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Reviewing Immune Checkpoint Targeting in Cancer Research

The cancer research establishment is not a single monolithic entity, but rather consists of many diverse fields and approaches to treatment. Researchers in one area may or may not be paying all that much attention to other areas. This is an important issue in modern scientific development, where there is simply too much information and too much going on for any one person to know everything of relevance to the work at hand. There is need for at least a few scientists in every field to spend much of their careers in synthesis and knowledge exchange, bringing together research groups who would otherwise not know that they might benefit from collaboration:

The prospect of combining genomically targeted therapies with drugs that free the immune system to attack cancer suggests "we are finally poised to deliver curative therapies to cancer patients." While individual researchers and pharmaceutical companies are studying and developing both types of drugs, a major initiative is needed to understand how both drug types might best work together. "Without a major initiative, it will be harder to make progress because the groups focused on genomically targeted therapy and the checkpoint blockade researchers will largely stay in their own camps."

Drugs that hit a specific genomic defect that drives a patient's cancer provoke good initial responses in most patients, the review notes. For example, drugs that target a specific BRAF gene mutation commonly found in melanoma shrink tumors in about half of patients with the mutation. However, resistance almost always develops because tumors harbor multiple genomic defects capable of driving the disease after a targeted drug knocks down one driver. BRAF inhibitors prolonged median survival in clinical trials by about seven months.

Checkpoint blockade is an approach that treats the immune system, rather than the tumor directly, by blocking molecules on T cells that shut those attack cells down, protecting tumors from immune response. Knowing that the immune system is capable of recognizing distinctive features of cancer cells and launching a T cell attack against those tumor antigens, and that checkpoint blockade removes a roadblock to that attack, it's logical that these drugs should work against many tumor types. But the impact varies across cancers.

There's a school of thought that combining multiple genomically targeted therapies might prove effective. However, evidence suggests that tumor genomic diversity might still defeat such combinations, and that it's axiomatic in oncology that side effects increase in number and intensity as more drugs are added to treatment. Targeted therapies might act as effective cancer vaccines, killing tumor cells and releasing new target antigens for T cells to identify and associate with tumors. And they might vary in their ability to enhance or inhibit immune response, because little is known right now about how targeted agents affect the immune system.

Early efforts to combine approaches have yielded interesting results. One phase I trial of an immune checkpoint blockade drug combined with two established targeted therapies yielded 40-50 percent response rates among patients with metastatic kidney cancer. "At this stage, it does not seem a stretch to say that increasing funding to combination therapies will be key to development of new, safe treatments that may prove to be curative for many patients with many types of cancer."

Link: http://www.mdanderson.org/newsroom/news-releases/2015/potential-cancer-immunotherapy-plus-targeted-therapy.html

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