ontorpacept (PF-07901800)

P2, N=76, Terminated, Pfizer | Phase classification: P1/2 --> P2 | Active, not recruiting --> Terminated; Pfizer decided to terminate the study for administrative reasons. The termination was neither due to safety concerns nor a request from the regulatory authorities.

P1/2, N=80, Recruiting, Pfizer | Phase classification: P2 --> P1/2

P2, N=62, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

We investigated the relationship between MYC and CD47 and PD-L1 expression and found that MYC shRNA knockdown and MYC functional suppression by TTI-621 (SIRPαFc) and anti-PD-L1 (durvalumab) in CTCL cell lines reduced the expression of CD47 and PD-L1 mRNA and protein as measured by qPCR and flow cytometry, respectively. These effects were mediated by cell‒death-related pathways, including apoptosis, autophagy, and necroptosis. Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of immune surveillance in CTCL and dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy for CTCL.

CTCL specimens at baseline and during treatment with anti-CD47/SIRPα (TTI621) and anti-PD-L1 (durvalumab) were used to analyze immune cell gene expression. Collectively, our findings demonstrate that CD47 and PD-L1 are critical regulators of the immune microenvironment in CTCL and that dual targeting of CD47 and PD-L1 may potentiate anti-tumor responses in CTCL.

P2, N=62, Not yet recruiting, Mayo Clinic

Notably, TTI-621 (SIRPαFc) treatment decreased M2 macrophage, immature dendritic cells, and inhibitory receptors expressed natural killer cells in CTCL patients at the end of the treatment, compared to baseline. RNA-sequencing analysis indicated that these effects were mediated by cell death related pathways such as apoptosis, autophagy, and necroptosis. Collectively, our findings demonstrated that CD47 and PD-L1 are critical regulators of innate and adaptive immune surveillance in CTCL and that dual targeting of CD47 and PD-L1 will provide insight into tumor immunotherapy to improve tumor control in CTCL.

Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions.

No abstract available

Testing of TTI-621 in alternative dosing schedules is in progress. With demonstrated good tolerability and robust single agent antitumor activity in heavily pre-treated patients, additional testing of TTI-621 beyond relapsed/refractory lymphoma has started.

TTI-621 was well tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.