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The main therapeutic target of nonsteroidal anti-inflammatory drugs (NSAIDs) is the enzyme cyclooxygenase (COX). One of the isoforms of COX, named COX-2, is implicated in several physiological responses, including angiogenesis and metastasis. COX-2 is overexpressed in most solid tumors, and is associated with resistance to apoptosis and cancer immunotherapy, while selective COX-2 inhibitors can inhibit cell proliferation, tumor invasiveness, and angiogenesis.

The impact of COX-2 inhibitors in reducing cancer and cancer risk, and improving survival in several types of cancer, is well established, and furthermore, preclinical data demonstrate that COX inhibitors could be useful adjuvants for immune-based therapies in cancer.

Drug Discovery & Development (DDD) spoke to Joseph Murphy, Ph.D., director of science, R&D at Charles River Laboratories about using NSAIDs as an effective anticancer immunotherapy.

 

DDD: How can COX-2 inhibitors be used with immunotherapies in the fight against cancer?

Joseph Murphy: Although the underlying mechanisms of these chemo-preventive effects have yet to be fully elucidated, some studies have shown that specific COX-2 inhibitors can increase the infiltration of CD4+ and CD8+ T cells to tumor sites, thus positively regulating the tumor specific host immune response. Moreover, by inhibiting prostaglandin E2 (PGE2), a key immuno-suppressor, COX inhibitors can also modulate the activity of T-regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells. Given these results, NSAIDs are potentially a good partner for immunotherapies, such as checkpoint inhibitors, in fighting cancer.

DDD: Are there other combination immunotherapy treatments currently being used to fight cancer?

JM: A deeper understanding of the mechanisms underlying the generation of tumor immunity has provided a framework for developing more potent immunotherapies. A major insight is that combinatorial approaches that address the multiplicity of defects in the host response are likely required for clinical efficacy. Since the approval of ipilimumab (Yervoy), different immune checkpoint inhibitors, vaccines, and costimulatory agonists have been developed with success, improving patient's survival for a number of different tumor types.

Although immunotherapy results in durable responses, a large cohort of patients remain unresponsive to treatment. In order to improve outcomes, a combination of different immune agents is currently being attempted in the clinic. Combinatory regimens may have synergistic effects by acting at different points of the cancer immune cycle from initiating and propagating anticancer immunity to accessing, recognizing, and killing the cancer cell.

Moreover, combination therapies with conventional treatments are also being evaluated. It is expected that combination therapies represent the next wave of immune treatments available for cancer patients, and will become the standard of care in the near future.

DDD: Why do you think the potential for NSAIDs in combination with immunotherapy isn’t receiving more attention?

JM: Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemo preventive agents. Although much potential exists in this area for novel cancer prevention and treatment strategies, clinical research to support targeting cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy.

One reason may be because of the well-publicized side-effects of some NSAIDs. Rofecoxib (Vioxx) was withdrawn from the US market in 2004 after initial FDA approval based on findings of increased cardiac events. Rofecoxib gained worldwide acceptance among physicians treating patients with arthritis and other conditions that caused chronic or acute pain. It was withdrawn because of concerns about the increased risk of heart attacks and strokes associated with long-term, high-dosage use. Moreover, findings published in the New England Journal of Medicine indicated that another NSAID, celecoxib (Celebrex), although an effective agent for preventing colorectal adenomas, could not be routinely recommended due to potential cardiovascular events.

Joseph Murphy, Ph.D.
Director of Science, R&D at Charles River Laboratories

DDD: Has any research been done on NSAIDs and immunotherapy? If so, what were the findings?

JM: In spite of the positive results with respect to the anti-cancer effects of NSAIDs, very few studies have addressed the potential for NSAIDs in combination with cancer immunotherapies. One recent study reported that administering aspirin in combination with immunotherapy could enhance the efficacy of treatment. Here, researchers reported that skin, bowel, and breast cancer can produce large amounts of PGE2, resulting in a reduction of the immune system’s ability to attack aberrant cells, allowing cancers to hide from immuno-surveillance. Preclinical data demonstrate that inhibiting COX synergizes with anti-PD-1 blockades to induce the eradication of tumors. This implies that COX inhibitors could be useful adjuvants for immune-based therapies in cancer.

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