Schliehe, C. | Search bioRxiv

bioRxiv2026

Prime-Target neoantigen vaccination unleashes unprecedented T cell immunity within ''cold'' immunosuppressive tumors

"Cold" immunosuppressive solid tumors are hard-to-treat cancers that are non-responsive to immunotherapies. Their immunosuppressive tumor microenvironment (TME) excludes and inhibits T cells and thereby hampers the therapeutic efficacy of cancer vaccines and immune checkpoint blockade. To overcome this, we employed a "Prime-Target" (P/T) neoantigen vaccination strategy that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations to first prime potent systemic neoantigen-specific T cell immunity and then trigger intratumoral T cell recruitment. Using immunotherapy non-responsive murine tumor models with pronounced immunosuppressive TMEs, we demonstrate that P/T neopeptide vaccination resulted in extraordinary tumor control and TME remodeling. P/T vaccination elicited strong systemic anti-tumor responses as well as potent and rapid recruitment of clonal CD4+ Th1 and non-exhausted CD8+ T cells into tumors that carried novel T cell receptors (TCR) and were vaccine neopeptide-specific. Concurrently, P/T vaccination reshaped the TME by decreasing suppressive Treg and M2 macrophages, and dramatically increasing the ratio of effector T cells to Treg and M2 macrophages. Vaccination-induced tumor control was neopeptide-dependent and required concurrent IT administration of both neopeptides and adjuvants. Our study highlights P/T neoantigen vaccination as a promising strategy to overcome T cell exclusion within "cold" immunosuppressive solid tumors and thereby unleash unprecedented anti-tumor immunity.

immunology↗

bioRxiv2025

Adoptive cell therapy using T cell receptors equipped with ICOS yields durable anti-tumor response

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses including delay of tumor recurrence and cures in a mouse tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NF{kappa}B pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy. HighlightsNewly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3{varepsilon} intracellular domains (in short TCR:ICOS) provides:[tpltrtarr] durable anti-tumor response and T cell persistence in mouse model [tpltrtarr]inflammatory T cell phenotype and resistance to T cell exhaustion [tpltrtarr]effects via PI3K and NF{kappa}B activation [tpltrtarr]translation to human T cells upon single amino acid mutation in TCR:ICOS tail [tpltrtarr]extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/682056v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1ff752borg.highwire.dtl.DTLVardef@6579d9org.highwire.dtl.DTLVardef@22bdc4org.highwire.dtl.DTLVardef@d8c445_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗