Clinical Development of a Gastrointestinal Tumor-Initiating Cell Targeted Therapeutic Antibody
Cancer claims the lives of more than 7.5 million people annually worldwide and is responsible for one in four deaths in the State of California. Furthermore, colorectal cancer is both the third most common cancer and cause of cancer deaths in California. Although the last few decades have witnessed significant advances in therapeutics yielding improved time to tumor recurrence, overall survival has failed to improve meaningfully over this time period. Recent work has demonstrated that a subpopulation of tumor cells with the unique capacity to fuel tumor growth (i.e. tumor-initiating cells; TIC) exists within the complex mixture of cells that make up solid tumors. This observation may shed light on the disconnect between clinical response and overall survival, as TIC are not targeted by current therapies and appear responsible for resistance and tumor recurrence. As such, overall survival of patients with solid tumors is not likely to significantly improve.
Though proposed to exist in the late 1960’s, TIC remained unidentified in solid tumors until 2004, largely because the tools to identify and isolate these cells were non-existent. Recent technological advancements have enabled more accurate identification, isolation and characterization of these cells. This characterization has led to the discovery of new oncology targets that are being exploited to develop more potent and targeted therapies that are proving capable of eliminating TIC in human patient-derived tumor models that closely reflect tumor biology as it exists in patients.
Tumor recurrence is inevitable for the majority of cancer patients who currently receive therapy, largely because the standard of care drugs currently on the market are not targeted to, and/or do not actively kill, TIC. By targeting TIC and/or targeted delivery of potent toxins able to actively kill these cells without damaging normal tissue, quality of life should also improve as current standard of care chemotherapeutics and radiation consist of grueling regimens that also kill many normal cells.
It has been proposed that targeting TIC is the only way to obtain durable cancer responses. In taking advantage of proprietary platforms and focusing squarely on TIC, we have the advantage of generating the appropriate and necessary therapeutics to achieve this goal. The final stages of efficacy and safety testing of a TIC-targeted drug candidate are now underway in preparation for the initiation of clinical trials.
Of every four deaths in California, one is from cancer. Current statistics also suggest that of the more than 130,000 California residents diagnosed with cancer last year, greater than 40% will die from their disease within five years if current therapies are not improved upon. Recent scientific discoveries show that traditional therapies such as chemotherapy and radiation largely fail to target the tumor cells responsible for initiating solid tumor growth, recurrence and metastasis (i.e. tumor-initiating cells; TIC). To truly impact overall survival and target the underlying root cause of cancer, the next generation of cancer drugs will have to better target TICs; but more specifically, TIC-targeted therapeutics will likely need to be extremely potent if these cells are to be eliminated without providing an opportunity to escape or evade therapy. Rather than systemically administer current standard of care chemotherapeutics that kill dividing cells, have intolerable side effects and are ineffective at improving overall survival, new therapeutic approaches are maturing that link potent toxin molecules to targeting vehicles known as monoclonal antibodies. By linking toxin warheads to monoclonal antibodies, potent toxins can be delivered directly to TIC. Significant improvements to these antibody-drug conjugates, or ADCs, have been made over the past decade resulting in both greater activity and increased safety in the clinic. The key to successfully delivering these conjugates lies in their targeting through the use of monoclonal antibodies directed to appropriate targets.
Patients with KRAS-mutated colorectal and pancreatic cancer represent major unmet needs in the clinic, as these patients have few therapeutic options that provide hope for improving survival. We have demonstrated that our lead therapeutic candidate, which is targeted to the TIC subpopulation of colorectal and pancreatic cancer and dosed only once a week for three to four weeks, effectively eliminates patient-derived tumors in mice and results in long-term cures in these models regardless of KRAS mutation status. These therapeutics are aggressively being advanced to the clinic where their safety and efficacy in humans will be thoroughly evaluated. The desired impact of this work is to improve survival and quality of life of patients who have failed standard therapies and have few therapeutic options, but the far-reaching goal is to cure subsets of patients with currently intractable tumors.