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Dec 12, 2013

Creating a New Hero from an Old Story

A unique immunotherapy approach takes aim at cancer.

Creating a New Hero from an Old Story

A protein known as gp96, sometimes referred to as the immune system’s “Swiss Army Knife,” holds promise as a vaccine that directs cytotoxic T cells to target cancer. [University of Miami Miller School of Medicine]

  • 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. 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.

    The saga of developing a drug that effectively and efficiently harnesses the power of gp96 highlights the differences between an autologous versus allogeneic approach. Autologous drugs are derived from patient-specific tumors, making the treatment highly personalized. While this path has the potential to be effective, it is also enormously costly. The failure of Provenge, for instance, to become a significant immuno-oncology product is due to a combination of limited efficacy, inherent drug complexity and high manufacturing cost.

    Allogeneic drugs, in contrast, may be mass-produced at much lower cost and hold potential to be equally if not more effective as their autologous cousins. By utilizing laboratory tumor cell lines developed from specific cancers, an off-the-shelf drug can be efficiently delivered to a vast patient population—offering a unique and highly differentiated way to treat a wide range of cancers.

    An allogeneic approach to engineering vaccines to secrete gp96, together with a complete repertoire of tumor targets that stimulate killer T cells, is fully scalable. Moreover, the continual emission of gp96 proteins offers a natural “time-release” delivery system that may have significant therapeutic potential.

    Allogeneic tumor vaccine approaches are possible because tumors are known to share immune targets with one another. In developing a secretable gp96-based vaccine, it is critical to select an appropriate tumor type and an appropriate cell line that expresses an array of tumor targets known to be shared amongst a high proportion of patients with a given tumor type. The specific response of patient killer T cells against those predetermined tumor targets can then be monitored in patients, and has been shown to correlate with overall survival following treatment with gp96 secreting vaccines.

    The promise of this technology extends to a broad range of tumors including orphan cancer indications, or in patients whose response to the toxicity of traditional chemotherapy limits the duration of therapy. In addition, this therapy can be utilized by patients with good responses to initial surgery or therapy but remain at very high risk of relapse.

    Immunotherapies will continue to hold promise as a growing number of cancer vaccines combine with an allogeneic gp96-Ig approach. As clinical studies in this area progress, evidence will mount demonstrating the benefits of this variety of immunological manipulation, and whole-cell cancer vaccines that continually secrete gp96-Ig will increasingly gain the attention of pharmaceutical research teams progressing cancer remedies into the marketplace. Eventually, tremendous synergy in immunotherapies will enable combination treatments that will truly transform the landscape of immuno-oncology.



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