Only about one-fifth of cancer patients respond to immunotherapies like Keytruda, which is credited with helping Carter survive an advanced form of skin cancer. What makes “responders” different, previous studies in melanoma and lung cancer have suggested, is that they have a huge number of mutated genes producing molecules that find their way to the surface of the tumor cell. There, the aberrant molecules, known as neoantigens, stick out like pushpins in a corkboard.
What are immunotherapy drugs ?
Immunotherapy drugs known as checkpoint inhibitors continue to generate buzz, for good reason. Since 2010, when the first such drug, ipilimumab (Yervoy), was approved to treat advanced melanoma, a number of patients have seen positive results—some with few significant side effects. These drugs work by unmasking cancer cells and exposing them to the immune system for attack. Now researchers and cancer doctors are trying to unravel the mystery behind why in some cases—about half the time immunotherapy is tried on most cancers—the patient’s immune system doesn’t respond at all.
Some patients who have little or no reaction to immunotherapy drugs may be suffering from T cell exhaustion, “the scenario where there are not enough available or functioning T cells to mount a response,They may already be occupied or are not in the right location, or there is something else that’s preventing them from reacting.” Researchers are exploring how so-called “co-stimulators” may work in jump-starting the production of T cells so they are hardy and plentiful enough to launch an immune response.
Researchers in London, meanwhile, are exploring the role neoantigens may play in preventing immunotherapy from doing its job. An antigen is a molecule on a cell that attracts immune cells. Neoantigens are new antigens that develop on cancer cells. In some cases, researchers found, cancer cells did not produce enough neoantigens to summon T cells to attack the tumor, even after they were exposed by an immunotherapy drug. It would appear that neoantigens have to be in almost every tumor cell to produce an effective immune response. (Source)
Relapsing Keytruda & More
Researchers are also trying to determine why some patients relapsed after initially responding to immunotherapy. In separate studies, researchers have discovered specific genomic mutations in cancers that developed resistance to immunotherapy drugs. Scientists at MD Anderson reasoned that cancer cells express genetic mutations in order to develop resistance to ipilimumab (a CTLA-4 checkpoint inhibitor). (Source)
In this perspective, UCLA scientists concluded that the JAK1 and JAK2 proteins are resistant to the drug pembrolizumab (a PD-1 checkpoint inhibitor sold as Keytruda) in patients who relapsed after early responses to the drug. (Source)
In both studies, researchers concluded that cancer mutations disrupted the interferon-gamma signaling pathway, a critical immune system function. Interferon-gamma (IFN-y) are cancer-fighting cytokines that not only attack cancer cells directly, but also act as messenger molecules that help direct an immune response. But cancer cells also outsmart these molecules and put in place an arsenal to checkpoint inhibitors. (Source)
Discussion and Tentative conclusion
Despite some succcess with conventional immunotherapy drugs, for most cancer patients, either these drugs dont work or else they do provoke some immune response, but at the cost of serious autoimmune attack side effects. They also promote resistance. Relapses and resistance to checkpoint inhibitors are not unexpected or unique to immunotherapies. Cytotoxic chemo, radiation and conventional targeted therapies also develop cancer resistance.
In the beginning cancer cells are not prepared for conventional attack, so many do die. But because conventional oncology attacks symptoms and does nothing about root causes and mechanisms, cancer cells express in their genome their evolutionary-based survival program, including but not lmited to DNA repair. Cancer stem cells are decisive in this “come back” resistance strategy.
This is not surprising, as we’ve shown before, cancer cells are smart, they adapt to external stimuli and aggression, they recruit allies in the immune system, in the microbiota, in the tumor micro-environment. This is why the ACR Institute prefers to outsmart them with their own mechanisms of action rather than using the weapons of massive destruction the Conventional Oncology experts put in place with the hundreds of billions of dollars that the Cancer pharmaceutical industry has used to develop these weapons . (1)
Pr. Joubert (ACRI director)