One of the important areas of cancer research and development that appears to receive a great deal of attention and funding, but in practice seems slow to make it from the laboratory to the clinic, is the targeting of therapeutics to cancerous cells. Reductio ad absurdum, near any of dozens of existing chemotherapeutics would do the job of completely clearing tumors, with minimal to no side-effects, if one could only find a way to delivery tiny amounts of the therapeutic to every cancer cell while avoiding every healthy cell. The inability to target treatments this effectively is exactly why cancer remains such a problem. Killing cells is easy. Killing only the desired cells is hard.
Today's research materials provide an example of this principle. Tumors compromise the immune system, and many of the more recent cancer therapies involve delivery of signals to rouse otherwise suppressed immune cells to unfettered aggression. This is a double-edged sword: an aggressive immune system is capable not only of attacking the cancer, but also of causing a great deal of harm to the patient in the worse cases. Still, this balance of benefit and harm is largely a better one for patients than is the case for chemotherapy. Why not make this delivery of immune-modulating signals much more targeted, however? As it turns out, this greatly improves the therapy.
The researchers used implantable "drug factories" the size of a pinhead to deliver continuous, high doses of interleukin-2, a natural compound that activates white blood cells to fight cancer. The drug-producing beads can be implanted with minimally invasive surgery. Each contains cells engineered to produce interleukin-2 that are encased in a protective shell.
Interleukin-2 is a cytokine, a protein the immune system uses to recognize and fight disease. It is an FDA-approved cancer treatment, but the drug factories provoke a stronger immune response than existing interleukin-2 treatment regimens because the beads deliver higher concentrations of the protein directly to tumors. "Once we determined the correct dose - how many factories we needed - we were able to eradicate tumors in 100% of animals with ovarian cancer and in seven of eight animals with colorectal cancer. If you gave the same concentration of the protein through an IV pump, it would be extremely toxic. With the drug factories, the concentration we see elsewhere in the body, away from the tumor site, is actually lower than what patients have to tolerate with IV treatments. The high concentration is only at the tumor site."
Proinflammatory cytokines have been approved by the Food and Drug Administration for the treatment of metastatic melanoma and renal carcinoma. However, effective cytokine therapy requires high-dose infusions that can result in antidrug antibodies and/or systemic side effects that limit long-term benefits. To overcome these limitations, we developed a clinically translatable cytokine delivery platform composed of polymer-encapsulated human ARPE-19 (RPE) cells that produce natural cytokines.
Tumor-adjacent administration of these capsules demonstrated predictable dose modulation with spatial and temporal control and enabled peritoneal cancer immunotherapy without systemic toxicities. Interleukin-2 (IL2)-producing cytokine factory treatment eradicated peritoneal tumors in ovarian and colorectal mouse models. Furthermore, computational pharmacokinetic modeling predicts clinical translatability to humans. Notably, this platform elicited T cell responses in non-human primates, consistent with reported biomarkers of treatment efficacy without toxicity. Combined, our findings demonstrate the safety and efficacy of IL2 cytokine factories in preclinical animal models and provide rationale for future clinical testing in humans.