Tumors responding to immune checkpoint inhibitors (ICIs) have a higher level of immune infiltrates and/or an Interferon (IFN) signature indicative of a T-cell-inflamed phenotype. Melanoma and lung cancer demonstrate high response rates to ICIs and are commonly referred to as “hot tumors”. These are in sharp contrast to tumors with low immune infiltrates called “cold tumors” or non-T-cell-inflamed cancers, such as those from the prostate and pancreas. Classification of tumors based on their immune phenotype can partially explain clinical response to ICIs. However, this model alone cannot fully explain the lack of response among many patients treated with ICIs.Dichotomizing tumors based on their mutation profile into high tumor mutation burden (TMB) or low TMB, such as many childhood malignancies, can also, to some extent, explain the clinical response to immunotherapy. This model mainly focuses on a tumor’s genotype rather than its immune phenotype. High TMB tumors often have higher levels of neoantigens that can be recognized by the immune system. In the current era of immunotherapy, with the lack of definitive biomarkers, we need to evaluate tumors based on both their immune phenotype and genomic mutation profile to determine which patients have a higher likelihood of responding to treatment with ICIs.

Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein a (SIRPa) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPaFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPa axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication.Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPaFc constructs with different Fc tails.Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo, TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcg receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies.Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications.

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