Background

Traditional cancer therapies, such as surgery, radiation, and chemotherapy, are often insufficient in treating patients and usually cause severe side effects. Today, only about 60% of all cancer patients are cured from their disease. Cancer vaccines, which trigger the immune system to destroy harmful substances, have shown promise as additional effective treatments with fewer side effects. The immune system recognizes and attacks that which is foreign to the body, but the problem with cancer is that tumor cells are not considered unknown invaders. This makes it difficult for the immune system to effectively neutralize tumor cells, which is why several methods have been developed, mainly with cellular vaccines, for enhancing the immunological response against cancer.

It is now well established that the immune system has cells, particularly CD8+ cytotoxic T-lymphocytes (CTLs) that can recognize and potentially kill tumor cells. Nevertheless, a major problem is that these T-cells are either not induced or only weakly induced, i.e. the T-cells are not evident in the systemic circulation. One possibility is that there is inadequate tumor antigen presentation by dendritic cells (DCs), “nature's immune boosters/adjuvants” for eliciting T-cell immunity. Another is that tumor-reactive T-cells are tolerated by the tumors.

Dendritic cells are vital in all immune responses

Dendritic cells (DCs) can be derived from immature white blood cells (monocytes) and are the single most important substances in all immune responses since they activate systems that help the body eliminate harmful foreign material.

DCs process antigens and present them to T-cells, whose job it is to attack cells that have been invaded by harmful agents. Antigens are proteins or other types of molecules that can be found on the surface of, or inside, a cell and that may be able to stimulate an immune response. Many vaccine companies have to go through the rigorous process of identifying/characterizing what is thought to be appropriate antigens, namely substances that can be found abundantly on dangerous cells (such as tumor cells) but not on normal cells. And even when the antigens have been identified, one cannot be certain that they will be adequately immunogenic until they have been tested extensively in human trials. DCs have been described as the most potent and efficient antigen-presenting-cells, capable of activating both mature and immature T-cells. Immature T-cells “learn” to respond to new dangerous substances by being presented with antigens that are specific for the harmful substances. In this way, the immune system also learns how to attack cancer cells, instead of regarding them as harmless. Once DCs are activated, they migrate to the draining lymph nodes where they interact with immature T-cells by presentation of antigens and trigger the immune system.

To circumvent some of the problems in cancer therapy, several immunotherapeutic studies have focused on optimizing the antigen presentation function of autologous (from the patient) DCs in vitro (in test tube) so that these antigen-loaded DCs can be transferred back into the body. Ideally, this should yield DCs that, following injection, traffic to the draining lymph node and efficiently activate tumor-specific T-cells, leading to the generation of an effective immune response against tumor cells. However, the immune responses to such DC-based vaccines are often weak, and clinical responses are rarely complete and long lasting. Nevertheless, the only therapeutic cancer vaccine, Provenge (owned by Dendreon) that has managed to gain market approval (in 2010) is based on autologous DCs.

The problems of autologous DC-vaccines

Adjuvants (immune boosters) can work either as immunomodulators, meaning that they stimulate DCs or other antigen-presenting-cells (APCs) to migrate to the draining lymph nodes for activation of the immune system, or they act as delivery vehicles, meaning that they deliver the antigens to DCs or to other APCs. According to Datamonitor’s report, Stakeholder Opinions: Vaccine Adjuvants, the optimal adjuvant approach would be to combine a delivery vehicle with an immunomodulator since you would not only be able to deliver the antigen to the APCs but at the same time stimulate the APCs to migrate to the draining lymph nodes for interaction with T-cells. This happens to be exactly what Immunicum’s core-concept is capable of doing (see more info below). It is common knowledge that DCs from one human being injected into another (allogeneic DCs) as foreign material will be eliminated by the host’s immune system. DC-research has thus focused on autologous concepts. Autologous DC-vaccines, such as those of Dendreon’s, extract patients’ own DCs, load them with tumor antigens and then stimulate/activate them in vitro before re-injecting them into the patients. However, since autologous DC cancer vaccines have to be tailor made for each individual patient there are several other drawbacks. Creating a new, unique vaccine for each patient is: complex, time consuming, expensive, and physically stressful for the sick patients, whose blood will have to be drawn several times.

Allogeneic DCs are great immune boosters

Little has been known regarding the fate and function of ex vivo generated autologous DCs after they have been injected. In the human setting, the migration pattern of injected vaccine DCs was recently tracked in vivo (in human) and notably, less than 5% of the injected DCs reached the draining lymph nodes while the majority of DCs remained at the injection site (Verdijk et al 2009). These locally trapped vaccine DCs rapidly lost their viability and were subsequently cleared by recruited APCs. In line with these findings, data has now been provided that injected vaccine DCs indirectly prime naïve CD8+ T-cells in vivo by acting as a pure immune adjuvant that recruits and activates endogenous APCs (Yewdall et al 2010). By using allogeneic DCs as vaccine cells, such cells will further be regarded as MHC-incompatible foreign invaders that most likely will induce an inflammatory reaction that further promotes the recruitment and activation of endogenous DCs at the vaccination site (Wallgren et al 2005). This hypothesis has now been verified in rat and mouse cancer models in which tumor growth was significantly reduced by therapeutic vaccinations with tumor-loaded allogeneic DCs