The overall aim of cancer immunotherapy is to activate the immune system to cure cancer. The immune system is capable of recognizing and eradicating tumor cells, and is thought to play a role in immune surveillance against cancer. However, tumors may develop defense mechanisms, notably the production of immune suppressive cytokines and the up-regulation of “immune checkpoint” molecules. While growing tumors are usually infiltrated by immune cells, the activity of these cells may be suppressed in the tumor. Immunotherapy has been shown to overcome the suppression and to re-activate the immune cells, thereby resulting in eradication of the tumors. In addition, immunotherapy may induce immunity towards the tumor, further contributing to the therapeutic effect. Chemotherapy and targeted therapies may be very effective treatments of metastasizing cancer on a short term basis. However, relapse of the disease almost always occurs. Immunotherapy on the other hand, has the potential to induce long term remission in these patients, as recently demonstrated by the impressive 4-year survival data of Yervoy® in metastasizing melanoma patients. Likewise, the immune activating PD-1 inhibitors show promising long term survival data in metastasizing melanoma, as well as in renal cell cancer and non-small cell lung cancer. These data strongly supports the concept of immunotherapy of cancer.


Local immunotherapy of cancer
Alligator Bioscience has developed a concept for local immunotherapy of cancer, providing powerful systemic anti-tumor effect with minimal systemic toxicity. Systemic treatment with immune activating drugs is often associated with severe immune related side effects that prohibit treatment of the patient with higher and potentially more optimal doses. By local (intra-tumoral) administration of FIND®-optimized immunoregulatory molecules (engineered for optimal function in the tumor environment) toxic side effects can be minimized while greater efficacy may be obtained. Local immunotherapy activates tumor-specific T cells, resulting in effective eradication of the treated tumor as well as distant metastases. Due to the local administration and lower total dose required, less systemic immune activation is induced, thereby minimizing the risk for toxicity. The concept of local immunotherapy of cancer has been developed in collaboration with Professor Thomas Tötterman at Uppsala University, a pioneer in the field of local cancer immunotherapy.

An alternative approach to intra-tumoral administration is the systemic administration of drugs that, once in the body, localize to the tumor area. Thereby it may be possible to retain the advantages of local immunotherapy, while allowing treatment also of patients with metastases inaccessible for intra-tumoral injections. This new platform of systemic localizing immunotherapies has been the focus of Alligator´s drug discovery activities during 2012 (see ADC-1016 below). The prerequisite to enable development of systemic localizing immune activators is technologies that allow the generation of bispecific drug compounds.


Bispecific immune activating drugs
Immunotherapy is associated with powerful anti-tumor effects combined with the induction of long term anti-tumor immunity. These effects may be further augmented by combining the immunotherapy with another therapy such as radiation or chemotherapy. It has also been demonstrated that the combination of two immunotherapies is likely to be superior to the treatment with a single agent. This has led Alligator to initiate the development of bispecific immunotherapies. ADC-1015 was the first bispecific compound to enter the Alligator pipeline during 2012.


Advantages of local and localizing immunotherapy
Local immunotherapy allows powerful activation of the immune system in the immediate tumor area, while minimizing systemic exposure. Hence it is possible to induce superior efficacy while reducing the risk of immune related adverse effects. In cancer patients, tumors are usually infiltrated by immune cells, including tumor-specific T cells. However, the activity of these T cells is suppressed in the local tumor microenvironment, e.g. by inhibitory cytokines induced by the tumor. Immunotherapy overcomes this suppression and activates tumor-specific T cells resulting in eradication of tumor cells. Such local immunotherapy results in a systemic anti-tumor immune response and has effect not only on the treated tumor, but also on distal metastases. In addition, local immunotherapy mediates immunity towards tumor relapse. ADC-1013, ADC-1015 and ADC-1016 are examples of such drug development candidates.


Local immunotherapy of cancer: drug development candidates in pipeline
Alligator Bioscience has currently two development projects for local immunotherapy, ADC-1013 and ADC-1015, both inducing powerful immune activation, but through different biological mechanisms. Both compounds have been FIND®-optimized to improve properties for intra-tumoral administration, and both are aimed for the treatment of various types of metastasizing cancer. The treatment concept is highly innovative and is expected to result in better efficacy and less adverse events compared to what is normally seen in clinical investigations with systemically administered immunotherapies.