Phase II year
2023
(last award dollars: 2024)
Phase II Amount
$2,046,919
Despite the success of immune checkpoint inhibitors for some types of cancer, the overall response rate remains suboptimal. The majority of solid tumors exclude T-cells (termed "cold"), thus presenting a key limiting factor for cancer immunotherapy. Activation of the cGAS-STING pathway has been demonstrated to induce anti-tumor immune responses with impressive efficacy in preclinical studies. However, clinical stage STING agonists, based on cyclic dinucleotides (CDNs), suffer from major limitations, including: 1) Administration via intratumoral injection. STING agonists administered intratumorally are cleared rapidly, and intratumoral injection reduces their utility against metastatic cancer. 2) Conventional STING agonists do not readily cross the cell membrane, failing to maximize activation of STING located within the cytosol. 3) Cell penetration of conventional STING agonists is not biased to the dendritic cells and macrophages which is the cell type needed to drive an anti-tumor immune response. 4) Conventional STING agonists do not work across the human population due to variations in STING haplotypes. Indeed, in recent phase I clinical trials, STING agonists given intratumorally exhibited only marginal efficacy. Hence, a potent platform for systemic delivery of STING agonists is urgently needed to improve patient outcomes. Saros Therapeutics is developing a novel nanotechnology (referred to as SNP) that addresses each of these limitations by: 1) Incorporating manganese along with CDA, a CDN-based STING agonist, in the nano- formulation. We have shown that Mn augments the activation of STING by CDA, lowering the dose necessary to achieve a significant biologic (Type I IFN expression) and therapeutic (tumor growth/survival) benefit. 2) Incorporating the Mn-CDA complex in a nanoparticle protects the CDA from degradation, extending half-life and facilitating uptake by myeloid cells (DC, macrophages) that drives a Type I IFN response by the immune cells in the TME. The combination of Mn+CDA incorporated into a nanoparticle formulation also improves the safety profile of this therapy and allows administration by IV, ensuring systemic exposure and improved responses in settings of multiple tumors and metastasis. Based on our compelling data, we will examine the potency of SNP preparations in human patient biopsy samples. We will assess pharmacokinetic and tissue retention characteristics of SNP in both mice and non-human primates and benchmark against other STING agonists. We will develop microfluidic methods for large scale production of SNP in anticipation of transfer to a contract development and manufacturing organization (CDMO). Results from these studies will accelerate the development of our novel nanotechnology with the aim of quickly bringing immunotherapy's benefits to more patients with cancer.
Public Health Relevance Statement: Narrative: The proposed research is most relevant to public health as these studies will generate new fundamental knowledge in the development of a novel cancer immunotherapy and will advance one promising new therapy in preparation for clinical trials. The SNP nanoparticle formulation will improve the transformation of "cold" into "hot" tumors by prolonging stimulation of the STING pathway leading to a robust immune response in the tumor microenvironment. This approach may be efficacious as a monotherapy in some cancers and will also augment the activity of other immunotherapies, particularly immune checkpoint inhibitors. Terms:
