TL-118 is a drug combination which consists of a chemotherapeutic alkylating agent and 3 non-toxic agents. It is designed to disrupt and modulate the tri-branched tumor microenvironment aspects: The cancer cells, the tumor vasculature and the immune system by the following properties:
The chemotherapeutic component of TL-118 is administered in a metronomic regimen. That is, frequent administration of low doses of cytotoxic drugs at close intervals, with no prolonged drug-free interruptions. Metronomic chemotherapy advantages are: (i) It reduces toxicity and allows the patient higher consumption-tolerance (ii) It sustains tumor-growth inhibition and (iii) lowers the chance of tumor resistance to therapy because of the relatively low doses administered.
Metronomic chemotherapy is contrasted to conventional chemotherapy regimens which are administered at their maximal tolerated dose (or nearly maximal tolerated dose) at intervals with extended drug-free periods. Conventional chemotherapy brings about (i) robust tumor and host toxic effect, (ii) tumor regrowth during therapy breaks and (iii) frequently enhances tumor resistance to therapy due to the high dose of the chemotherapy.
By constantly targeting rapidly dividing cells, metronomic chemotherapy is able to target not only the cancer cells, but also newly formed blood vessel endothelial cells (anti-angiogenic therapy), thus leading to hypoxia, nutrient deprivation and tumor burden decrease.
Angiogenesis is the process of new blood vessel formation (Neovascularization) from pre-existing vessels.
It is a hallmark capability of cancer to promote self-delivery of oxygen and nutrition that are essential for it to grow and later metastasize.
As angiogenesis is a complex process that involves multiple steps (e.g. endothelial cell proliferation, cell migration, tube-formation, accessory cell recruitment, secretion of pro-angiogenic factors etc.) many conditions must be met in order for proper angiogenesis to take place. Coordinated orchestration of distinct cells and a battery of secreted factors are necessary for functioning blood vessels to be formed. In addition, angiogenesis in general and cancer-related angiogenesis in particular, is a robust phenomenon with built-in redundancy in signaling molecules.
Anti-angiogenic therapy aims to inhibit tumor growth and spread by destroying the tumor vasculature and depriving the tumor of oxygen and nutrients.
Anti-angiogenic therapy has emerged as one of the most promising anti-cancer therapies due to its (i) improved selectivity (ii) applicability to a broad spectrum of solid tumors and (iii) ability to target endothelial cells, thus less likely to induce drug-resistance.
Single anti-angiogenic agents, which aim to disrupt a single molecular target, have produced only modest results in a limited number of indications. The complexity of the angiogenic process is probably responsible for the failure of single agents to achieve results that are more significant. Perhaps the induction of bypass angiogenic pathways compromises the activity of single agents.
Contrary to a single-agent approach, Tiltan has decided to take advantage of the complexity of the angiogenic process and use it as an asset to launch an attack on angiogenesis from several independent angles, simultaneously.
The immune system is the body's defensive arm. It protects the host from external invaders but also internal undisciplined cell processes like tumor formation.
Once the immune system recognizes a tumor as having abnormal cell-behavior, it will launch an attack to eliminate the rebellious cells. In response, the tumor manipulates the involved immune cells and inhibits their action by different means such as masking cancerous cells or using secreted factors to inhibit the immune activity and accelerate the malignant process.
Within the tumor microenvironment, a balance is established between the normal defense put up by the immune system and the resisting tumor.
Breaking the balance and encouraging immune stimulation is desired in order to inhibit the tumor growth.
Immuno- modulatory therapy aims to alleviate the chronic inflammation in the tumor microenvironment and thereby inhibit tumor growth. It also encourages normal host anti-tumor immune surveillance.
Immune modulation possesses several advantages: (i) It enhances anti-tumor immunity.
(ii) It is less likely to induce drug-resistance as the targeted cells are genetically normal with low mutation rates and (iii) it is applicable to all solid tumors.
TL-118 consists of three par excellence anti-inflammatory agents, each targets a different path of the inflammatory process, thus creating a combined offense against the tumor.
Importantly, in the tumor microenvironment there is constant cross-talk between the immune cells and tumor new-vessel formation, each feeding the other in respect of cytokine, chemokine and growth factor secretion. From the immune system's aspect such "soup" of factors maintains the chronic inflammation; anti-tumor immune cells are inhibited and other inhibiting cells are dominate. From the vasculature's aspect, molecular requirements for proper angiogenesis are present and the tumor can flourish.
Breaking such a balance to achieve immune cell attack and attenuation of the angiogenesis process will attenuate tumor growth.
The multi-targeted nature of TL-118, utilizing drug repurposing, paves the way for a unique new therapeutic potential.