Personalized Cancer Immunotherapy

Targets Tumor Neoantigens.

About: Therapeutic Need

Cancer is caused by a variety of defects that occur in nucleotides and genes that encode proteins, causing disruption of the machinery involved in cell growth. It is the progressive growth of tumors, along with anaplasia (loss of structural definition of cells), invasiveness, and metastasis, which characterize malignant diseases. Various approaches are used to eliminate or control cancer, including surgical excision of solid tumors, radiation therapy, chemotherapy, monoclonal antibody therapy, and more recently cell-based therapeutic vaccines. Each approach seeks to reduce or eliminate the burden of disease. Prevention of disease progression is the minimum desirable outcome and inhibition of tumor recurrence is the ultimate goal. Success with current therapies is highly variable from patient to patient and the ‘cure for cancer’ is still an undiscovered holy grail; novel treatment paradigms are needed to further the quest. Read more...

A rapidly growing field of cancer research is immunotherapy – harnessing of the body’s own immune system to seek out and kill cancer cells. Immunotherapies will likely become the treatment backbone in up to 60% of cancers over the next 10 years, compared to less than 3% today, with a market potential of around US$35 billion per annum. Read more...

The problem with cancer cells is that they cloak themselves in a manner that prevents their recognition by the immune system. Therapeutic cancer vaccines are a type of immunotherapy that involves programming the patient’s own immune cells, firstly to recognize and destroy tumor cells, and secondly to control tumor relapse by inducing immunological memory. Read more...

A further problem with mounting an immunological response is that cancer cells within primary tumors and metastatic tumors rapidly mutate, and the new genetic and protein markers (neoantigens) further elude immune surveillance. Importantly, however, tumor cells “bud off” small portions of cellular contents packaged in their cell membrane, called “exosomes.” These can be isolated from the blood of individual patients, and are essentially “liquid biopsies” that have the full neoantigen repertoire of their malignant origin. Certain other strategies to capture the neoantigens from cancer patients are flawed in that they rely on tissue biopsies to create therapies. These tissue biopsies represent only a small snapshot of the cancer, and are difficult (and sometimes impossible) to obtain. Furthermore, the use of biopsies to generate personalized immunotherapies relies on expensive and time-consuming gene sequencing, neoepitope construct production, and imperfect algorithms to select which antigens are relevant. Exosomes, by contrast, contain all the protein and genetic neoantigen fingerprints from primary and metastatic tumors in a package that may stimulate a more comprehensive immune response than tissue biopsy material. Read more...

About: DIAGNOSTIC NEED

Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell-mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell transfer (ACT) using expanded tumor infiltrating lymphocytes (TIL) or genetically modified cytotoxic T cells (CTLs). However, despite clear clinical responses, only a fraction of patients respond to treatment and there is an urgent call for characterization of predictive biomarkers. Currently much work in tumor immunology and oncology has focused on targeting the ‘tumor escape phase’ to increase tumor immunogenicity and on developing new therapeutic modalities. Many ongoing clinical trials are testing potential synergistic effects of treatments combining immunotherapy with other therapies. The numerous immune escape mechanisms employed by mutating cells in human tumors are a significant barrier to success. Read more...

The elimination of tumor cells by the activated immune system and the success of cancer immunotherapies depends on the proper co-presentation of tumor-specific antigens and major histocompatibility complex-1 (MHC-I) protein molecules. MHC-1 proteins on tumor cell surfaces “present” their antigen markers and the tumor-specific antigens to cytotoxic T cells, which then muster an immunological response against the tumor. Identification of molecular aberrations responsible for altered tumor MHC-I expression in mutated tumor cells, as well as causes of the same, becomes essential for the success of T cell-mediated cancer immunotherapy and for the development of novel complementary approaches for MHC-I upregulation. Read more...

Understanding the alteration of MHC-I proteins, otherwise known as human lymphocyte Antigen – 1 (HLA-1) in people, by tumor gene expression would have clinical significance, since in many cases HLA-1 has been associated with disease-free interval and with overall survival in patients with different types of cancer. Hence, loss of this particular MHC-1 (in animals) or HLA-1 (in humans) protein by genetic mutation in a tumor could compromise the efficacy of immunotherapy. Exosomes derived from tumors reflect these mutations and are a target of an Exosis-based diagnostic test (patent pending). This test will be useful to predict responses to existing immunotherapies (e.g. checkpoint inhibitors as well as ET-08). Read more...

About: COMPANY PROFILE

Exosis, Inc. is developing a novel cancer vaccine strategy that represents the next generation of personalized cancer immunotherapy. We are developing the means by which to educate a patient’s immune system to fight their specific malignancy. Exosis’ vaccine strategy is premised on the electroporation of the patient’s tumor-derived exosomes into autologous dendritic cells that are then co-administered with a checkpoint inhibitor. Using this approach, the Company expects to be able to treat all tumors, regardless of their origin. Exosis holds issued patents (US, China, Japan) and PCT applications over the use of exosome-electroporated dendritic cells for cancer therapy and anticipates evaluating the vaccine in first-in-man clinical studies starting in 2019. The Company has a low-capital-structure, semi-virtual business model with low cash burn, high-profile collaborators and a fast-track development program. Read more...

About: BUSINESS STRATEGY

The Exosis dendritic cancer cell vaccine (ET-08) will be commercialized through a network of franchised cell therapy centers established in partnership with leading medical institutions worldwide. Our initial commercialization plan is to engage the European marketplace with a dendritic cell vaccine through a “named patient program” that enables the early use of experimental therapeutics. Phase 1-2 clinical trials for the exosome-electroporated dendritic cell vaccine (ET-08) will be conducted in Europe. The Asian marketplace enables product launching in countries such as Japan where the regulatory framework for cell-based immunotherapies allows for an expedited path to market. Read more...

Unlike other cell-based cancer immunotherapies, neither the patient’s exosomes nor dendritic cells will be mailed to centralized facilities for clinical preparation. Instead, cell processing will be performed at cancer centers where Exosis will provide franchisees with standardized protocols (for cell and exosome harvest, processing and vaccination), equipment specifications, and comprehensive training, as new centers are established. Thereafter, Exosis will provide regular oversight and quality assurance to ensure compliance to GMP (Good Manufacturing Process) and Exosis SOPs (Standard Operating Procedures). Franchisees will pay royalties to Exosis on a per patient basis. Each cell therapy center may support a number of peripheral oncology clinics for the recruitment of patients and administration of vaccine prepared at the regional cell therapy center. Read more...

Much like dialysis centers, this model of commercialization will allow the Exosis vaccine to be made available at a wide number of locations, reducing the burden of travel on patients. It also allows early establishment of treatment centers in countries with accommodating regulatory pathways while experience, data and early revenues are generated to support regulatory activities and corporate growth in more highly regulated markets such as the US. Read more...

Technology Platforms: Introduction

Exosis’ patented vaccine technology directly educates a cancer patient’s own immune system by activating their dendritic cells to fight their disease. “Dendritic cells” are the master orchestrators of the immune response that trigger the cascade of antibody production and activation of T cells, killer cells, etc., that circulate to identify and then fight diseases. “Antigens” are the protein markers that characterize tumors. “Exosomes” are microvesicles containing tumor antigens that are released by tumors into biological fluids like blood and urine. To educate a patient’s dendritic cells, exosomes are first harvested from the blood, urine or other fluids, then combined with dendritic cells from that patient using flow electroporation technology. The electroporated dendritic cells, which now carry the tumor antigens, are subsequently returned to the patient as a “vaccine” that activates players of the immune system to hunt out and kill tumors. The Company’s therapeutic vaccine approach provides a solution to treat all tumors, regardless of their origin, aggressiveness or mutagenicity. To complement the therapeutic vaccine, Exosis is developing a diagnostic that determines whether cancer cells have the mechanisms to express antigens on their surface. The mutation of cancer cells as they evolve includes loss of certain components of the HLA-1 antigen expression machinery, which allows them to escape immunotherapy. The Company has developed a prototype assay to detect whether cancer cells will respond to immunotherapy based on the presence or absence of MHC-1 on their surfaces. Read more...

Technology Platforms: EXOSOMES

Exosomes are biological “nanoballs” between 30-100 nanometers in size that are secreted by cells under normal and pathological conditions. They are surrounded by a protective lipid bilayer derived from the original cell membrane, and contain that cell’s proteins and nucleic acids, such as mRNA, miRNA and double stranded DNA; in physiological conditions, these can be shuttled from one cell to another, affecting the recipient cell's protein production. Read more...

Tumor exosomes contain the genetic and protein fingerprints of the cancer that sheds them, which means they include all the mutations and markers that are specific to the malignancy. In addition, they contain factors that help the tumor grow and metastasize. Exosomes are shed into body fluids, such as blood, urine, cerebral spinal fluid, pleural fluid and ascites fluid, and may be retrieved for use in vaccines. With disease progression, increasing concentrations of exosomes are found in these biological fluids. Read more...

Cancers are polymorphic, and tumor fingerprints, such as those found in exosomes, typically evolve and change over the course of the cancer’s progression. The use of exosomes as the genetic material for arming the immune system allows the therapeutic vaccine program to be constantly revised against the changing genome of the cancer over time, adding a distinct advantage to Exosis’ therapeutic strategy. Read more...

Importantly, exosomes have the full neoantigen repertoire of their malignant origin. Neoantigens are the new genetic markers that rapidly evolve in growing malignancies as they mutate. Other strategies to capture the neoantigens from cancer patients rely on tissue biopsies to create therapies. These biopsies represent only a small snapshot of the cancer, are difficult (and sometimes impossible) to obtain, and the use of biopsies to generate personalized immunotherapies relies on expensive and time-consuming gene sequencing, neoepitope construct production, and imperfect algorithms to select what is relevant. Exosomes, by contrast, contain all the protein and genetic neoantigen fingerprints from primary and metastatic tumors in a package that may stimulate a broader immune response than tissue biopsy material. Read more...

Technology Platforms: DENDRITIC CELLS

Dendritic cells are the conductors of the immune orchestra, traveling throughout the bloodstream to identify foreign pathogens, digest them and present their antigen messages to T and B cells to mount an immune defense. In cancer, dendritic cells don’t readily recognize malignant cells since they are cloaked in markers of “self,” which are not processed as foreign antigens to activate an anti-cancer immune responses. Read more...

In order to obtain large numbers of dendritic cells from a patient, it is necessary to nurture them from their monocyte cellular precursors. A patient’s monocytes are withdrawn and purified from blood plasma, and then mixed with a cocktail of chemical stimulants (cytokines) to mature them into dendritic cells. This process typically uses IL-4 and GM-CSF, two cytokines, to mature dendritic cells in a process that takes 5-6 days in culture. Read more...

By contrast, Exosis is collaborating with Prof. Zwi Berneman of the University of Antwerp, Belgium, who has developed a new cytokine process using IL-15 to mature monocytes. This not only makes dendritic cells that present cancer antigens, but ones that by themselves have natural killer activity against tumors (see below). IL-15-generated enhanced dendritic cells (eDCs) take less time to mature, approximately 4 days, and target both innate and acquired immunity. Read more...

Technology Platforms: ELECTROPORATION

Exosis uses electroporation to insert exosomes into the dendritic cells, which, when returned to the patient as a vaccine, are armed with the neoantigen messages of the cancer. The general principles of electroporation involve the application of an electric field to cells in suspension, causing the cell membranes to become transiently permeable and encouraging external materials, such as peptides, proteins and RNA, to enter the cells. Other methods of getting the exosome message into dendritic cells, such as co-incubation, are far less effective (5-20 fold) and not efficient in expressing antigens on dendritic cells. Read more...

Technology Platforms: CHECKPOINT INHIBITORS

A significant challenge in cancer immunotherapy is that cancers typically employ strategies to suppress and evade the immune system. One of the key strategies used is the hijacking of immune checkpoint pathways by cancer. Immune checkpoints are a regulatory mechanism that the immune system uses to modulate the size and duration of an immune response to a foreign challenge. Checkpoint pathways are regulated by ligand/receptor interactions. A ligand can be thought of as a key, whilst the receptor is the lock. Cancer cells may express high numbers of ligand molecules on their surface in order to interact with the receptors on cells of the immune system, thereby applying a brake to their anti-cancer activity. These ligand/receptor interactions may be targeted by the use of blocking monoclonal antibodies (called checkpoint inhibitors) aimed at either the key (ligand) or the lock (receptor), to prevent their interaction. Thus, either checkpoint strategy releases the brake on the immune system to enhance the response against cancer. Read more...

Amongst the checkpoint inhibitors in development or on the market, anti-PD-1 has attracted the most attention. The PD-1 (programmed death-1) receptor is expressed on T cells and pro-B cells (immune cells). PD-1 and its ligands, PD-L1 and PD-L2, play important roles in down-regulating the immune system by preventing the activation of T cells and inhibiting T cell proliferation. The PD-L1 ligand is expressed by non-lymphoid tissues as well as by activated antigen presenting cells (APCs). PD-L1 is a protein frequently overexpressed on the surface of cancer cells that suppresses the immune system and immune surveillance. When the anti-PD-1 antibody attaches to the PD-1 receptors on immune cells, the cancer can no longer hide from the patient’s immune system, allowing the patient’s T cells to fight the cancer. An alternative approach is to use an antibody to the anti-PD-L1 ligand on the cancer cell, similarly blocking the interaction of PD-1 with PD-L1. Antibodies to checkpoints other than PD-1 are also marketed or in development. We plan to evaluate which checkpoint inhibitor would be the best partner for our vaccine. Read more...

Vaccine Strategy

Tumor-derived exosomes (TEX) containing the neoantigen messages of the mutating cancer are harvested from a patient’s peripheral blood (or other body fluid) together with the patient’s immune cell precursors (monocytes). The monocytes are subsequently matured over a few days in culture to produce enhanced dendritic cells (eDCs) using IL-15. The patient’s exosomes are then inserted into their matured dendritic cells using flow electroporation, and the loaded dendritic cells are administered to the patient as a course of ET-08 vaccine injections. Back inside the body, the eDCs in ET-08 process the patient-specific cancer-derived genetic and protein information from the to present the epitopes of tumor-specific neoantigens to circulating T cells in lymph nodes, thereby activating tumor-antigen-specific cytotoxic T lymphocytes (CTLs) to kill any tumor cells that display those same tumor epitopes on their cell surface human lymphocyte Antigen – 1 (HLA-1) molecules. In addition, eDCs release chemokines and cytokines that can recruit and activate cytotoxic NK cells to also kill tumor cells. Read more...

The patient’s immune response is supported by the concomitant treatment with a checkpoint inhibitor that “removes the brakes” from the immune system, enabling it to detect and destroy the tumor (whether primary or secondary malignant cells) and promoting the patient’s return to homeostasis and health. Read more...

MANUFACTURING

Cell-based therapeutics can be manufactured using either a centralized or decentralized model. Exosis is currently exploring a decentralized manufacturing model for ET-08. Exosis plans to produce Phase I material in a manual, semi-closed process which could then be transferred to a scalable, closed and automated manufacturing process following the success of initial clinical trials. This model allows for reduced capital investment to evaluate the product in Phase I, followed by transfer of the process in a timely manner to ensure a scalable and cost-effective product supply for late-stage clinical development and commercial supply. Read more...

We favor an ‘autonomous microfactory’ approach, where process automation is used to ensure that the manufacturing process is carried out in a way that can be reproduced to the same control strategy at different times and in different locations. This ensures that therapeutic production takes place closer to patients, reducing transit times and viability hurdles. Read more...

A phased introduction of microfactories would allow Exosis to be capital-efficient until ET-08 can generate a positive return; capital investment would occur in line with market growth. Read more...

MHC-1 IMMUNO-DIAGNOSTIC

The elimination of tumor cells by the activated immune system and the success of cancer immunotherapies depends on the proper co-presentation of tumor-specific antigens with Major Histocompatibility Complex-1 (MHC-I) protein molecules. MHC-1 proteins on tumor cells “present” their antigen markers to cytotoxic T-cells which then muster an immunological response against the tumor. MHC-1 molecules on the surfaces of cancer cells present the tumor antigens, and these tumor antigens are the messengers to the immune system that are required to elicit immunotherapy responses. Identification of molecular aberrations responsible for altered tumor MHC-I expression in mutated tumor cells, as well as their cause, becomes essential for the success of T-cell mediated cancer immunotherapy and for the development of novel complementary approaches for MHC-I upregulation. Read more...

Alterations in MHC-I protein by tumor gene expression has clinical significance, since in many cases it has been associated with disease-free interval and with overall survival in patients with different types of cancer. Hence, loss of this particular MHC-1 protein by genetic mutation of the gene that encodes it (Human Lymphocyte Antigen – 1, or “HLA-1”) in a tumor could compromise the efficacy of immunotherapy. Exosomes derived from tumors reflect these mutations and are a target of an Exosis-based diagnostic test (patent pending). This diagnostic test will be useful to predict responses to existing immunotherapies (e.g. checkpoint inhibitors) as well as to Exosis’ cancer vaccine, ET-08. Read more...

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