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261 Evidence for durable anti-tumor responses by TAC-T cells in preclinical models of solid tumors
  1. Heather MacGregor1,
  2. Duane Moogk2,
  3. Stacey Xu1,
  4. Joanne Hammill2,
  5. Philbert Ip1,
  6. Ling Wang1,
  7. Swati Shetty1,
  8. Kyle MacDonald1,
  9. Laura Shaver1,
  10. Sailaja Pirati1,
  11. Prabha Lal1,
  12. Christopher Helsen1,
  13. Jonathan Bramson1,2,
  14. Sadhak Sengupta1 and
  15. Andreas Bader1
  1. 1Triumvira Immunologics Inc., Hamilton, ON, Canada
  2. 2McMaster University, Hamilton, ON, Canada


Background T cell antigen coupler (TAC) is a chimeric receptor that redirects T cells (TAC-T) towards surface-expressed tumor antigens to create safe and durable anti-cancer immune responses. The TAC activates T cells by co-opting the endogenous T cell receptor machinery via a CD3ε-specific binding motif and a cytoplasmic co-receptor tail. TAC01-HER2, a first-in-class TAC-T product targeting HER2 (ERBB2), has entered a phase I/II clinical trial. Here, we have characterized the fate of TAC-T cells during anti-tumor responses in vitro and in vivo.

Methods In vitro, HER2-specific TAC-T products were challenged with HER2-expressing and HER2-negative tumors. Kinetics of proliferation, degranulation, activation, differentiation, and memory generation was assessed by flow cytometry. TAC-T products were subjected to multiple rounds of tumor cell exposure in vitro to test the durability of the T-cell-mediated immune response. Bioinformatic clustering analysis of flow cytometry data was performed to identify T cell populations and track them over time.

T cell expansion in blood, tumor, bone marrow, and spleen were evaluated in vivo after primary xenograft tumor treatment and secondary tumor rechallenge. Tumor- and spleen-infiltrating or circulating T cells were phenotyped by flow cytometry after treatment with TAC-T cells.

Results Co-culture studies revealed that TAC-T products become rapidly activated and degranulate upon contact with HER2-expressing, but not HER2-negative, cell lines. Activation coincided with rapid downregulation of the TAC receptor. A large proportion of the T cells expressed activation markers, and a majority of these also expressed degranulation markers, indicating ongoing cytotoxicity. In vitro and in vivo studies demonstrated a CD8-biased response characterized by a considerable expansion in the activated CD8 population enriched at the tumor site. Later, activation and differentiation markers returned to baseline concurrently with the re-emergence of surface TAC expression, initiating T cell proliferation. Importantly, central memory T cells were expanded, and stem-like cells were maintained, suggesting strong self-renewal potential. In vitro serial cytotoxicity assays showed that TAC-T products could repeatedly kill tumor cells up to several rounds. In tumor rechallenge experiments, a single dose of TAC-T cells expanded to clear solid tumor xenografts and protected mice from a second tumor challenge 30 days post initial tumor clearance, indicating long-lasting T cell persistence.

Conclusions The TAC-T product mounts an effective anti-tumor response in multiple preclinical models, comprising activated TAC-T cells that do not become terminally exhausted but are dominated by an activated CD8 response and supported by the expansion of a memory population, indicating robust self-renewal capacity.

Ethics Approval Animal studies were approved by McMaster University’s Animal Research Ethics Board under AUP 20-10-37.

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