TriSalus’ proprietary Pressure-Enabled Drug Delivery™ (PEDD™) approach with SmartValve™ technology powers its TriSalus Infusion Systems, which deliver therapeutics to liver metastases and pancreatic solid tumors through interventional arterial and venous outpatient procedures.

In small prospective and retrospective clinical studies, the proprietary PEDD approach with SmartValve technology delivered more therapy into the vasculature of liver metastases and pancreatic solid tumors while decreasing exposure to normal tissue.^1,2*† In retrospective clinical evaluations, PEDD with SmartValve technology demonstrated the potential to achieve improved tumor response.^1,3*‡

Study Designs:

*Titano et al: A small, retrospective, single-center study included 88 treatment-naive patients with solitary HCC tumors <6.5 cm who underwent treatment utilizing either SIS (n = 18) or standard EH microcatheters (n = 70). Twenty-three patients (5 SIS, 18 EH) received a liver transplant during the study, with 1 SIS and 6 EH patients excluded from the tumor necrosis analysis for receiving subsequent therapies prior to transplant. A pathologist performed a blinded review of the liver explant specimens to assess tumor necrosis and treatment distribution. Pathological analysis of explanted livers showed greater concentrations of microspheres within the tumor relative to the surrounding tissue in SIS explants (88.7 ± 10.6%) versus the EH explants (55.3 ± 32.7%) (p = 0.002).

†Pasciak et al: A small, prospective study including 9 patients with unresectable liver cancer who were enrolled for the treatment of HCC (n = 6), liver-dominant metastatic disease (n = 2), or intrahepatic cholangiocarcinoma (n = 1). Each patient was treated via SIS or standard EH microcatheter. Decreases in hepatic nontarget embolization were found in all patients when SIS was used (mean 42%; σ = 19%), representing a 24%–89% reduction. Increased tumor deposition was also noted in all patients (mean 68%; σ = 20%), representing a relative increase of 33%–90%. Both findings were statistically significant (P <0.05).

‡Kim et al: Retrospective study of 22 patients with 39 HCC lesions who received treatment via SIS with SmartValve™ technology. Tumor response assessment was made according to mRECIST criteria.

Proprietary PEDD™ Approach with SmartValve™ Technology

With PEDD

In a small, retrospective clinical study, the PEDD approach demonstrated increased therapeutic uptake in the tumor.^1*

For illustrative purposes

Barriers of the Tumor Microenvironment

Achieving better response depends, in part, on overcoming the unique challenges of the TME. Current delivery methods can be impacted by TME infusion barriers.^5,6

SOLID STRESS

Solid stress compresses the already compromised blood and lymph vessels, limiting drug delivery within the tumor mass⁶ and leading to a lack of therapeutic uptake.

PEDD with SmartValve Technology

PEDD^TM modulates pressure during infusion.⁷ This has been shown to overcome the infusion barriers of the tumor microenvironment and improve therapy penetration.¹

PEDD™ ALLOWS THERAPY TO BE INFUSED AT A HIGHER PRESSURE

THAN THE BASELINE MEAN ARTERIAL PRESSURE

Study Designs:

*Titano et al: A small, retrospective, single-center study included 88 treatment-naive patients with solitary HCC tumors <6.5 cm who underwent treatment utilizing either SIS (n = 18) or standard EH microcatheters (n = 70). Twenty-three patients (5 SIS, 18 EH) received a liver transplant during the study, with 1 SIS and 6 EH patients excluded from the tumor necrosis analysis for receiving subsequent therapies prior to transplant. A pathologist performed a blinded review of the liver explant specimens to assess tumor necrosis and treatment distribution. Pathological analysis of explanted livers showed greater concentrations of microspheres within the tumor relative to the surrounding tissue in SIS explants (88.7 ± 10.6%) versus the EH explants (55.3 ± 32.7%) (p = 0.002

†Pasciak et al: A small, prospective study including 9 patients with unresectable liver cancer who were enrolled for the treatment of HCC (n = 6), liver-dominant metastatic disease (n = 2), or intrahepatic cholangiocarcinoma (n = 1). Each patient was treated via SIS or standard EH microcatheter. Decreases in hepatic nontarget embolization were found in all patients when SIS was used (mean 42%; σ = 19%), representing a 24%–89% reduction. Increased tumor deposition was also noted in all patients (mean 68%; σ = 20%), representing a relative increase of 33%–90%. Both findings were statistically significant (P <0.05).

^§Data on file (CEA 001 trial). TriSalus™ Life Sciences, 2019.* Study design: Single patient infusion. Pressure continuously monitored during initial positioning at target site, deployment of the PEDD™ device, and infusion of 3 cc saline bolus.

PEDD Demonstrated Significant Targeted Distribution^2†

This small, prospective study evaluated differences in hepatic distribution of embolic particles following infusion with a standard end-hole catheter versus PEDD. The procedure was performed on each patient on the same day, the same tumor, and in the same catheter location.

Study Design:

†Pasciak et al: A small, prospective study including 9 patients with unresectable liver cancer who were enrolled for the treatment of HCC (n = 6), liver-dominant metastatic disease (n = 2), or intrahepatic cholangiocarcinoma (n = 1). Each patient was treated via SIS or standard EH microcatheter. Decreases in hepatic nontarget embolization were found in all patients when SIS was used (mean 42%; σ = 19%), representing a 24%–89% reduction. Increased tumor deposition was also noted in all patients (mean 68%; σ = 20%), representing a relative increase of 33%–90%. Both findings were statistically significant (P <0.05).

PEDD Significantly Improved Response¹*

In this small, retrospective study of patients with solitary hepatocellular carcinoma (HCC), drug-eluting microspheres transarterial chemoembolization (DEM-TACE) procedures with PEDD were associated with improved tumor response.

PATHOLOGICAL RESPONSE

% tumor necrosis after 1 treatment

P = 0.026

Study Design:

*Titano et al: A small, retrospective, single-center study included 88 treatment-naive patients with solitary HCC tumors <6.5 cm who underwent treatment utilizing either SIS (n = 18) or standard EH microcatheters (n = 70). Twenty-three patients (5 SIS, 18 EH) received a liver transplant during the study, with 1 SIS and 6 EH patients excluded from the tumor necrosis analysis for receiving subsequent therapies prior to transplant. A pathologist performed a blinded review of the liver explant specimens to assess tumor necrosis and treatment distribution. Pathological analysis of explanted livers showed greater concentrations of microspheres within the tumor relative to the surrounding tissue in SIS explants (88.7 ± 10.6%) versus the EH explants (55.3 ± 32.7%) (p = 0.002).

Proof of Concept – Hepatic Artery Infusion (HAI) of Investigational CAR-T using PEDD^{10 |}

This small study demonstrated that hepatic artery infusion of an investigational CAR-T using PEDD technology resulted in increased delivery of CAR-T to the tumor and showed encouraging activity against CEA+ liver metastases.

CAR-T EFFECTIVELY TRAFFIC TO CEA+ TUMOR CELLS

Key Outcomes

Study Design:

^│Katz et al: This small, investigational study was an exploratory Phase 1b clinical trial using biopsy to assess CAR-T activity of a second generation (IgCD28TCR) anti-CEA CAR-T (Sorrento Therapeutics) administered using HAI via PEDD in five patients with stage IV, chemotherapy resistant, CEA+ adenocarcinoma liver metastases (LM). Patients received 3 HAI of 10^10 anti-CEA CAR cells and low dose IL-2 (50,000 IU/kg/day). The endpoints included safety and response (tumor marker kinetics and mRECIST/irRC), and tumor and liver CAR-T activity post-treatment. Compared to previous HITM CAR-T HAI trials with a standard catheter, PEDD significantly increased the frequency of CAR-T by 5.2-fold within LM, as detected by quantitative PCR (p=0.03). All patients showed decrease in CEA post-treatment with mean CEA decrease of 15ng/ml (3-39 ng/ml). No Grade (G) 4 or 5 Adverse Events related to CAR-T HAIs via PEDD were detected. G1/2/3 events were largely attributed to IL-2 infusion. (NCT02850536)

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Study Designs:

*Titano et al: A small, retrospective, single-center study included 88 treatment-naive patients with solitary HCC tumors <6.5 cm who underwent treatment utilizing either SIS (n = 18) or standard EH microcatheters (n = 70). Twenty-three patients (5 SIS, 18 EH) received a liver transplant during the study, with 1 SIS and 6 EH patients excluded from the tumor necrosis analysis for receiving subsequent therapies prior to transplant. A pathologist performed a blinded review of the liver explant specimens to assess tumor necrosis and treatment distribution. Pathological analysis of explanted livers showed greater concentrations of microspheres within the tumor relative to the surrounding tissue in SIS explants (88.7 ± 10.6%) versus the EH explants (55.3 ± 32.7%) (p = 0.002).

†Pasciak et al: A small, prospective study including 9 patients with unresectable liver cancer who were enrolled for the treatment of HCC (n = 6), liver-dominant metastatic disease (n = 2), or intrahepatic cholangiocarcinoma (n = 1). Each patient was treated via SIS or standard EH microcatheter. Decreases in hepatic nontarget embolization were found in all patients when SIS was used (mean 42%; σ = 19%), representing a 24%–89% reduction. Increased tumor deposition was also noted in all patients (mean 68%; σ = 20%), representing a relative increase of 33%–90%. Both findings were statistically significant (P <0.05).

‡Kim et al: Retrospective study of 22 patients with 39 HCC lesions who received treatment via SIS with SmartValve™ technology. Tumor response assessment was made according to mRECIST criteria.

§Data on file (CEA 001 trial). TriSalus™ Life Sciences, 2019.* Study design: Single patient infusion. Pressure continuously monitored during initial positioning at target site, deployment of the PEDD™ device, and infusion of 3 cc saline bolus.

^│Katz et al: This small, investigational study was an exploratory Phase 1b clinical trial using biopsy to assess CAR-T activity of a second generation (IgCD28TCR) anti-CEA CAR-T (Sorrento Therapeutics) administered using HAI via PEDD in five patients with stage IV, chemotherapy resistant, CEA+ adenocarcinoma liver metastases (LM). Patients received 3 HAI of 10^10 anti-CEA CAR cells and low dose IL-2 (50,000 IU/kg/day). The endpoints included safety and response (tumor marker kinetics and mRECIST/irRC), and tumor and liver CAR-T activity post-treatment. Compared to previous HITM CAR-T HAI trials with a standard catheter, PEDD significantly increased the frequency of CAR-T by 5.2-fold within LM, as detected by quantitative PCR (p=0.03). All patients showed decrease in CEA post-treatment with mean CEA decrease of 15ng/ml (3-39 ng/ml). No Grade (G) 4 or 5 Adverse Events related to CAR-T HAIs via PEDD were detected. G1/2/3 events were largely attributed to IL-2 infusion. (NCT02850536).

References:

1. Titano, J.J., et al. Cardiovasc Intervent Radiol. 2019;42:560-568.
2. Pasciak, A.S., et al. J Vasc Interv Radiol. 2015;26:660-669.
3. Kim, A.Y., et al. PloS One. 2017;12(9):e0183861.
4. Jain, R.K., et al.  Nat Rev Clin Oncol. 2010;7(11):653-664.
5. Sheth, R.A., et al. J Vasc Interv Radiol. 2013;24:1201-1207.
6. Jain, R.K., Sci Am. 2014;310:46-53.
7. Data on file (CEA 001 trial). TriSalus™ Life Sciences, 2019. *Study design: Single patient infusion. Pressure continuously monitored during initial positioning at target site, deployment of the PEDD™ device, and infusion of 3 cc saline bolus.
8. Data on file (510K). TriSalus™ Life Sciences, 2019.
9. Clark, T.W.I., Semin Intervent Radiol. 2006;23:119–125.
10. Katz, S.C., et al. HITM-SURE: Phase Ib CAR-T hepatic artery infusion trial for stage IV adenocarcinoma using Pressure-Enabled Drug Delivery technology. Society of Immunotherapy for Cancer (SITC). 2018; Washington, D.C.