295P Strategies to enhance antigen-specific immune responses and anti-tumour efficacy through combination therapy with mRNA-based neoantigen vaccines in a mouse model of colorectal cancer

Background: High levels of CD163 expressing tumor-associated macrophages (TAM) correlate with poor patient outcome across solid tumors.We have previously shown that CD163+ TAM inhibit anti-tumor T cell responses in preclinical mouse models and recently the T cell inhibitory effect of CD163+ TAM was validated in the clinic as CD163+ TAM was shown to directly inhibit T cell engager mediated anti-tumor T cell activity.Thus, depleting CD163+ TAM to enable increased anti-tumor T cell activity represents a potentially viable therapeutic strategy. Methods:We developed a humanized anti-CD163 depleting antibody, ST101.Its ability to deplete CD163+ macrophages was tested using co-cultures of matched PBMCs and CD163+ human monocyte derived macrophages (CD163+ hMDM).Subsequently, co-cultures of tumor cells, PBMCs and CD163+ TAM were used to analyse the ability of ST101 to relieve CD163+ hMDM mediated suppression of anti-tumor Tcell activity.Lastly, a surrogate anti-mouse CD163 antibody was to evaluate the capacity of antibody mediated depletion of CD163+ TAM to enable increased T cell activity in preclinical mouse tumor models.Results: ST101 efficiently depleted CD163+ hMDM and was associated with NK cell and monocyte activation in PBMC/hMDM co-culture assays.Subsequent phenotypic analysis of non-depleted CD163-negative macrophages revealed inflammatory activation measured by increased expression in CD86.Furthermore, ST101 reversed CD163+ hMDM suppression of T-cell proliferation and T-cell engager responses.In a short-term preclinical mouse tumor model, anti-CD163 treatment, using an antimouse CD163 surrogate molecule, depleted CD163+ TAM, increased the infiltration of iNOS+ TAM and led to an increase in tghe the ratio of activated cytotoxic T cells.Conclusions: ST101 mediates efficient depletion of T-cell suppressive CD163+ macrophages and enables increased anti-tumor T cell activity in clinically relevant in-vitro assays.The antibody mediated depletion of CD163+ macrophages is associated with an increased inflammatory activation of remaining macrophages potentially assisting increased T-cell responses.Collectively these data support the continued development of ST101 in oncology.