MIE-101: Lead immuno-oncology candidate
Not an oncolytic virus
Based on a non-infectious plant virus, (cowpea mosaic virus, CPMV) nanotechnology platform
TLR Tri-agonist that activates the innate immune system through TLRs 2, 4 and 7
Robust anti-tumor responses in preclinical studies across multiple tumor types
Activates neutrophils (tumor killing function, cytokine secretion) and cytotoxic and memory T cells (adaptive immune response)
Downregulates MDSCs and expands tumor-specific T- cells (as indicated by upregulation of MHC II and CD86) – and therefore is distinct from checkpoint inhibitors that are not tumor-specific
Not neutralized by anti-drug antibodies (ADA)
Single agent and combination therapy synergy in multiple preclinical tumor studies
Single agent and combination therapy activity in dogs with naturally occurring tumors
Human immune cell activation is consistent with immune activation in preclinical animal models
Preclinical study results support combination potential with current standard of care including chemotherapy, radiation and checkpoint inhibitors
Immune memory and protection from tumor rechallenge in preclinical studies
Synergistic TLR activation of MIE-101
Our preclinical studies have demonstrated that the activation of multiple TLRs by a single agent provides increased immune stimulation versus targeting individual TLRs. Results of MIE-101 targeting TLRs 2,4 &7 together versus individually include:
More recruited and activated dendritic cells
Stronger inhibition of T-regulatory cells
Bridging of innate and adaptive immunity
Increased T-effector cells
Broad and consistent anti-tumor effects
About toll-like receptors (TLRs)
Discovered in the 1980's, TLRs make up a class of evolutionary conserved pattern recognition receptors found on the surface and the interior of multiple immune cell types. These receptors function as a first line of defense against foreign microbes. Once TLRs on or inside immune cells have recognized a foreign pathogen based on its exterior molecular patterns or interior nucleic acid, innate immune cells become activated, fighting the pathogen and secreting chemicals known to recruit and activate additional cells to support the fight to clear the foreign entity. In recent years, molecules that stimulate TLRs have demonstrated anti-tumor efficacy in multiple cancer models by activating immune cells to better recognize and fight cancer. The intratumoral administration of TLR agonists has become an active area of research and product development in oncology with several treatment candidates showing promise in clinical trials.
About MIE-101: First-in-class TLR tri-agonist
Most TLR activating treatment candidates in development for oncology indications target a single TLR. MIE-101 engages multiple TLRs which has been shown to increase the breadth and potency of the immune response. TLRs are highly conserved across mammalian species, which provides rationale for preclinical data that demonstrate consistent anti-tumor effects when CPMV is used to treat multiple tumor types, whether in established preclinical animal models or in naturally occurring cancers in canine companion animals. Supporting the consistency of TLRs across species, our researchers have observed similar signs of immune activation when CPMV is assessed with human immune cells in vitro.
Activating the Immune System Through Multiple Pathways
Combination of immune activation and blocking tumor-based immune inhibition
The illustration below outlines the breadth of immune activation and anti-tumor responses induced by our lead immuno-oncology candidate, MIE-101, observed in preclinical studies. Upon intratumoral administration, TLRs on the surface and inside of host immune cells are engaged by MIE-101. The cells become alerted to a foreign threat. These cells then recognize tumor antigens as foreign, fighting the tumor while also secreting cytokines and chemokines known to attract and activate additional immune cells. The result is a broad innate and adaptive antitumor immune response.
Immune activation through TLRs 2,4,7
Neutrophil activation (tumor killing function, cytokine secretion) and cytotoxic and memory T cells (adaptive)
Downregulates MDSCs and expands tumor-specific T cells (as indicated by upregulation of MHC II and CD86)
Not cytolytic – and therefore distinct from oncolytic vectors
Distinct from checkpoint inhibitors
CPMV in situ vaccination activates multiple innate immune responses and antitumor T cell responses. CPMV nanoparticles are recognized and taken up by tumor-associated neutrophils and macrophages. The subsequent early inflammation phase (upregulation of IL-12, IL-6 and IFN-γ ) recruits G-MDSCs and MDSCs which may be converted to immunostimulatory myeloid cells. Reduced levels of IL-10 and TGF-β promotes infiltration by N1 and M1 anti-tumor neutrophils and macrophages and supports their immunostimulatory phenotype. The populations of DCs, NK cells, and myeloid cells positive for MHC II/costimulatory molecules are increased by the pro-inflammatory tumor microenvironment. Naive tumor infiltrated T cells can then engage with MHC on those potent APCs presenting tumor antigens. These tumor-specific T cells can activate tumor cell cytotoxicity and further expand to effector memory T cells.
Illustration: Wang, Fiering and Steinmetz: Cowpea Mosaic Virus Promotes Anti-Tumor Activity and Immune Memory in a Mouse Ovarian Tumor Model. Advanced Therapeutics. 2019, 2, 1900003
Turning cold tumors hot
Checkpoint inhibitors as a stand-alone therapy can provide significant life changing benefit for many cancer patients, however the majority of patients have incomplete or even no response to therapy. Why and how patients respond to checkpoint inhibitors appears to be determined by the immunological status of the environment within their cancer. Scientists and clinicians in immunotherapy describe tumors as either immunologically “cold” meaning the immune system in the tumor is suppressed or they are immunologically “hot” indicating that the local tumor immune response is more active and thus can respond more readily to checkpoint inhibitor treatment.
Mosaic IE’s MIE-101 program is based on a CPMV nanoparticle that was carefully selected because of its features that allow it to stimulate a particularly strong immune response when delivered into the tumor. Despite the fact that the nanoparticle is non-infectious, the immune cells inside the tumor immediately sees it as a foreign entity because of its structural characteristics and genetic material. The approximately one trillion nanoparticles delivered with each injection cause the innate immune cells to immediately signal the local immune system into action resulting in what is effectively a call to arms. The activated immune response inside the tumor results in an attack on the nanoparticle but also results in the destruction of tumor cells leading to the release of tumor antigens that trigger a further anti-tumor immune response.
More specifically, MIE-101 converts a “cold” tumor into a “hot” tumor via an intra-tumoral cytokine and chemokine response through activation of Toll- Like Receptors (TLRs) on the resident innate immune cells, inducing activation of tumor-associated macrophages and neutrophils with recruitment of dendritic cells and natural killer cells. In addition, it converts pre-existing immunosuppressive myeloid cells into activated antigen-presenting cells, improving effector and memory T cell responses thereby creating systemic tumor-specific cytotoxic CD8+ T cell activity. The result is conversion of an immunosuppressive tumor microenvironment into an anti-tumor microenvironment with a systemic search and destroy function that attacks not only the local tumor but also other tumor sites through immune surveillance which is referred to as an “abscopal effect”.
In preclinical studies, MIE-101 has been combined with other current standard of care treatments including chemotherapy, radiation and checkpoint inhibitors to further boost the effect of treatment. The studies have validated the potential of combination therapy that can result in complete destruction of the primary tumor, destruction of other tumors via the abscopal effect and even protection against re-challenge with the same tumor type. We expect to advance MIE-101 into human clinical studies in 2022.
Tumor residence time
The molecular weight of our MIE-101 nanoparticle is roughly 5.6 million Daltons. In comparison, small molecule TLR agonists typically have a molecular weight in the hundreds to thousands of Daltons. This difference provides rationale for the long residence time inside tumors observed with MIE-101.
Czapar, Steinmetz et al: Slow-Release Formulation of Cowpea Mosaic Virus for In Situ Vaccine Delivery to Treat Ovarian Cancer. Advanced Science 2018, 5, 1700991
Single agent and combination with anti-PD-1 enhance survival and immune activation in ovarian ID8 model
Single agent anti-tumor effects
aPD-1/MIE-101 combination is curative in the majority of animals
Protective immune memory prevents tumor growth on rechallenge
Immune mediated mechanism
Increased Pro-inflammatory cytokines
MIE-101/antiPD-1 combination significantly increases NK cells
MIE-101/antiPD-1 combination significantly increases CD8+ memory T Cells
* p<0.05 vs PBS * * p<0.01 vs PBS * * * * p<.0001 vs PBS. #### p<0.0001 vs CPMV
Wang and Steinmetz: A Combination of Cowpea Mosaic Virus and Immune Checkpoint Therapy Synergistically Improves Therapeutic Efficacy in Three Tumor Models. Advanced Functional Materials 2020, 2002299
CPMV in combination with cyclophosphamide (CPA) systemically reduces tumor burden and inhibits lung metastasis in breast 4T1 model
Cai et al 2019. Cowpea Mosaic Virus Immunotherapy Combined with Cyclophosphamide Reduces Breast Cancer Tumor Burden and Inhibits Lung Metastasis. Advanced Science 2019, 6, 1802281
CPMV in combination with radiation initiates immune-mediated
tumor regression in ovarian ID8 model
Tumor sections stained for CD4 and CD8 lymphocytes 10 days post treatment
Patel et al 2018. Radiation Therapy Combined with Cowpea Mosaic Virus Nanoparticle in Situ Vaccination Initiates Immune-Mediated Tumor Regression. ACS Omega 2018, 3, 3702−3707
Combination of the viral in situ vaccine with RT may be a particularly powerful strategy because RT debulks tumors, providing a burst of tumor antigens in the context of immunogenic cell death, therefore, synergizing with the CPMV in situ immune stimulation that further augments antitumor immunity.