IRX Therapeutics

Science and Technology

mechanism of action

IRX-2 Therapy for Squamous Cell Head & Neck Cancer (H&NSCC)
H&NSCC often occurs in patients who have severe depression of cellular immunity derived in part from poor nutrition and zinc deficiency. This depression of cellular immunity results from tumor produced factors (like IL-10, TGF-β, PGE2 prostaglandins, VEGF, etc.) and the induction of host suppressor cells (T regulatory cells (T regs), myeloid suppressor cells, and suppressor macrophages and perhaps even suppressor dendritic cells). This immune depression is characterized by reduced T cell number and function and defective function of monocyte/macrophages and antigen-processing dendritic cells.

The end result is that although the tumor has antigens capable of inducing tumor rejection, the tumor is able to successfully subvert the cellular immune response. The IRX-2 regimen, which is currently in clinical trials, is a therapy designed to re-establish an effective tumor rejection process.

The cytokine components of IRX-2 (includes IL-1, IL-2, IL-6, IL-8, IFN-γ, TNF-α, G-CSF and GM-CSF) are known to promote both T lymphocyte and dendritic cell development and function and monocyte function. The use of low dose cyclophosphamide as an immunomodulator and indomethacin as a prostaglandin synthesis inhibitor is designed to block the key mechanisms that cause the defects of cellular immunity. The use of zinc supplementation in multivitamins is important in restoring normal function to the thymus, which matures and promotes the function of T lymphocytes, as they constitute the most effective tumor killing cell.

Mechanism of Action
Tumor antigens are part of the mechanism by which the tumor paralyzes T cells (anergy) and kills them (apoptosis). These antigens are present in regional lymph nodes even before the tumor itself spreads there. The antigens have been engulfed by dendritic cells; yet, the dendritic cells have been “frozen” in their development. Our studies indicate that a critical action of IRX-2 is to mature dendritic cells, which could allow an effective immunization to take place in the regional lymph node.

As a result, we hypothesize that T cells are then triggered by mature dendritic cells displaying tumor antigens to multiply and produce cytokines and killer T cells. The effector T cells then traffic by blood to the tumor and can infiltrate the tumor. (See left figure).

There is data that suggests that memory T cells are produced in addition to effector killer cells, indicating that if the tumor recurs it may be recognized and attacked before it has an opportunity to take hold. The Phase 3 study will assess long term survival in H&NSCC patients treated with IRX-2.

It is important to note that the subversion of effective cellular immune response is a characteristic of most, if not all, tumors and that the processes involved are shared. The observations we have made in H&NSCC are, therefore, thought to be applicable to other cancers. Indeed, the use of the IRX-2 therapy has been shown in pre-clinical research studies to be effective in selected cases of other cancers.

It is likely that patients who will benefit most from IRX-2 treatment are those with less extensive disease, good nutrition and better immune competence.