Engineering Magic Bullets for Pancreatic Cancer
Originally published on February 4, 2019 in Johns Hopkins’ blog Biomedical Odyssey (link)
In a 1909 manuscript titled “Ueber den jetzigen Stand der Chemotherapie” (“About the Current State of Chemotherapy”), Nobel laureate Paul Ehrlich proclaimed, “We must learn to aim in a chemical sense.” What did he mean? Ehrlich was referring to his “magic bullet” theory of chemical specificity, the observation that certain drugs can eliminate disease-causing entities (example: bacteria) without inflicting damage on healthy tissue. He outlined a nascent form of this concept in his doctoral dissertation, describing how to visually distinguish between subtypes of white blood cells using certain dyes that preferentially stain the cellular structures in one subtype versus another. Ehrlich surmised that the chemical structure of each dye determined its preference for painting biological structures that are present in certain cell types but are absent in others. He wondered: If chemical dyes could selectively color certain cells, could other chemical compounds selectively kill rogue cells that confer disease? Ehrlich extended his thinking to search for compounds we now recognize as “antibiotics” — drugs that disrupt biological processes essential for the survival of pathogenic microorganisms but do not affect human tissue. In 1908, his efforts led to discovery of the first modern antibiotic, arsphenamine. Armed with the ability to selectively kill the bacteria that cause syphilis, arsphenamine indeed served as a “magic bullet” in contrast to the metaphorical blunderbuss that is mercury, the universally toxic standard of care at the time.
Just as Ehrlich used his insight into chemical specificity to discover and develop antibiotic agents, investigators following in his footsteps founded the field of immuno-oncology. Its practitioners aim to therapeutically target cancer using the immune system, which can generate its own pathogen-recognizing chemicals (antibodies, T-cell receptors, etc.). Current immuno-oncology strategies generally involve the following processes:
- Training the immune system to recognize recurrently mutated or unusually overexpressed proteins (called “neoantigens”) that are present in cancer but are absent in normal cells.
- Emboldening the immune system to attack such cancer cells upon encounter.
On Oct. 18, 2018, investigators at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins reported on a targeted therapy that combines both strategies of immuno-oncology to eliminate pancreatic cancer in mice. The therapy involved administration of an immune-training vaccine called PancVAX, supplemented by intermittent doses of two immune-emboldening compounds: a PD-1 antagonist and an OX40 agonist. PancVAX consists of a STING ligand, which recruits immune cells called T-cells, mixed with 38 synthetic long peptides, which mimic several proteins found to be mutated in pancreatic adenocarcinoma cells and that have amino acid sequences determined to elicit an immune response according to a prediction algorithm called NetMHC. In other words, PancVAX taught T-cells to “aim in a chemical sense” at pancreatic cancer cells that bear certain mutated proteins, just as Ehrlich had envisioned. Although the vaccine was shown to suppress the growth of pancreatic cancer in mice, the antitumor effect only lasted a few days. Why? T-cells that managed to make their way into the vicinity of pancreatic tumors displayed several markers of exhaustion, a state in which immune cells have a diminished capacity to attack target cells upon encounter. To counteract this disarming effect, researchers supplemented PancVAX with a PD-1 antagonist, which blocks one of the pathways that cancer cells exploit to throw T-cells into a state of exhaustion, and an OX40 agonist, which prolongs the life span of activated T-cells. Thus, the two supplementary agents were intended to embolden T-cells to attack tumor cells. Mice with pancreatic cancer that had been treated with the triple-combination showed tumor shrinkage and increased survival, with 30 percent of mice completely cleared of tumors. In contrast to mice treated with PancVAX only, mice treated with the triple therapy displayed durable responses that lasted for an extended period of time (56 days). Four out of five of these same mice almost completely eliminated new pancreatic tumors upon reintroduction without any additional treatment, demonstrating the staying power of the combination therapy.
Investigation of the PancVAX, anti-PD-1 and OX40-stimulating combination therapy in mouse models of pancreatic cancer yielded promising results that support follow-up studies to assess its safety and efficacy in nonrodent animals. The treatment would need to deliver significant survival benefits to patients in clinical trials before it could become commercially available. Neeha Zaidi, an oncology fellow and co-author of the publication, says pilot clinical trials of patients with advanced pancreatic cancer could initiate within the next year or so. Paul Ehrlich’s grand synthesis of chemistry and biology, the “magic bullet” theory of chemical specificity, still serves as the foundation of rational drug development more than 100 years later. Indeed, it is a principle that will be critical in the ongoing effort to engineer more “magic bullets” against cancer.
