Figure 1: Tumors are protected by ‘fortress-like’ barriers
The maxim that “a man’s home is his castle” is made literal by tumors, which firmly entrench themselves behind castle-like barriers as a defense against the attritional war waged against them by chemotherapy, radiation, and immunotherapy. These barriers are nearly impregnable and tumors are so well-resourced from the support of surrounding stromal cells that therapeutic resistance is more common than not – even more so the longer the treatment drags on. Figuratively speaking, from high atop the ramparts, tumors can surveil the battlefield at their leisure, adjust as needed to harden their defensive positions, siphon more resources from the host, and neutralize, suppress and counter virtually any attack thrown against them. Key layers of their defensive position include
- A moat-like morass of abnormal blood vessels where blood flows sluggishly or not at all instead of freely
- Rigid walls of connective tissue or extracellular matrix (ECM) that encircle and buttress tumor cells
- An abundant inner phalanx of protective guards in the form of immune cells such as tumor associated macrophages or TAMs that have been co-opted and corrupted to protect and to not eat tumor cells (macrophage literally means “big eater”).
To overcome and breach these formidable defensive layers of solid tumors requires particular weaponry such as RRx-001 and AdAPT-001 from EpicentRx. RRx-001 is a patent-protected and very well-tolerated small molecule that improves or normalizes the tumor vasculature and tumor blood flow for better delivery of oxygen, chemotherapy, radiation, and immunotherapy. RRx-001 also reprograms the tumor associated macrophages (TAMs) to fulfill their natural function as ‘big eaters’ of tumor cells and protects normal tissues against the toxicities of standard therapies. RRx-001 is under investigation in Phase 1-3 clinical trials as a treatment for solid tumors such as small cell lung cancer (SCLC), as a chemoradioprotector for head and neck cancer (H&N), as a medical countermeasure against a catastrophic nuclear or radiologic event, and as an anti-neurodegenerative agent in Parkinson’s disease, amyotrophic lateral/sclerosis (ALS)/motor neuron disease (MND), and Alzheimer’s disease.
AdAPT-001 is a reengineered and patent-protected oncolytic adenovirus, agent of the common cold, that has been specifically designed to infect, copy itself, and lyse tumors but not normal cells. Additionally, AdAPT-001 carries a transforming growth factor beta trap or TGFß trap, which it overexpresses when infection of tumors is initiated. TGFß, in effect, serves as one of the ‘keys to the castle’ because its neutralization, by AdAPT-001, for example, disrupts the tumor vasculature and the extracellular matrix and stimulates the suppressed immune system.
AdAPT-001, which is currently enrolling to a Phase 1/2 trial both alone and in combination with a checkpoint inhibitor, has two main mechanisms of action:
- Direct destruction or lysis of infected tumor cells with release of a) newly produced viral descendants or progeny for reinfection of neighboring tumor cells and b) tumor debris and tumor-associated antigens (TAAs) that contribute to stimulation of the immune system
- Neutralization of TGFß with activation of the immune system and immunotherapy such as the FDA approved checkpoint inhibitors, reduction of extracellular matrix (ECM) accumulation and vascular normalization.
Like RRx-001, AdAPT-001 is well-tolerated with no dose limiting toxicities or related serious adverse events in approximately 30 patients treated to date. In this way, RRx-001 and AdAPT-001 both attack tumors directly as single agents with minimal collateral damage to normal tissues and cells (and possibly even protection of normal tissues and cells in the case of RRx-001) and also indirectly through modification of the defensive foundations such as the highly abnormal vasculature, abundant extracellular matrix (ECM) and global immunosuppression that support and protect tumors for potentially better sensitization to combinations with chemotherapy, radiation and immunotherapy.