Abstract 1321: CarboCell provides new opportunities for image-guided high-precision intratumoral combinatorial immunotherapy
Authors: Jensen Sophie B. , Chavez Elizabeth S. , Haldórsdóttir Hólmfridur R. , Melander Fredrik , Scheeper Marouschka J. , Bruun Linda M. , Henriksen Jonas R. , Hansen Anders Elias , Andresen Thomas L. 
Published: July 2021

Abstract
Intratumoral immune activating therapy is biologically supported by the cancer immune response being generated in the tumor microenvironment (TME) and draining lymph nodes. Successful intratumoral immune activation is however challenging as the cells in the TME are plastic and reactive, and therefore requires continuous stimulation. This is problematic as drugs are rapidly washed out of tumors, and frequent intratumoral injections limit manageable locations, patient compliance and provides risks for cancer cell dissemination. The CarboCell technology overcomes this by forming a positionally stable drug release depot at the injection site with tailored release profiles of single or multiple drugs. Here we demonstrate the therapeutic performance of a CarboCell formulation releasing a TLR7/8 agonist and a TGFb inhibitor (CarboCell TLR:TGFb). CarboCell provides intratumoral drug retention up to 90% at day 3 and 50% at day 7 after injection in mouse tumors and beyond 14 days in canines. By control of the release kinetics, more than five times the systemically tolerated drug dose was tolerated for intratumoral CarboCell TLR:TGFb even at repeated dosing. CarboCell TLR:TGFb combinatorial therapy provided complete tumor rejection in 71%, 67% and 89% of mice carrying large MC38, EMT-6 and CT26 tumors. The dual drug CarboCell TLR:TGFb formulation was therapeutically superior to single drug CarboCell formulations, which underlines the synergistic value the combinatorial therapy. CarboCell TLR:TGFb was further demonstrated to inhibit lung metastasis in highly metastatic cancer models. Mechanistically, CarboCell TLR:TGFb activated the innate and adaptive immune system. Inflammatory cytokines were rapidly induced and accompanied by cancer cells necroptosis. This was followed by an increased number and activation of central DCs in the tumor draining lymph node and anti-cancer specific T cells in the tumor. CarboCell TLR:TGFb demonstrate potent immune activating properties and overcomes the multifactorial immunosuppressive barriers in the TME. Clinically attractive features of CarboCell further includes intrinsic MR and US visibility and radiographic contrast. This, in combination with full compatibility with high precision thin needle injection technologies, makes image guided injection, therapeutic planning, interpretation and validation of clinical performance possible. Combined, the unprecedented drug release and imaging properties of CarboCell makes the technology highly attractive for clinical advancement.
Citation Format: Sophie B. Jensen, Elizabeth S. Chavez, Hólmfridur R. Haldórsdóttir, Fredrik Melander, Marouschka J. Scheeper, Linda M. Bruun, Jonas R. Henriksen, Anders Elias Hansen, Thomas L. Andresen. CarboCell provides new opportunities for image-guided high-precision intratumoral combinatorial immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1321.