problems and engineering solutions in immunotherapy+ · 6/17/2020 · defining clinical problems...

Defining Clinical Problems and Engineering Solutions in Cancer Immunotherapy+

Science SartoriusJune 17th, 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

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

Chen DS Science Sartorius 2020

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 Science Sartorius 2020

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

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

Synthetic Immunity Inflamed and Non‐Inflamed


SYNTHETIC IMMUNITY AND THE CANCER IMMUNITY CYCLE

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


EARLY APPROACHES TO BISPECIFIC T CELL ENGAGERS FOCUSED ON OPTIMIZING POTENCY

Diego Ellerman Methods 2019

Santich et al. Sci Trans Med 2020

Log nM

T cell engager in vitro Killing Curve

Similar clinical benefit?


EARLY APPROACHES TO BISPECIFIC T CELL ENGAGERS FOCUSED ON OPTIMIZING POTENCY

Diego Ellerman Methods 2019

Santich et al. Sci Trans Med 2020

Log nM

T cell engager in vitro Killing Curve Similar clinical benefit?

Log nM

CRS limits dosing to similar points on the killing curve?


T 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?

T cell state?

Hernandez et al. ASH 2019

Cancer Cell Target Expression?


Plates coated with anti-CD3 antibodies

T Cell Signaling and Activation

YYYY YY YY YYYYYY YY YYYY YYYYYYYYYY YY YYYY

YYYYYY YY YYYY

Plate Bound T Cell Activation

T cellT cell dependent

cytotoxicity

+++

Generalized cytokine release

MOST OF WHAT WE THINK WE KNOW ABOUT T CELL ENGAGERS 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)


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


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/


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 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?


HOW CAN ENGINEERED THERAPEUTICS HELP ADDRESS THESE CHALLENGES IN IMMUNOTHERAPY?


ADDRESSING THE PROBLEM: EXAMPLE OF ENGINEERED IGM ANTIBODIES HYPOTHESES

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 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?

High Affinity High Avidity

Affinity modulation

Dissociate cytotox and CRST cell engager +complement fixation

Prevent decreased T cell function

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

Anti-CD20

Anti-CD3


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

“How to irreversibly target cancer cells?”


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 KeytChen DS Science Sartorius 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

“How to avoid cytokine storm?


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 Science Sartorius 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 Science Sartorius 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- and human cancer can present with different mechanisms to inhibit anti-cancer immune responses

• T cell engagers present a highly potent opportunity to utilize the immune system to eliminate cancer cells

• 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

Appendix

problems and engineering solutions in immunotherapy+ · 6/17/2020 · defining clinical problems...

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