e15644 Background: All-Trans-Retinoid-Acid (ATRA) is a naturally occurring vitamin A metabolite that participates in many biological processes. Beside its highly potent effect of promoting terminal differentiation of acute promyelocytic leukemia blasts into mature granulocytes, there have been many other studies suggesting its activity on the myeloid derived suppressor cells (MDSCs) and tumor specific CD8+ T cells in animal models as well as using clinical samples. But the use of ATRA as an immune-oncological agent in solid tumor therapy has been limited by the very poor solubility of the compound, its fast metabolism, and very limited exposure achieved after oral administration. Methods: We prepared a new dosage form by encapsulating ATRA inside PEGylated liposomes. The liposomes were shown to accumulate inside solid tumor tissues and deliver more ATRA with longer duration. Results: The effect and dose response of the liposomal ATRA on CT26 murine tumor growth were examined, as well as specific molecular signatures concerning tumor infiltrating myeloid cells. Notably, there was significant higher expression of CD86 and lower expression of PD-L1. These myeloid cells had very low inhibitory effect on ex vivo activated T cells, while on the other hand could promote specific antigen presentation to amplify CD8+ T cells. Furthermore, the liposomal ATRA was also shown to synergize with anti-PD-1 treatment to result in more CD8 T cell distribution in the tumor tissues. Conclusions: These data may suggest an exciting opportunity for targeting MDSCs using liposomal ATRA for combination with T cell based therapeutics in cancer immunotherapy.
T cells are one of the most important effector cells in cancer immunotherapy. Various T cell-dependent bispecific antibody (TDB) drugs that engage T cells for targeted cancer cell lysis are being developed. Here, we describe supra-molecular T-cell redirecting antibody fragment-anchored liposomes (TRAFsomes) and report their immune modulation and anti-cancer effects. We found that TRAFsomes containing different copies of anti-CD3 fragments displayed different T cell modulation profiles, showing that optimization of surface density is needed to define the therapeutic window for potentiating cancer cell-specific immune reactions while minimizing nonspecific side effects. Moreover, small molecular immunomodulators may also be incorporated by liposomal encapsulation to drive CD8 + T cell biased immune responses. In vivo studies using human peripheral blood mononuclear cell reconstituted mouse models showed that TRAFsomes remained bounded to human T cells and persisted for more than 48 hours after injection. However, only TRAFsomes containing a few anti-CD3 (n = 9) demonstrated significant T cell-mediated anti-cancer activities to reverse tumor growth. Those with more anti-CD3s (n = 70) caused tumor growth and depletion of human T cells at the end of treatments. These data suggested that TRAFsomes can be as potent as traditional TDBs and the liposomal structure offers great potential for immunomodulation and improvement of the therapeutic index. Abbreviation : Chimeric antigen receptor T cells (CAR-T cells), Cytokine release syndrome (CRS) Cytotoxic T cell (CTL) Effector: target ratios (E:T ratios), Heavy chain (HC) Immune-related adverse events (irAE), Large unilamellar vesicle (LUV), Peripheral blood mononuclear cells (PBMCs, Single-chain variable fragment (scFv), T cell-dependent bispecific antibody (TDB), T cell redirecting antibody fragment-anchored liposomes (TRAFsomes), Methoxy poly-(ethylene glycol) (mPEG)
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