Poster S18 - Enhancing Cancer Vaccine Efficacy Through T Memory Stem Cell Induction

Introduction: Despite significant advancements in cancer immunotherapy, solid tumors remain a major cause of cancer-related deaths, outpacing hematopoietic cancers. CAR-T cell therapies, although revolutionary for hematopoietic cancers, have yet to achieve similar success in solid tumors due to challenges such as insufficient activation and effector T cell exhaustion. This study introduces a novel biomaterial-based platform designed to enhance dendritic cell (DC) and T cell function, promoting the formation of T memory stem cells (TMSCs) for long-term immunity. We fabricated a series of PLGA-based nano- and microparticles encapsulating a GSK-3β inhibitor to promote TMSC formation. These particles are also designed to deliver CpG adjuvant and cancer antigens or tumor lysates in a sustained manner, boosting the in-situ formation of antigen-specific TMSCs. Such induction by these cancer vaccine candidates can provide long-term immunity against solid tumors, including melanoma and breast cancer, as tested here. Results demonstrate that our approach successfully modulated the long-term anti-cancer immune response.

Materials and

Methods: Following fabrication of nano-/and microparticles in size range of 200 nm to 50 um. We analyzed the loading efficiency and release profiles, followed by in vitro studies on primary murine and human T cells to optimize the platform. Using melanoma tumor lysates obtained from immunocompetent C57BL/6J mice, we fabricated cancer vaccine candidates. These were co-injected into young (8 weeks-old) and aged (>15 months-old) mice. We examined the formation of TMSCs over 12 weeks, comparing the presence and absence of the booster, and assessed tumor growth suppression. In a murine model of melanoma post-tumor resection, we tested the cancer vaccine's protective effects against recurrence by re-challenging rescued mice. We investigated long-term protection and the prevention of tumor recurrence.

Results, Conclusions, and Discussions: Our results demonstrate that the developed particles effectively promote efficient T cell expansion in vitro. In vivo studies confirmed successful induction of TMSCs, leading to prolonged immune memory and enhanced protection against tumor recurrence. Specifically, we observed significant suppression of tumor growth and prevention of recurrence in both young and aged mice, with a more pronounced effect in the latter group. Our biomaterial-based approach represents a significant advancement in cancer immunotherapy by addressing the limitations of current T cell therapies and enhancing long-term immunity through TMSC formation. This platform offers a promising solution for improving treatment outcomes, by providing sustained delivery of activation signals and promoting localized immune responses. The results of our research validate the potential of this approach to prevent cancer recurrence and improve patient survival. Further clinical studies are warranted to translate these findings into effective human therapies, with the goal of providing a robust, long-term defense against solid tumors.

Acknowledgements (Optional): California Institute for Regenerative Medicine (CIRM) DISC2-14169.