Immune-Modulating Cancer Drugs Finally Get Some RespectJune 2016
By Chancellor Faloon
Cancer kills more than 1,600 Americans every day.1
When an effective cancer drug is delayed by even a few months, the death toll can run into the tens of thousands.
When the delay is measured in decades, the number of needless cancer deaths escalates into the millions.
In 1996, a remarkable study was published in the prestigious journal Science.2 Two groups of mice with tumors were tested in the experiment. One group received a novel immunotherapy that resulted in eradication of tumors and immunity against a second tumor exposure.
The group of mice that did not receive the immunotherapy had to be euthanized because their tumors had grown out of control.
Instead of greeting this discovery as a potential treatment breakthrough, the medical establishment’s response was rather apathetic.
Nearly two decades later, immunotherapy drugs that work by this mechanism are garnering headlines around the world.
You’re seeing these drugs advertised as being able to add longer life to advanced-stage cancer patients. Brand names include Yervoy®, Opdivo®, and Keytruda®.
Former President Jimmy Carter credits one of these drugs (Keytruda®) with helping induce a remission to his advanced-stage melanoma. (The media used the word “cure,” but this is not accurate.)3
We at Life Extension® are appalled as to the length of time it took for cancer patients to access this class of immunotherapy. These drugs displayed remarkable results in animal models, yet it took too long for this class of drug to gain widespread recognition in the oncology mainstream.
These new immunotherapy drugs are not without serious side effects.4 Efficacy varies considerably based on the genetic makeup of the tumor. These drugs work by tearing down defenses tumors erect against immune cell eradication.
There is evidence indicating that judicious use of these drugs in earlier-stage cases combined with immune-augmenting drugs like low-dose interleukin-2 might increase the number of remissions, complete responses, and outright cures of metastatic malignancies.5
This editorial describes cancer treatments that are not being optimally utilized, pointing to the urgent need for cancer patients to gain quicker access to new and potentially better therapies.
Sparking an Immune Alert against Cancer
The dilemma that exists with many malignancies is that the cancer itself can “trick” the body into pretending there is no cancer present. In other words, it’s not that the body doesn’t have the ability to defend itself; the problem is the body doesn’t know what it needs to defend against. If the immune system could identify the cancer early on, the resulting immune response might defeat the malignancy in many cases.4,6-8
Some T cells contain receptors that are actively searching for unhealthy cells to destroy. Cancer cells can evade T cell immune destruction by shielding themselves with high amounts of a ligand called “programmed death ligand,” or PD-L1.
Ligands are molecules that bind to other molecules. PD-L1 binds to receptors on our body’s T cells. When PD-L1 binds to immune T cell PD-1 receptors, it hacks and tricks the T cell into thinking there is no cancer present in the cell.
PD-L1 thus inhibits T cells from creating an immune attack necessary to destroy the cancer.
The new immunotherapy drugs (described previously) attach to the PD-1 receptors on T cells. These drugs are called checkpoint inhibitors because they block a tumor cell checkpoint by preventing tumor cell PD-L1 ligand from attaching to the PD-1 receptor on the body’s T cell membranes. These checkpoint inhibitor drugs neutralize the ability of certain tumor cells to shield themselves against T cell immune attack.4,6-8
Yervoy®, Opdivo®, and Keytruda® are the checkpoint inhibitors approved today. Despite published research dating back to 1996 showing the efficacy of these drug’s mechanisms,2 stifling bureaucracy delayed development and clinical testing. The result is that these lifesaving drugs have only painstakingly gained approval for certain cancers in years 2011-2015. (They are still not approved for the majority of cancers) 9-12.
Role of Gene Mutations in Cancer
One way cancer develops is as a result of the accumulation of mutations in genes that regulate cellular proliferation. Specific mutations in certain genes increase cancer risk.13
For instance, if there is a mutation in the BRCA gene, it increases one’s risk of breast cancer.14 A mutation in the BRAF gene can lead to uncontrolled growth of melanocytes causing a melanoma.15
Risk factors such as sunlight, ionizing radiation, heavily cooked food, and smoking cause gene mutations.16,17 A genetic mutation can also occur because of errors during DNA replication.18
The More Gene Mutations, the Better
A gene mutation is usually considered undesirable because it can cause or contribute to a wide range of diseases. Cancers with many gene mutations are often more difficult to treat because they have more survival options to escape eradication.19
When it comes to the new checkpoint inhibitor drugs such as Keytruda® and Opdivo®, however, researchers made an unusual discovery. It turns out that cancer cells with the most gene mutations respond far more favorably to treatment with this class of drug.20
For instance, Opdivo® (nivolumab) was given to a group of patients who had non-small cell lung cancer with high levels of mutations. The response rate was 73% compared to 13% for those who had low amounts of mutations.20,21
One way the immune system detects cancer cells is because of their mutations, which make the tumor cells appear as a foreign body. Tumor cells with more mutations are more effectively treated with checkpoint inhibitor drugs since these tumor cells create more antigens that attract T cells. If the cancer did not have many genetic mutations, then treatment using these new drugs is less effective.
Improved Survival Using Opdivo®
Melanomas make up the majority of skin cancer deaths even though they only account for 1% of skin cancers. If melanoma is detected early and has not spread, then survival rates are relatively high. Stage IV (metastatic) melanoma has a very low survival rate.1
Recent studies have shown the checkpoint inhibitor Opdivo® offers a more favorable prognosis than the conventional treatments that have been used for decades.4,22-26
The New England Journal of Medicine released a study in 2015 comparing Opdivo® to the chemotherapy drug dacarbazine in 418 metastatic melanoma patients. The survival rate after one year was 72.9% for those who received Opdivo® compared to only 42.1% for those who received dacarbazine.22
In addition, there were (slightly) fewer treatment-related adverse effects for those who received Opdivo®. Of those who received Opdivo®, 6.8% had to discontinue treatment compared to 11.7% for those who used dacarbazine.22
Shortly after this study was released, Opdivo® was tested in two different studies. The first was on advanced squamous-cell non-small-cell lung cancer involving 272 patients previously treated and whose disease had progressed; the second involved 582 patients with advanced non-squamous non-small-cell lung cancer. Researchers compared Opdivo® to the chemotherapy drug docetaxel in both studies.23,24
After 12 months, the survival rate for the squamous-cell non-small-cell lung cancer study was 42% in the patients who received Opdivo® compared to 24% for the patients given docetaxel.23
At 18 months, the survival rate for the non-squamous non-small-cell lung cancer study was 39% in the patients who received Opdivo® compared to 23% for the patients given docetaxel.24
Results with Yervoy® and Keytruda®
Keytruda® (pembrolizumab) is showing results indicating it may be more effective than Yervoy® (ipilimumab) for metastatic melanoma patients. A detailed study compared the two drugs, as well as their dosing, on an average of 278 patients in each group. Those who received Keytruda® had a one-year survival rate of 74.1% compared to 58.2% for Yervoy®. It is important to note that 34% of all these patients had previously received other systemic therapies.27
The response rate refers to the percentage of patients whose cancer disappeared or shrunk after treatment.28 The group that received Keytruda® had a response rate of 33.7% compared to only 11.9% for Yervoy®. The best results were seen when Keytruda® was used every two weeks at a dose of 10 mg per kilogram of body weight. The Keytruda® treatment was also associated with less severe side effects.
Strengthening the Immune System
Interleukin-2 (IL-2) enhances overall immune function, most notably by enhancing natural killer cell activity.29-31
Interleukin-2 can be highly effective when delivered before immune-suppressing conventional therapies. A number of studies reveal that pretreatment with interleukin-2 before a standard cancer treatment protocol can improve clinical outcomes.32-35
Pancreatic cancer has the lowest survival rate of most any form of cancer.1 Only 15% to 20% of pancreatic cancer patients are eligible for a complex surgery that involves the removal of the head of the pancreas and other digestive organs.36 This horrific surgery, known as the Whipple procedure, has a mortality rate of 15% and a five-year survival rate of only 10%.37
A study released in the journal Hepato-Gastroenterology revealed that when moderate-dose interleukin-2 was administered before the Whipple procedure, the survival rate after three years was 22% compared to 0% in the group that did not receive interleukin-2.38
In 2015, the Journal of the American Academy of Dermatology reported on another study that used interleukin-2 and other immune boosters. Eleven patients with cutaneous (skin) metastatic melanoma were given injections of interleukin-2 directly into skin lesions along with applications of the drug imiquimod and a topical vitamin A drug (tazarotene).39
All 11 patients had a 100% complete response rate from this three-drug combination (interleukin-2, imiquimod, vitamin A). Biopsies confirmed that there was an absence of malignant cells in the treated areas. Two-year survival rate was 82% in these patients receiving the three-drug combo.39
The results of this study were so impressive that the study was included in the US National Comprehensive Cancer Network guidelines.39
Synergistic Combination of Interleukin-2 and Checkpoint Inhibitors
Checkpoint inhibitors and interleukin-2 have unique mechanisms of action on the immune system. The checkpoint inhibitors break down shields that cancer cells erect against immune attack while interleukin-2 promotes natural killer cell immune activity.
It is therefore logical to speculate that the combination of interleukin-2 and a checkpoint inhibitor drug would be more effective than either drug alone.
A recent study supports this hypothesis.5 In this study, mice were first injected with immune-resistant melanoma cells to infiltrate the mouse’s body similar to metastatic melanoma in humans.
Researchers then tested interleukin-2 alone, cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade (checkpoint inhibitor like Yervoy®) alone, or a combination of interleukin-2 and CTLA-4 blockade on these mice. The results were prolonged survival and significantly delayed tumor growth in the mouse group getting both drugs (interleukin-2 and checkpointinhibitor).5
In the control group, tumors reached a size of 76 mm2. In the mice that received interleukin-2 alone, tumor growth was 29 mm2.
By contrast, the checkpoint inhibitor group’s tumors grew by 14 mm2, which was only half the size as the mice treated with interleukin-2 alone.5
What is astonishing is the mice that received interleukin-2 and the checkpoint inhibitor combination had a tumor growth of only 2 mm2. This combination was seven to 14 times more effective than treatment with either drug alone.5
At day 23, there was 100% survival in the group receiving the interleukin-2 and checkpoint inhibitor combination compared to 30% survival in the interleukin-2-only group and 50% survival in the checkpoint inhibitor-only group. Control-treated mice were all dead by day 23.5
This study, along with a cumulative knowledge of the mechanisms of action of interleukin-2 and checkpoint inhibitors, indicates that the combination of these two immunotherapies might be suitable to study in human metastatic patients.
Fighting Brain Tumors
Researchers at Duke University are conducting trials on an innovative therapy that uses a genetically engineered poliovirus to fight glioblastoma.40,41
Scientists have removed a specific genetic sequence from the poliovirus and replaced it with an innocuous part from the rhinovirus. This completely changes the structure of the poliovirus into an oncolytic virus, which is a virus that attacks cancer cells.42,43
This genetically engineered poliovirus naturally targets cancer cells since the receptor for poliovirus is abnormally present in most tumor cells. This oncolytic or “cancer-fighting” virus only kills cancer cells because their ability to grow depends on the biochemical abnormalities that are only present in cancer cells.41
A report on 60 Minutes about the use of this poliovirus treatment on glioblastoma brain tumor patients was nothing short of astounding. The genetically engineered poliovirus extended the lives of most of the patients. Some glioblastoma patients appeared to go into a complete remission, with no evidence of residual remaining tumor.44
The researchers are conducting further studies and are enrolling all glioblastoma patients who meet eligibility criteria. In less than a year, the FDA is expected to make a decision on approving this immunotherapy for glioblastoma patients.44
Immunotherapy Prevents Breast Cancer Metastasis
A therapy called photodynamic immunotherapy (PDIT) was described in the November 2012 and September 2015 editions of Life Extension® magazine.
This immunotherapy works by first delivering a photosensitizing agent to the breast tumor. This enables the effects of a laser to be amplified in a way that destroys the primary tumor. The agent used also enables the immune system to mount a response against infiltrative or metastatic tumor cells. In addition, it breaks down cancer’s defense mechanisms that would otherwise thwart immune attack.45,46
When this therapy was studied on 15 breast cancer patients, survival rates were comparable or exceeded that of conventional treatments, which utilize mastectomy, radiation, and chemotherapies. What makes photodynamic immunotherapy newsworthy is that it is has no serious side effects.47
Current studies are testing photodynamic immunotherapy for prostate, lung, melanoma, and other advanced cancers. If you would like more information on the availability of photodynamic immunotherapy, please call the International Strategic Cancer Alliance (ISCA) at 1-610-628-3419.
How Regulations Create Delays
In 1971, the United States government enacted the National Cancer Act.48 It is almost half a century later and more than 1,600 Americans die of cancer every day.1
Dr. Vincent DeVita is a world-renowned physician. He has served as the director at the National Cancer Institute, physician-in-chief at Memorial Sloan Kettering Cancer Center, director of Yale University’s Cancer Center, and president of the American Cancer Society.49
Dr. DeVita writes, “The real impediment in the war is the regulatory environment and an outdated infrastructure for it, created well before we knew much about the disease.”49
The National Cancer Act was a step closer to the cure for cancer, but it wasn’t good enough.
The act attempted to shift the power of drug approval from the FDA to the National Cancer Institute, but instead the FDA became a roadblock for patients awaiting new drugs.
The National Cancer Act of 1971 also established cancer centers in universities, but they too often became entangled with academic politics and grants.
According to Dr. DeVita, cancer centers founded by the National Cancer Institute (NCI) should be allowed to practice independently. The authority to prioritize clinical trials needs to be taken away from the FDA and given to these NCI cancer centers.49
Dr. DeVita calls for a new National Cancer Act. He asserts that we have amassed the scientific knowledge, but bureaucratic regulations need to be circumvented to more effectively develop curative therapies.
We at Life Extension® have long concurred with what Dr. DeVita is now publically calling for, i.e. an end to inane regulations that hinder development of novel cancer treatments.
The delay of effective drugs translates to millions of needless deaths.
The efficacy of immunotherapy drugs (Yervoy®, Opdivo®, and Keytruda®) that target the genetic makeup of a tumor dates back to 1996, yet even today, they’ve only gained approval for use in a small number of cancers.
These drugs are known as checkpoint inhibitors, and when they are combined with interleukin-2, survival rates increase even more dramatically in the mouse model.
A Duke University study of genetically engineered poliovirus has shown outstanding results on glioblastoma patients.
These advances have managed to occur (slowly) despite bureaucratic roadblocks that innovative researchers must contend with.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
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- Kohlhapp FJ, Broucek JR, Hughes T, et al. NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade. J Immunother Cancer. 2015;3:18.
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