Creating a New Hero from an Old Story

For decades, immunotherapy seemed a tantalizing—yet maddeningly elusive—alternative to toxic treatments for cancer consisting mainly of chemotherapy and radiation therapy. Manipulating the immune system proved to work on certain allergies and microbes, but immunotherapeutic cancer vaccines historically overpromised and underdelivered.

It wasn’t until 2010 when the FDA approved Provenge for prostate cancer that immunotherapy gained status as a true contender for treating cancer. More recently, the realization that tumors require both immune evasion and active immune suppression to proliferate has fueled two successes so tremendous that certain pharmaceutical companies have entirely rebranded themselves as centered on immuno-oncology.

The first triumph involves a class of so-called “checkpoint inhibitor” drugs, including Yervoy and Nivolimumab. These checkpoint inhibitor drugs essentially take the brakes off the antitumor immune response and have generated dramatic clinical results in certain patients with advanced cancer. Cleveland kitchen pros cook up foodie gifts for the holidays. The second triumph involves a class of drugs that overcomes the evasive nature of tumors through engineering of patient-specific killer T cells, the body’s innate enemy of cancer. Known as “chimeric antigen receptor” or CAR therapies, these drugs have yielded unprecedented clinical efficacy in a small group of patients with certain blood-borne cancers. Both types of drugs underscore how the human immune system—and specifically killer T cells—are fully capable of recognizing and destroying even very large masses if they are educated and delivered against a tumor with compromised defenses.

As the synergy between immunotherapy drugs builds, vaccines that direct cytotoxic T cells to target cancer are the first order of business. In this area, a protein known as gp96, sometimes referred to as the immune system’s “Swiss Army Knife,”1 holds much promise. More than any other known natural immune stimulant, gp96 appears to have evolved specifically to educate killer T cells about cancer cells.

Gp96 is the carrier molecule for tumor-specific antigens that play a critical role in awakening killer T cells. The utility of gp96 as an immune stimulator stems from its unique ability to identify the full molecular fingerprint of cancer, flag tumor targets for the immune system with extraordinary efficiency, and deliver them exclusively to killer T cells. Normally ensnared within cells, gp96 can be untethered though a process that transforms it from observer to combatant. The result is a molecular warning system that heralds the presence of malevolent cells. Once injected into the body, secreted gp96 provides critical intelligence to killer T cells, teaching them how to seek and destroy cancer. In contrast, most prior and many current approaches are limited to a small array of tumor targets, require enormous doses to achieve immune stimulation, and inappropriately target the immune response that evolved to defeat bacteria—not cancer.