(616a) Nature-Inspired 3D Scaffolds to Improve Ex Vivo T-Cell Culturing Environments for Adoptive Cell Transfer Cancer Immunotherapy

There are very few people today who have not been affected by a cancer diagnosis either personally or through a loved one. Cancer can often appear as a growing, undefeatable threat. However, the portfolio of life saving treatments continue to expand with ever increasing success rates. One of the most promising cancer immunotherapy treatments on the market and in research today is the Chimeric Antigen Receptor (CAR) T-cell Adoptive Cell Transfer (ACT). During this treatment, a patient’s own immune-cells (T-cells) are extracted, proliferated, and activated ex vivo, genetically engineered to attack the specific tumor cells and then re-infused back into the patient. One of the main challenges with this treatment are the large number of activated T-cells required to proliferate.¹ Currently, ex vivo T-cell culturing environments are often 2D, which neglect to facilitate the 3D mechanical and physical interactions required for efficient T-cell proliferation and activation.² By applying the Nature Inspired Solution (NIS) methodology developed at the UCL Centre for Nature-Inspired Engineering, various bio-Inspired 3D T-cell culturing scaffolds have been designed.³

Ongoing research addresses two fundamental questions, with the goal to improve the design, efficiency, and scalability of these nature-inspired, 3D T-cell culturing environments. Firstly, how the T-cells migrate, proliferate, and activate on the 3D scaffolds and secondly, why. To answer how, a web-based network of the scaffolds integrates both the geometrical characteristics of the scaffolds (such as porosity, surface area and average Gaussian curvature) and biophysical aspects related to the cells (such as proliferation, and activation rates).⁴ This network is inspired by NK fitness landscapes, which are a method of connecting various similarly designed units based off their differing properties (such as a series of scaffolds with varying porosity and surface area) and then visual demonstrating which of those changing properties play the largest role in achieving a specified “fitness” parameter (such as T-cell proliferation or activation rates). Iteratively comparing with experimental results, this web-based network informs future scaffold designs to improve predictable T-cell growth on the scaffolds. To answer why the T-cells migrate, proliferate, and activate on the 3D scaffolds in the specific manner demonstrated, inspiration from the cell memory capabilities demonstrated in animal regeneration (such as worm-splicing regeneration) will be examined. This along with the new and upcoming field of “cell-conscience” informs potential explanations behind the T-cell’s “motivation” in their movements within the designed culturing environments. With this knowledge we aim to design improved T-cell culturing environments that can be applied within cancer therapy to make CAR-ACT a more affordable and efficient cancer treatment.

(1) Jin, Z.; Li, X.; Zhang, X.; DeSousa, P.; Xu, T.; Wu, A. Engineering the Fate and Function of Human T-Cells via 3D Bioprinting. Biofabrication 2021, 13 (035016). https://doi.org/10.1088/1758-5090/abd56b.

(2) Jensen, C.; Teng, Y. Is It Time to Start Transitioning From 2D to 3D Cell Culture? Frontiers in Molecular Biosciences 2020, 7, 33. https://doi.org/10.3389/FMOLB.2020.00033/BIBTEX.l

(3) Coppens, M.-O. Nature-Inspired Chemical Engineering for Process Intensification. Annu. Rev. Chem. Biomol. Eng. 2021, 12 (1), 187–215. https://doi.org/10.1146/ANNUREV-CHEMBIOENG-060718-030249.

(4) Chin, M. H. W.; Gentleman, E.; Coppens, M. O.; Day, R. M. Rethinking Cancer Immunotherapy by Embracing and Engineering Complexity. Trends Biotechnol. 2020, 38 (10), 1054–1065. https://doi.org/10.1016/j.tibtech.2020.05.003.