Immunotherapy of Cancer

Immunotherapy of Cancer

Immunotherapy of cancer has become increasingly important in clinical practice over the recent decade. By activating the patient’s own immune system, immunotherapy treatments have shown remarkable promise in extending the lifespan of previously untreatable cancer patients. Two approaches to immunotherapy, immune checkpoint inhibition and immune cell-based therapies, are particularly promising and advanced in the clinic.

Immune Checkpoint Inhibition

One of the key physiological functions of the immune system is to recognize and eliminate neoplastic cells. Therefore, an essential part of any tumor progression is the development of immune resistance mechanisms. An important part of these mechanisms is immune-inhibitory pathways, also called immune checkpoints. Immune checkpoints play a particularly important role in the interaction between tumor cells and CD8+ cytotoxic T-lymphocytes. Among important immune checkpoints are inhibitory receptors expressed on the T-cell surface, such as CTLA-4, PD1, LAG3, etc.

The importance of immune checkpoint attenuation has been recognized by the scientific and medical communities. One way to mitigate immunosuppression is to block the immune checkpoints by specially designed agents. The first such agents – the monoclonal antibodies Ipilimumab, blocking CTLA-4, and Pembrolizumab and Nivolumab, blocking PD1 – have recently been approved by the FDA. These antibodies have demonstrated long-term survival in subsets of patients with metastatic melanoma.

Immune Cell-Based Therapies

Another group of emerging immunotherapeutic approaches is based on the administration to the patient of cells capable of destroying tumor cells. In some of these approaches the administered cells are the patient’s own tumor-infiltrating lymphocytes (TIL), isolated and expanded ex-vivo. In some cases TIL are capable of recognizing a variety of tumor-associated antigens (TAA), in other cases TIL are reactivated and expanded in vitro to recognize specific antigens. The TIL-based therapeutic approaches are commonly referred to as adoptive cell transfer (ACT).

Further developments of ACT involve genetic modifications of T-cells to express receptors that recognize specific TAA. Such modifications may induce the expression of a specific T-cell receptor (TCR) or of a chimeric antigen receptor (CAR) consisting of a TAA-specific antibody fused to CD3/co-stimulatory molecule transmembrane and cytoplasmic domains.

The Promise of Combinations

One of the biggest advantages of immunotherapy is the effect of complete response and long-term survival of late-stage cancer patients. However, in many indications this effect is only achieved in small subsets, 10-30% of the patients. Numerous studies suggest that the efficacy of immunotherapeutic methods can be augmented by a combination of treatments, such as ACT and checkpoint inhibitors.

However, there are caveats in combining multiple immunotherapeutic treatments. It has been noted that an immune checkpoint blockade can lead to the breaking of immune self-tolerance, inflammatory events in multiple organ systems, and other side effects. Furthermore, there are only a few available checkpoint inhibitors, and the development of antibodies for new checkpoint targets involves a lengthy regulatory path.

Our Approach to immunotherapy of cancer is based on the adoptive transfer of cells, in which one or multiple immune checkpoints have been silenced by using our proprietary RNAi technique. This method potentially combines the advantages of the two most promising approaches to immunotherapy, while reducing the inherent side effects related to combinations.