Bioinspired virus-like nanovaccines boost CAR T and endogenous T cells in tandem against solid tumors with antigen heterogeneity

/Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) T cells targeting a single tumor-specific surface antigen has demonstrated remarkable long-term efficacy in certain hematological malignancies. This success led to its approval by the FDA for the treatment of multiple hematological cancers. However, the clinical outcomes of CAR T therapy in solid tumors have been largely disappointing. A key obstacle is the pre-existing antigen heterogeneity in solid tumors, which often results in antigen-negative tumor escape, because not all tumor cells express the antigen targeted by the CAR. Pre-clinical and clinical studies have shown that polyclonal T-cell responses against different tumor antigens, or even the same antigen, could lead to superior tumor control in the long term. We recently published that vaccine boosting of CAR T cells stimulated CAR T cell expansion with enhanced functionality and unexpectedly triggered antigen spreading, resulting in more effective treatment of tumors with antigen heterogeneity in an animal model. More specifically, this was achieved by using a lymph- node targeting lipid polymer to deliver the natural ligand recognized by the CAR to antigen-presenting cells (APCs). However, the kinetics and magnitude of antigen spreading may not be sufficient for treating tumors with a high proportion of tumor cells missing the CAR antigen. Building on these findings, we will develop an autologous tumor cell membrane-coated dual CAR and endogenous T cell boosting virus-like nanoparticle vaccine (dtVLP-vax) to overcome this barrier. The dtVLP-vax particles retain on their surfaces a collection of tumor-associated antigens (TAAs), including the antigen recognized by the CAR and peptide-major histocompatibility complexes (pMHCs) recognized by T cell receptors (TCRs). These antigens will be transferred onto the APCs upon arrival in the LN, allowing natural APCs to boost both adoptively transferred tumor-targeting CAR T cells and endogenous tumor-specific T cells, generating a polyclonal anti-tumor T cell response. The unbiased presentation of all TAAs, especially pMHCs, by dtVLP-vax also eliminates the need for tumor sequencing and neoantigen identification, which is often costly and time-consuming. We hypothesize that dtVLP-vax can efficiently support CAR T therapy and amplify endogenous T cells to rapidly diversify and broaden the anti-tumor T cell immunity, thereby facilitating a more effective control of solid tumors with antigen heterogeneity. Using multiple solid tumor models, we aim to (1) Characterize the biology and mechanisms of dtVLP-vax for stimulating CAR T and endogenous T cells in vivo. (2) Assess the versatility of the dtVLP-vax platform for reprogramming T cells. (3) Evaluate the capacity of dtVLP-vax to boost both CAR T cells and endogenous T cells with enhanced diversity and functionality against solid tumors displaying antigen heterogeneity. (4) Assess the human tumor-derived dtVLP-vax. These studies will establish key principles of dtVLP-vax designs to maximize the potential of adoptive cell therapy for solid tumors. Project Number: 1R01CA300077-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Leyuan Ma | Institution: CHILDREN'S HOSP OF PHILADELPHIA, PHILADELPHIA, PA | Award Amount: $737,082 | Activity Code: R01 | Study Section: Cellular Immunotherapy of Cancer Study Section[CIC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367505