Cold As Ice

Jun 24, 2024

A fantastic, and seriously catchy song from ‘80s British-American rock supergroup Foreigner is, “Cold As Ice“. If we had to choose one reason why many tumors are so hard to treat with checkpoint inhibitors (CIs) like Opdivo and Keytruda, it would be exactly this – that they are as cold as ice.

The fact is that for as many tumor types as CIs benefit, only a minority of patients outside these tumor types respond, with some totally resistant. The primary reason for resistance is the complete or near‐complete absence of T cells from the tumors, which makes them “cold.”

The current focus in oncology is how to transform these “cold as ice” 🧊 tumors with few to no immune cells into “hot as fire” 🔥 ones with many immune cells so that they respond better to checkpoint inhibitors and to other therapies like chemo and radiation.

One commonly used strategy is to trigger a type of cell death known as immunogenic cell death or ICD with oncolytic viruses, chemotherapy, or radiation. ICD stimulates an immune response against specific tumor proteins or antigens.

A second strategy is to target not the tumors themselves, but the neighborhood or microenvironment in which they live since tumors depend on this neighborhood/microenvironment to survive and thrive. This is a much broader, and more comprehensive strategy that may involve depletion of immune suppressive cells like macrophages, inhibition of transforming growth factor‐beta (TGF-β), and normalization of the tumor vasculature or hypoxic environment among others.

EpicentRx lead therapies, RRx-001 (nibrozetone), and AdAPT-001, each target both tumors and their microenvironment. Furthermore, both are very well tolerated, and lend themselves to combination with other therapies like checkpoint inhibitors, chemotherapy, and radiation.

AdAPT-001 directly eliminates cancer cells through ICD, and so does RRx-001 (nibrozetone) as a chemotherapy-like small molecule. In addition, both impact the tumor microenvironment as AdAPT-001 carries and expresses a TGF-β trap that inhibits TGF-β, while RRx-001 (nibrozetone) eliminates tumor-associated macrophages (TAMs) and normalizes the very abnormal tumor vasculature.

The result? Hotter, more treatment responsive tumors especially in combination with checkpoint inhibitors and other therapies, as abundant preclinical and clinical data suggest.

In this way, both AdAPT-001 and RRx-001 (nibrozetone) aim to make “cold as ice” tumors “pay the price,” as lead Foreigner vocalist, Lou Gramm, sings so compellingly.