The immune system protects us against infectious microbes like viruses and bacteria by providing an agent-specific response and maintaining immunological memory for future encounters with the same agent. Viruses and bacteria have antigens, unique chemical structures that make them foreign to the body. By being substantially different in chemical structure and appearance from an individual’s normal cells, microbes are “seen” by the immune system (Fig. 1) as being non-self and hence dangerous. Specialized cells, called dendritic cells (DC), ingest these infectious agents and present their non-self antigens on their surface, alerting and activating the immune system to mount a defensive response. During a viral infection, cytotoxic T cells (virus specific killer immune cells) are mobilized. These T cells kill virus infected cells and thereby prevent the spread of infection. In addition, some cells called natural killer cells (NK cells) are naturally able to kill virus infected cells. In order to mobilize and expand all these killer cells, the immune system uses primarily Interleukin-2 (IL-2), a critical factor.
Like viruses and bacteria, cancer cells have antigens (tumor antigens), many of which are unique for each individual. The immune system provides routine protection against cancer cells through a cellular killing process called immune surveillance . The surveillance works when cancer cells are “seen” as non-self. By continuously changing their antigenic make-up, tumor cells “blind” the immune system and escape unharmed. The escape from surveillance leads to the unhindered growth and spread of tumor cells. Making the immune system aware of these changes can bring tumors again under surveillance such that they can be killed.
Fig.1. The Immune system: note the distribution of the lymph nodes, as collectors of the lymph. The vaccine is injected in the legs or arms and it is transported by lymphatic vessels to the lymph nodes, where the immune response takes place (Fig. 1 is adapted and reproduced with permission from Janeway’s Immunobiology.)
Unlike viruses or bacteria that can multiply very fast, thereby easily alerting the immune system, when cancer cells first appear they represent a very small and “silent” event with very subtle changes from normal cells. Essentially, cancer cells take advantage of mechanisms developed by the immune system to prevent autoimmunity by “pretending” to be normal cells that need to be tolerated. Malignant cells thus escape immune surveillance without providing danger signals to the DCs. The immune system is insufficiently or never activated and the tumor has a chance to grow and establish itself. Once established, cancer cells fight to maintain the equilibrium with the immune system. They subvert the immune system by making substances that block activation of DC and killer lymphocytes. They even recruit some immune cells, called regulatory T cells, to induce local and systemic immune suppression. In addition, some aggressive cancer cells make inhibitors to protect themselves from the killing machinery of cytotoxic T cells and NK cells.
Based on this information, the scientists at XEME considered that a successful cancer vaccine needs to fulfill the following requirements:
1. an “alien” structure that is taken up by non-specific immune cells to provide danger signals and induce specialized cytokines to activate the immune system;
2. tumor cell antigens, which are mostly unique to the tumor of each patient, presented as part of the “alien” structure in order to induce a specific immune response with killer T cells;
3. a large amount of IL-2, released at the local lymph node level where the immune response evolves, to rapidly increase the number of activated killer T cells and NK cells.
XEME’s AGGREGON™ cancer vaccine provides in one structure a combination of these fundamental needs.
Proposed Mechanism of Action
The AGGREGON™ vaccine represents:
A strong danger signal induced in local dendritic cells (DC) upon subcutaneous administration because the AGGREGON™ vesicles, like bacteria and viruses, have many chemical and physical repetitive units;
The patient’s cancer, because the AGGREGON™ contain the patient’s own tumor cell antigens and as such it can be considered an artificial mini-tumor cell; and
Reservoirs of IL-2 concentrated at the site of vaccine inoculation. These reservoirs could be considered surrogate or artificial helper T cells that naturally produce IL-2. Concentrated in the local immune system, IL-2 will stimulate and expand the number of cytotoxic lymphocytes (CTL) and promote their capacity to kill cancer cells. IL-2 also recruits and increases the number of natural killer cells (NK cells). The CTL and NK cells are the most important immune cells able to kill cancer cells.
The result of these representative properties is the generation of strong cellular immune responses against the original tumor cells. The activated CTL and NK cells migrate to the site of the tumor and eliminate tumor cells, including those at sites of metastases. Repeated immunizations yield stronger anti-tumor responses and an immunological memory, which plays a crucial role in preventing relapse of the disease.
The proposed mechanism of action of AGGREGON™ is based on the known mechanism of response to virus infections (or live virus vaccines). Cells that will become mature dendritic cells pick up in macropinosomes the injected AGGREGON™ vaccine material and carry it to the lymph nodes through the lymphatic vessels. In the lymph nodes the naïve T cells are activated and “learn” how to attack the cancer cells.
Fig.2. Involvement of dendritic cells during the early phase of the immune response (A and B) leading to activation of T cells (C). (Fig. 2 is adapted and reproduced with permission from Janeway’s Immunobiology.)
Unlike all the cellular DC-based vaccines, XEME’s AGGREGON™ goes several steps further and ultimately activates directly the most effective anti-tumor killer cells (cytotoxic T cells and NK cells). The three main stages of the proposed mechanism of anti-cancer cell response induced by AGGREGON™ vaccine can be explained using Fig. 3: A) The ingested AGGREGON™ activate dendritic cells (DC); the AGGREGON™ are digested and their antigens “presented” to T cells. B) The T cells become activated to the antigens and proliferate in response to IL-2 that stimulates the IL-2 receptors. The T cells make some of the IL-2 for their own use but also take advantage of the abundance of IL-2 provided by AGGREGON™. Some specialized T cells “differentiate” i.e. become killers (cytotoxic T cells). C) These differentiated (mature) killer T cells travel, find cancer cells and deliver their killing mechanism.
Fig.3. Schematic representation of the steps leading to the specific anti-cancer T cell immune response from recognition (A) to proliferation and differentiation (B) to effector tumor cell killing function of the activated T cells (C). (Fig. 3 is adapted and reproduced with permission from Janeway’s Immunobiology.)