Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple - - PowerPoint PPT Presentation

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Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple - - PowerPoint PPT Presentation

Oct 22, 2023 270 likes •421 views

T cells Engineered with a Novel Chimeric Receptor Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple Myeloma Ksenia Bezverbnaya Laboratory of Dr. Jonathan Bramson T Cell Antigen Coupler (TAC) Receptor Modular design

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SLIDE 1

Ksenia Bezverbnaya Laboratory of Dr. Jonathan Bramson

T cells Engineered with a Novel Chimeric Receptor Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple Myeloma

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SLIDE 2

T Cell Antigen Coupler (TAC) Receptor

  • Modular design
  • HLA-independent target recognition
  • Engagement of TCR-CD3 complex
  • No signaling domains in the receptor
  • No evidence of tonic signaling
  • ↑ efficacy and ↓ toxicity, compared to

28ζ and BBζ second-generation CARs (Helsen et al., Nat. Comm. 2018)

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SLIDE 3

TACs for Multiple Myeloma

Target = BCMA

  • B-cell maturation antigen
  • ↑ expression on MM cells
  • Involved in survival and pathogenesis of MM
  • BCMA-specific CAR-engineered T cells show

efficacy in clinical trials

Antigen-binding domains

  • C11D5.3 scFv
  • J22.9-xi scFv
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SLIDE 4

In Vitro Efficacy

% Positive

10 20 30 5 10 15

IFN-γ

20 40 60

TNF-α

25 50 75 5 10 15

IL-2

10 20 30

CD8(+) CD4(+) C11D5.3 J22.9-xi Control

  • 20

20 40 60 80 100 0.25:1 0.5:1 1:1 2:1 4:1

C11D5.3 J22.9-xi Control Effector: target ratio % Cytotoxicity

  • Both C11D5.3 and J22.9-xi TAC T cells produce

cytokines and kill BCMA(+) KMS-11 tumor targets

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SLIDE 5

In Vivo Model

NRG 106 KMS-11 tumor cells i.v. Label = effLuc Substrate = D-luciferin 1 x 106 TAC(+) cryopreserved T cells i.v. Label = NanoLuc-eGFP Substrate = Furimazine Alternate T-cell and tumor imaging Tumor T cells 12 days

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SLIDE 6

In Vivo Efficacy

25 50 75 100 30 60 90

Days post-treatment % Survival 106 TAC+ T cells/mouse Rechallenge with KMS-11 tumor (106 cells/mouse)

  • Both types of BCMA TAC T cells

clear KMS-11 tumors and lead to long-term remissions

C11D5.3 J22.9-xi Days post-treatment Average radiance

Tumor burden

  • J22.9-xi TAC T cells provide

better protection from tumor rechallenge

1.E+03 1.E+04 1.E+05 1.E+06 1.E+07

  • 10

10 30 50 70 Control

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SLIDE 7

T Cell Proliferation

  • Only J22.9-xi TAC T cells proliferate upon activation in vivo, despite equal

proliferative capacity in vitro CD8(+) CD4(+) In vitro

1.E+05 1.E+06 2.E+06 3.E+06 4.E+06 5.E+06 2 4 6 8 10 12

C11D5.3 J22.9-xi Control

Days post-treatment Average radiance

In vivo

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SLIDE 8

Competition with APRIL

  • Natural ligand for BCMA
  • Produced by cells in the BM

microenvironment and MM cells

  • Elevated in serum of MM patients
  • Disruption of BCMA-APRIL interaction

reduces proliferation and survival of MM cells

MM cell

BCMA

TAC T cell

TAC APRIL

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SLIDE 9

APRIL Inhibits TAC T Cell Activation In Vitro

  • CD8+ (shown) and CD4+ BCMA TAC T cells show reduced cytokine production in the

presence of murine APRIL

  • C11D5.3 TAC T cells are more susceptible to inhibition by APRIL than J22.9-xi TAC T cells

C11D5.3 J22.9-xi

20 40 60 80 100 10 20 30 40 50

IL-2

20 40 60 80 100 10 20 30 40 50

IFN-γ

20 40 60 80 100 10 20 30 40 50

TNF-α

  • Conc. of mAPRIL (ng/mL)

% Activity

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SLIDE 10

APRIL Inhibits TAC T Cell Activation In Vitro

  • mAPRIL hinders proliferation of BCMA TAC T cells, with C11D5.3 TAC T cells showing more

susceptibility, compared to J22.9-xi TAC T cells CD8(+) CD4(+) C11D5.3 C11D5.3 J22.9-xi J22.9-xi

KMS-11

+ + + + +

  • mAPRIL

50 20 10 5

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SLIDE 11

Summary

  • BCMA-specific TAC-engineered T cells lead to tumor clearance and long-

term remissions in an orthotopic xenograft mouse model

  • The choice of antigen-binding domain influences in vivo T cell

proliferation and efficacy

  • BCMA natural ligand APRIL can inhibit activation of BCMA-redirected

engineered T cells

  • Engineered T cell therapies could potentially benefit from a combination

with APRIL-blocking agents

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SLIDE 12

Acknowledgements

Supervisor

  • Dr. Jonathan Bramson

Supervisory Committee

  • Dr. Carl Richards
  • Dr. Ronan Foley

Funding Sources

Craig Aarts Arya Afsahi Kaylyn Bacchiocchi Christopher Baker

  • Dr. Bojana Bojovic
  • Dr. Ian Brain
  • Dr. Kimberly Braz

Gomes Rebecca Burchett

  • Dr. Jana Burkhardt

Derek Cummings

  • Dr. Galina Denisova

Megan Hagerman

  • Dr. Joanne Hammill
  • Dr. Christopher Helsen

Jessica Irwine Vivian Lau Sally Li Li-Min Liu Phillip Marvyn Jamie McNicol

  • Dr. Duane Moogk

Allyson Moore Kenneth Mwawasi Robin Parsons Jennifer Seager Michael Sun Ying Wu

  • Dr. SeungMi Yoo

Bramson Lab

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SLIDE 13

Thank You