Introduction
Pancreatic ductal adenocarcinoma (PDAC) is characterized by very poor 5-year survival of only 8-12% due to a late diagnosis and a highly desmoplastic environment, limiting therapeutic options [1]. Current treatment options for PDAC patients are mostly restricted to chemotherapy followed by surgery or palliative care [2]. These treatments have limited efficacy and are accompanied by severe side effects, strongly affecting the quality of life of these patients. Recent advances in nanotechnology have optimized targeted drug delivery in tumors with high stromal density by improving intratumoral drug retention, enhancing local drug concentrations, and thereby boosting treatment efficacy and potentially reducing side effects [3-6]. This would enable an efficient endoscopic delivery of a local depot of concentrated chemotherapy.
Aims & Methods
Here we investigated the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell (CG), loaded with gemcitabine in preclinical human and mouse PDAC models. To evaluate the efficacy of CG, in vitro experiments using patient-derived organoids and PDAC explants were performed. This was further explored in vivo by using a human patient-derived xenograft (PDX) and the syngeneic KPC3 mouse model. Two intratumoral injections with saline, CG and gemcitabine-loaded CG (CG-Gem) were performed in both PDX and KPC3 models and compared to systemic gemcitabine administration. To evaluate potential off-target effect, other vital organs and haematological toxicity related to gemcitabine were evaluated.
Results
Both CG and CG-Gem were safe and well-tolerated in vivo. Upon CG-Gem, both in vitro and in vivo models showed strongly increased cytotoxicity compared to unloaded CG and control groups. Remarkably, we were able to inject a much higher dose (~125x) intratumorally compared to systemic gemcitabine dose. By increasing gemcitabine cytotoxicity, locally treated mice showed a significant improved survival. In a human PDX model, complete survival of mice (100%) was observed compared to control groups in which all reached humane endpoint. Given the enhanced treatment efficacy, we are currently investigating the role of the tumor microenvironment, particularly looking at stromal and immune cell dynamics. Interestingly, preliminary data shows that CG-Gem depots are surrounded and/or infiltrated with fibroblasts, macrophages, and other immune cells. To reveal the mechanism behind, further experiments looking at the different cell subtypes are undergoing.
Conclusion
Our findings represent a potential strategy for integrating localized (endoscopic) and systemic treatment modalities, addressing critical challenges in hard-to-treat PDAC management, and improving patient prognosis through more effective and targeted therapeutic strategies.
References
1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.
2. Conroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O’Reilly EM, et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023/11/01;34(11).
3. Ramazani F, Nostrum CFv, Storm G, Kiessling F, Lammers T, Hennink WE, et al. Locoregional cancer therapy using polymer-based drug depots. Drug Discovery Today. 2016/04/01;21(4).
4. Luo W, Zhang T. The new era of pancreatic cancer treatment: Application of nanotechnology breaking through bottlenecks. Cancer Letters. 2024/07/10;594.
5. Jiang Z, Fu Y, Shen H. Development of Intratumoral Drug Delivery Based Strategies for Antitumor Therapy. Drug Design, Development and Therapy. 2024 Dec 31:2189-202.
6. Rossi SM, Ryan BK, Kelly HM. Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer. British Journal of Cancer 2020 123:3. 2020-05-27;123(3).
Disclosure
Helena Kelly is a named inventor on granted patent US20230126053 ‘Thermo-responsive hydrogel for intratumoral administration as a treatment in solid tumor cancers’ and is also co-founder and CSO of OncoLize LLC. Mike de Leeuw is co-founder and CEO of OncoLize LLC. Tushar Tomar is drug development director of OncoLize LLC. This work was supported by a research grant from OncoLize to LH.