May 2014 Edition Vol.11, Issue 5

Can Innate Immune Cells Engage in Anti-Tumor Activity?

Can Innate Immune Cells Engage in Anti-Tumor Activity?

By Myra L. Patchen, PhD

 

Although cancer immunotherapies have been around for decades, most of the various treatment approaches have not worked very well. However, with a fundamental shift in the variety of immunotherapeutic approaches now available, the possibility to engage both the innate and adaptive arms of the immune system to kill cancer cells exists.

Until recently, the focus of many of the most successful immunotherapies — monoclonal antibodies — has been to target cancer cells. Essentially, monoclonal antibodies compensate for the fact that the body often does not recognize cancer cells as a threat and therefore does not generate natural antibody-mediated immune responses against them. Once bound to their target, monoclonal antibodies do sometimes indirectly harness the body’s repertoire of immune cells to fight the cancer. But more often, they rely on directed actions such as blocking receptors on the cancer cells or preventing the ability of the tumor microenvironment to support the continued growth of the tumor. The issue with such an approach has been that monoclonal antibodies alone, while very successful commercially, have often brought relatively limited clinical benefit to the patient.

Traditionally, direct recruitment of the body’s immune cells in the fight against cancer has been a strategy more or less limited to cancer vaccines. These vaccines typically work through presenting cancer antigens to the adaptive immune system (either T-cells or B-cells, and sometimes both) in order to alert the immune system to the threat. However, this approach relies very heavily on the highly specific nature of the adaptive immune response and, as a result, has generally been met with limited efficacy to date.

The 2011 approval by the U.S. Food and Drug Administration of ipilimumab (Yervoy®), Bristol-Myers Squibbs’ first in class immune modulator for patients with advanced forms of melanoma, has changed this situation markedly. Yervoy is a monoclonal antibody, but rather than targeting the tumor, Yervoy targets the adaptive immune system, and in doing so, aims to unleash its killing power.

Yervoy blocks binding of the CTLA-4 receptor on cytotoxic T-cells. CTLA-4 is normally involved in down-regulating these important immune cells, which serves to minimize immune-mediated damage to healthy tissues. When Yervoy binds to CTLA-4, in essence, it “takes the brakes off” the cytotoxic T-cells so that they are able to more freely function and kill cancer cells. The key difference in the strategy employed by Yervoy is that it is modulating, and in this case derestricting, the immune system, essentially making it easier for the immune system to find and kill cancer cells. The activity of Yervoy is not specific to the cancer cell itself, but rather is mediated through modulating responses of T-cells against the cancer cells in general.

Although overall response rates with Yervoy in clinical trials were modest (~11%),1 it is the first melanoma drug to show substantial improvement in survival, yielding a median overall survival of greater than 10 months, with ~20% of patients surviving 3 years and 17% of patients surviving 7 years or beyond.1,2,3 Thus, Yervoy may extend survival in some patients by years, not just months or weeks, as is the case with most conventional cancer treatments for advanced disease.

By directly targeting and modulating the patient’s immune system, Yervoy has validated immune checkpoint blockade as a therapeutic paradigm, and new data for other immune modulating drug candidates presented at the 2013 American Society of Clinical Oncology (ASCO) meeting last June led many to believe that a new era in cancer medicine had begun.

The ASCO buzz focused on a new class of monoclonal antibodies targeting another T-cell receptor, this time the PD-1 receptor function, binding of which also negatively regulates immune responses and inhibits cytotoxic T-cell activity. Bristol-Myers Squibb reported an overall response rate of 31%, a median overall survival of 16.8 months, and a 3-year survival rate of 40% in stage IV melanoma patients treated with its anti-PD-1 drug, nivolumab,4 further exceeding effects of previous melanoma therapies.

Interim data for Merck’s anti-PD-1 drug, lambrolizumab, which is also being evaluated in patients with advanced melanoma, showed an impressive 52% overall response rate in the treatment arm receiving the highest dose.5 Both companies are conducting additional trials in a variety of cancers.

Although immune checkpoint blockers have garnered much recent attention, numerous other immunotherapy agents are also under investigation, with more than 30 such agents currently in Phase 3 clinical trials, according to the Cancer Research Institute.6

The potential of immunotherapies is difficult to overstate. Citigroup Global Markets (CGM) analysts believe that in a decade from now immunotherapy will be the “backbone” of treatment regimes for 60% of all cancer types. The potential revenue opportunity for the biopharmaceutical industry by 2023 is projected at more than $35 billion, according to a CGM report entitled, “Immunotherapy – The Beginning of the End for Cancer.”

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