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 • 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 28 ζ and BB ζ second-generation CARs (Helsen et al., Nat. Comm. 2018)
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
In Vitro Efficacy • Both C11D5.3 and J22.9-xi TAC T cells produce cytokines and kill BCMA(+) KMS-11 tumor targets 100 TNF- α IFN- γ IL-2 80 C11D5.3 30 60 15 CD8 (+) 60 20 10 40 J22.9-xi 40 5 20 10 Control 0 0 20 0 % Cytotoxicity 30 15 75 0 CD4(+) % Positive 20 50 10 -20 0.25:1 0.5:1 1:1 2:1 4:1 10 25 5 0 0 0 Effector: target C11D5.3 J22.9-xi Control ratio
In Vivo Model Tumor 10 6 KMS-11 1 x 10 6 TAC(+) tumor cells i.v. cryopreserved T cells i.v. Alternate T-cell and tumor imaging 12 days Label = NanoLuc-eGFP NRG Label = effLuc Substrate = Furimazine Substrate = D-luciferin T cells
In Vivo Efficacy Tumor burden 10 6 TAC + T cells/mouse 1.E+07 100 1.E+06 C11D5.3 75 J22.9-xi Average radiance 1.E+05 50 Control 1.E+04 Rechallenge with 25 % Survival KMS-11 tumor 1.E+03 0 (10 6 cells/mouse) -10 10 30 50 70 0 30 60 90 Days post-treatment Days post-treatment • Both types of BCMA TAC T cells • J22.9-xi TAC T cells provide clear KMS-11 tumors and lead better protection from tumor to long-term remissions rechallenge
T Cell Proliferation In vivo In vitro C11D5.3 CD8(+) CD4(+) 5.E+06 J22.9-xi 4.E+06 Control Average radiance 3.E+06 2.E+06 1.E+06 1.E+05 0 2 4 6 8 10 12 Days post-treatment • Only J22.9-xi TAC T cells proliferate upon activation in vivo , despite equal proliferative capacity in vitro
Competition with APRIL • Natural ligand for BCMA TAC T cell • Produced by cells in the BM APRIL microenvironment and MM cells • Elevated in serum of MM patients TAC • Disruption of BCMA-APRIL interaction BCMA reduces proliferation and survival of MM cells MM cell
APRIL Inhibits TAC T Cell Activation In Vitro IL-2 IFN- γ TNF- α C11D5.3 100 100 J22.9-xi 100 80 80 80 60 60 60 40 40 40 % Activity 20 20 20 0 0 0 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 Conc. of mAPRIL (ng/mL) • 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
APRIL Inhibits TAC T Cell Activation In Vitro CD8(+) CD4(+) mAPRIL KMS-11 C11D5.3 J22.9-xi C11D5.3 J22.9-xi + 0 + 5 + 10 + 20 + 50 - • 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
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
Acknowledgements Supervisor Dr. Jonathan Bramson Supervisory Committee Bramson Lab Dr. Carl Richards Craig Aarts Derek Cummings Jamie McNicol Dr. Ronan Foley Arya Afsahi Dr. Galina Denisova Dr. Duane Moogk Kaylyn Bacchiocchi Megan Hagerman Allyson Moore Funding Sources Christopher Baker Dr. Joanne Hammill Kenneth Mwawasi Dr. Bojana Bojovic Dr. Christopher Helsen Robin Parsons Dr. Ian Brain Jessica Irwine Jennifer Seager Dr. Kimberly Braz Vivian Lau Michael Sun Gomes Sally Li Ying Wu Rebecca Burchett Li-Min Liu Dr. SeungMi Yoo Dr. Jana Burkhardt Phillip Marvyn
Thank You
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