Thursday, November 12th, 2020

Daniel S. Chen MD PhDChief Medical OfficerIGM Biosciences

2

Disclosures

I am an employee of IGM Biosciences

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

3

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 EU 2020

4

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?


5A 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


6

Tumor immunity continuum

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

7

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


…and learn and adjust to emerging data!

8How can Engineered Therapeutics help address these challenges in immunotherapy?


9Engineering 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

~100-150 nmSARS-CoV-2

Therapeutic IgG in bloodLeMessurier et al. 2020Mucosal barrier


10

Nanobody direct pulmonary delivery

Schoof et al. pre-print 2020

Trimeric-mNb6 kd of 1.0x10-6 s-1femtomolar affinitypicomolar neutralization

EXAMPLE:Trimeric nanobody targeting SARS-CoV-2 with direct

pulmonary administration


11

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


12Community map of cancer immunity: A multitude of suppressive factors in Inflamed Cancer

Chen and Mellman. Nature 2017

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

• How many of the suppressive factors are important?

• How will we target multiple suppressive factors at once?


13

Example: Enzymatic Glycomodulation

Rodriguez et al 2018 Nature Reviews

Stanczak et al ChemRxiv 2019

Cao et. al. SITC 2019


14

2. Agonize and Activate T cells only in the TME


ACTIVATE Non‐inflamed

IMMUNE DESERT

Immune cells are absent from tumor

and its periphery


15Immune 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?


16

Targeted co-stimulation: 4-1bb, CD28 and other T cell agonists?


Sanmamed et. al. Sci Trans Med 2019

Waite et. al. Sci Trans Med 2020

Melero et. al. ESMO 2020

FAP x 41bbPhase 1

FAP x 41bb monotherapy PD

FAP x 41bb + Atezolizumab waterfall plot

Targeted 4-1bb stimulation Targeted CD28 stimulation

17

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


18

Synthetic Immunity and the Cancer Immunity Cycle

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

19New 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)


20T cell engagers are HIGHLY potent: many other determinants of benefit

T cells adjacent to cancer cells?IMMUNE EXCLUDED

CRS vs Cytotoxicity?

Faroudi et al. PNAS 2003

Shi et al. Cancer Med 2019

Hegde and Chen Immunity 2020

On target off cancer expression?

Galante et al. 2013

Exposure profile?

Hernandez et al. ASH 2019

T cell state?Induction of toleragenic MOA?

Cancer Cell Target Expression?


21CD20xCD3 TCE BIOMARKERS: RAPID AND TRANSIENT CYTOKINE ELEVATION

MosunetuzumabOdronextamab

• Peak cytokine levels after 1st infusion (~EOI-4h); • Reduced immune function and cytokine secretion

following first dose• Rationale and MOA for “step-up dosing”• First dose leads to global “de-sensitization” of T cells

Modified from Hernandez G IO360 Combinations 2020Brouwer-Visser, et al., EHA 2020Hernandez, et al., ASH 2019 Chen DS PEGS EU 2020

22

WHAT’S NEXT FOR BISPECIFIC TCE?

Challenges

• How to develop platforms and drug combinations (including dosing) that allow for preservation or even enhancement of T cell functionality without compromising safety?

• How to develop platforms and drug combinations (including dosing) that allow for selective T cell function?

Ji Li et al., Sci Transl Med 2019

Biomarkers are crucial in understanding/defining

T cell functionality

Hernandez G, IO360 Combinations 2020Chen DS PEGS EU 2020

23

PROBLEM STATEMENT for Bispecific T cell engagers

Eliminate cancer cells durably without significant toxicity• Challenges for Antibody Engineering:

• How to irreversibly target cancer cells?• How to avoid targeting normal cells?• How to get T cells adjacent to cancer cells?• How to avoid cytokine storm?• How to avoid tolerance, decreased T cell function and/or

activation induced cell death?• How to potently engage and kill cancer cells?• How to maintain anti-cancer activity over time?• How to induce endogenous immunity against cancer along

with synthetic immunity?


24Biophysical 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/


25TCR Signaling: Cytotoxicity vs Cytokine Release

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

Cytotoxicity and cytokine hierarchy 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


Itoh and Germain, J Exp Med 1997

TCR signal strength controls hierarchical T cell cytokine

secretion; IFN secretion is the most sensitive to TCR signal

Cytokine secretion detected

Cytokine RNA expression detected

26Addressing the problem: example of Engineered IGM antibodies Hypotheses

Eliminate cancer cells durably without significant toxicity and limiting overstimulation of T cells

High Affinity High Avidity

Affinity modulation

Dissociate cytotox and CRS

T cell engager +complement fixation

Provide upper limit to TCR signal induced

Induce cancer cell death and appropriate cytokine milieu without overstimulation and tolerance

Anti-CD20

Anti-CD3


• Challenges for Antibody Engineering:

• How to irreversibly target cancer cells?• How to avoid targeting normal cells?• How to get T cells adjacent to cancer cells?• How to avoid cytokine storm?• How to avoid tolerance, decreased T cell

function and/or activation induced cell death?• How to potently engage and kill cancer cells?• How to maintain anti-cancer activity over

time?• How to induce endogenous immunity against

cancer along with synthetic immunity?

27Synthetic 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 EU 2020

28

Conclusions

• 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, therapeutic formats and biophysical characteristics may enable such control

• Applications are well suited to cancer immunotherapy, but may also be applied to many other medical applications-including treatment for pandemic respiratory viruses


Acknowledgements

• Angus Sinclair• Beatrice Wang• Tasnim Kothambawala• Ling Wang• Manal Amoury• Steve Carroll• 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• Maya Leabman• John So• Ibrahim Qazi• Iris Sison• Rachel Mejia

• Fred Schwarzer • Misbah Tahir

• Ramesh Baliga

Genentech/Roche• Pablo Umana• Ira Mellman• Priti Hegde• CITC

325 East Middlefield Road Mountain View, CA 94043 Chen DS PEGS EU 2020

Documents

and Engineering Solutions in Cancer What Need Now?Checkmate 214 OS (Ipi+Nivo 1L Int/Poor risk RCC) Escudier, et al. ESMO 2017 Keynote 189 OS (CarboPem+Pembrolizumab 1L NSCLC) Gandhi