Cancer immunotherapy has revolutionized todays treatments for many forms of cancers. In particular, blocking antibodies to immune checkpoint proteins, such as programmed cell death-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1), effectively unleash immune cell destruction of cancerous cells. However, the high cost of these antibody-based immunotherapies, their intensive therapeutic regimen and availability only at specialized medical centers make current immunotherapies impractical in all but the most advantaged societies. We hypothesize that an effective vaccine which can overcome these significant shortcomings of antibody-based immunotherapies while simultaneously mimicking their potent therapeutic benefits can impact the lives of countless more patients: in particular, a vaccine that induces durable levels of host antibodies against the tumor-associated PD-L1 protein will have powerful anti-tumor effects by inhibiting the PD-L1:PD1 immunosuppressive checkpoint interaction. We, at VLP Therapeutics, have developed a proprietary, plug-and-play vaccine platform called inserted alphavirus virus-like particle (i-?VLP) using the Chikungunya (CHIK) VLP. VLPs mimic the conformation of native viruses without the viral genome, thus capable of stimulating a robust host response absent safety issues. Foreign antigens can be inserted into the surface loop domains of i-?VLP. Due to its unique structure, i-?VLP can efficiently present a dense array of 240 copies of the inserted antigen on the particle surface. i-?VLP induces highly effective immune responses to the inserted antigen, and CHIK VLPs have shown acceptable safety profiles in a Phase I clinical trial. We propose to establish proof of concept of our PD-L1-targeting vaccines efficacy in a triple negative breast cancer (TNBC)-like model given that (1) TNBCs have shown some responsiveness to PD-L1/PD-1 antibody therapies in clinical trials; and (2) there remains a high unmet need for effective therapies against this particularly aggressive form of breast cancer which has the worst five- year survival prognosis among all breast cancers and for which standard chemotherapy treatment is largely ineffective. The goal of this proposal is to determine the extent to which vaccination with our proprietary i-?VLP-based PD-L1 vaccine (PD-L1- ?VLP) can mimic the effects of passive PD-L1 monoclonal antibody therapy. This study will provide the basis for advancing this exciting approach into clinical trials. To create this vaccine, we propose the following Specific Aims: Aim 1: Determine the ability of PD-L1-?VLP to stimulate the production of antibodies that bind to tumor- associated PD-L1 and inhibit its binding to the T-cell immune checkpoint receptor, PD-1, in murine models. Aim 2. Determine the therapeutic effects of PD-L1-?VLP vaccination in a PD-1/PD-L1 antibody therapy-sensitive murine tumor model benchmarked against PD-L1 monoclonal antibody treatment. Aim 3: Determine whether potential immune-related adverse events including autoimmunity can be induced by our PD-L1-?VLP vaccine.
Public Health Relevance Statement: Narrative Cancer immunotherapy, in particular, blocking antibodies to immune checkpoint proteins, effectively unleash immune cell destruction of cancerous cells. However, their high cost, intensive therapeutic regimen and limited availability only at sophisticated medical centers make current antibody-based immunotherapies impractical in all but privileged societies. An effective vaccine directed against the tumor-associated PD-L1 protein which mimics the therapeutic benefits of antibody-based PD-L1 immunotherapy, while overcoming its significant shortcomings described above will have powerful anti-tumor effects and answer unmet medical needs for countless more patients in the US and worldwide.
Project Terms: Adverse effects; Adverse event; Alphavirus; aluminum sulfate; Antibodies; Antibody Formation; Antibody Therapy; Antigens; antitumor effect; Apoptosis; Autoimmunity; B-Lymphocyte Epitopes; base; Benchmarking; Binding; Blocking Antibodies; Blood; cancer immunotherapy; cancer subtypes; Cancer Vaccines; Cancerous; CD4 Positive T Lymphocytes; Cells; Checkpoint therapy; chemotherapy; chikungunya; Clinical Trials; cost; cost shifting; cytokine; Development; effective therapy; Future; Goals; Histologic; Immune; Immune Checkpoint; Immune response; Immunosuppressive Agents; Immunotherapy; Incubated; Injectable; Injection of therapeutic agent; innovation; insight; Intramuscular; intraperitoneal; Ligands; malignant breast neoplasm; Malignant neoplasm of lung; Malignant Neoplasms; Measures; Medical; Medical center; melanoma; Memory B-Lymphocyte; Modality; Modeling; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody Therapy; mouse model; Mus; nonhuman primate; novel; novel virus; outcome forecast; particle; Patients; Pharmacodynamics; phase 1 study; phase 2 study; Phase I Clinical Trials; Play; Production; Proteins; receptor; Regimen; response; Route; Safety; Societies; Spleen; Staining method; Stains; Structure; success; Surface; Survival Rate; T-Lymphocyte; Therapeutic; Therapeutic Effect; Tissues; Toxicology; triple-negative invasive breast carcinoma; tumor; tumor growth; Vaccinated; Vaccination; vaccination schedule; vaccine efficacy; Vaccines; Viral Genome; virtual; Virus; Virus-like particle
