Background Enrichment of memory B cells, plasma cells and tertiary lymphoid structure is a positive prognostic factor in patients (pts) with a variety of solid tumors.^1–3 Designed for systemic administration, TAC-001 is a Toll-like Receptor (TLR) Agonist Antibody Conjugate (TRAAC) comprised of a potent and differentiated TLR9 agonist (T-CpG) conjugated to an antibody against CD22, a receptor restricted to B cells, including tumor-infiltrating B cells. TAC-001 mouse surrogate elicited infiltration of activated B cells, effector T cells and modulation of suppressive myeloid cells within the tumor microenvironment of murine models, including those refractory to anti-PD-1 therapy.⁴ INCLINE-101 is a first in human Phase 1/2 open-label, non-randomized, dose escalation/dose expansion study to evaluate TAC-001 in pts with advanced or metastatic solid tumors.

Methods In Phase 1, TAC-001 is administered intravenously as monotherapy every two weeks in pts with advanced or metastatic solid tumors. Eligible pts in Phase 1 must have histologically or cytologically documented advanced, metastatic, unresectable malignancies that have progressed on or are intolerant to standard therapy. The Phase 1 study is exploring ascending dose levels of TAC-001 to assess safety, tolerability, efficacy, PK, pharmacodynamics (PD), and identify the maximum tolerated dose (MTD) or maximum administered dose (MAD), and recommended Phase 2 dose (RP2D).

Results As of 20June23, 15 pts (median age: 61 yrs), have been treated with TAC-001 (dose ranges from 0.1 to 3.0 mg/kg) intravenously every 2 weeks. Most common treatment related-adverse events include fatigue (n=11, 73.3%), chills (n=8, 53.3%), and pyrexia (n=7, 46.6%). One subject discontinued treatment after two doses due to a DLT of immune-mediated hepatotoxicity (grade 4 elevation of ALT, grade 3 elevation of AST and bilirubin) observed at the 3.0 mg/kg dose level. TAC-001 PK exposures (Cmax and AUC) exhibited dose dependent increase over the dose range tested. Preliminary PD biomarker assessment demonstrated CD22 engagement and internalization by TAC-001 on circulating B cells in subjects across dose levels. TAC-001 mediated activation of B-cells through TLR9 pathway induction has also been demonstrated among subjects across dose levels. Two of eight response evaluable pts have stable disease and remain on study (range 5+ to 10+ months).

Conclusions TAC-001 appears well tolerated with dose dependent PK and PD activity consistent with the proposed proof of mechanism - evaluation & enrollment is ongoing.

Acknowledgements Tallac Therapeutics wishes to acknowledge the patients and their families who participated in this ongoing trial.

Trial Registration NCT05399654

References

1. Griss J, Bauer W, Wagner C, et al. B cells sustain inflammation and predict response to immune checkpoint blockade in human melanoma. Nat Commun. 2019;10(1):4186.

2. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 2020;577:549–555.

3. Kroeger DR, Milne K, Nelson BH. Tumor-Infiltrating Plasma Cells Are Associated with Tertiary Lymphoid Structures, Cytolytic T-Cell Responses, and Superior Prognosis in Ovarian Cancer. Clin Cancer Res. 2016;22(12):3005–3015.

4. Kuo TC, Harrabi O, Chen A, Sangalang ER, Doyle L, Fontaine D, Li M, Han B, Pons J, Sim J, Wan HI. TAC-001, a toll-like receptor 9 (TLR9) agonist antibody conjugate targeting B cells, promotes anti-tumor immunity and favorable safety profile following systemic administration in preclinical models. Cancer Res 2021;81(13_Supplement):1721.

Ethics Approval All clinical subjects or participants provided informed consent prior to taking part in this clinical trial. WCG-IRB: IRB Tracking Number: 20222058