We are entering a new phase of cancer treatment, Allowing our own powerful immune system to stop cancer in our bodies.
Its interesting to know that there were at least 3-5 separate species of humans over the past hundreds of thousands of years. They all originated in Africa and migrated to all the various areas in the world. The Neanderthal , the Denisovians, Erectus all were before our species the Sapiens. However there was interbreeding and although these other species died out we still have 3-5% of their genes. A part of this gene swap was the important immune genes.
All vertebrates have a group of genes called the Major Histocompatability Complex (MHC) and in the humans it is called the Human Leucocyte Antigen genes (HLA). These differ in each individual and determine how our immune system determines our Self from Non self. Even close relatives will differ in their HLA genes. Each of our cells has a unique hair like beard on its surface that tells our immune cells it is self.
Self can be passed on. In a series of transplant patients sudden and dramatic changes can take place. Change in drinking or eating habits, interest in things that they were not interested in before. The transplanted organs were able to pass chemical messages to the new organ owner.
With infections or other cell abnormalities these HLA genes will identify the foreign molecules present and present pieces of viral proteins (antigens) or other abnormal fragments on the surface of an infected cell, where they can be recognized by T cells and trigger an immune response. Abnormal proteins produced by cancer cells give rise to tumor antigens, which are also presented on the cell surface by HLA molecules and can be recognized by T cells.
T cell activation can lead to recruitment of other immune cells, proliferation and differentiation of T cells, and direct killing of infected or cancerous cells. The exact nature of the response depends on the antigen and on other signals received by the T cell. Different peptides or antigens give different outcomes.
T cells, the managers of our immune systems, spend their days shaking hands with another type of cell that presents small pieces of protein from pathogens or cancerous cells to the T cell. But each T cell is programmed to recognize just a few protein pieces, known as antigens, meaning years can go by without the T cell, or its descendants, recognizing an antigen.
When the T cell does recognize an antigen, it gives the cell presenting the antigen (usually a dentritic cell) a "hug," so to speak, instead of a handshake. This initial interaction causes the T cell to search nearby to find other cells that are presenting the same antigen to give them "hugs" as well.
UCLA researchers have discovered that after the initial hug, T cells become more gregarious, giving something more like a bear hug to any cell presenting its antigen. These larger hugs help to activate the T cell, equipping it to go out into the body and coordinate multi-cellular attacks to fight infections or cancers.
The UCLA team learned that how stiff or soft T cells are controls their response � the cells react slowly when they are stiff and trigger easily when they are soft. By developing drugs that can alter the stiffness of the T cells they can be induced to be more active and attack (for cancer treatment) or less active (for autoimmune treatment).
Amazing Video of these primed T cells attacking and killing cancer cells.
Coloured scanning electron micrograph of T cells (pink) attacking a cancer cell. Editing T cells' genes could soon enhance their cancer-attacking abilities. � Science Photo Library / Getty Images
A mouse macrophage gripping its 'prey' � a microrobot.
Cancer cells are able to avoid this detection and action of the immune system.
Cancer is a self cell of the body and does not always express foreign antigens. Another Cancer defense is down regulating the HLA system.
Another method is inhibiting the actions of pro death ligands (proteins to stop cancer) such as PD-L1 and PD-L2 .
Also cancer cells recruit immune cells to the area that secrete proteins that downgrade or regulate (T regs) immune reactions.
The problem is how to overcome these problems and allow our immune system to kill cancer cells. One method is insertion of a Chimeric Antigen Receptor in to the T cells.
A Chimeric Antigen Receptor (CAR) is a single receptor that consists of components of multiple proteins that are genetically joined together. This new gene is inserted into a T cell by a virus vector. This allows a surface protein to be targeted by the T cell and is independent of the HLA function. The patients white cells are cultured and the CAR is inserted. Sometimes chemo is given for a few days to deplete the immune T regs that protect cancer cells. Using this technique for B cell cancer at various institutes an overall 70% to 90% reached minimal disease status.
Engineering a Cancer Killer Doctors are genetically modifying immune cells to hunt down and destroy cancer cells.
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T-cells are a type of white blood cell that can identify and kill other cells. Each T-cell has clawlike receptors on its surface that can lock ontoantigens, protein fragments on the surface of abnormal cells. Doctors remove millions of the patient�s T-cells and send them to a lab.
ENGINEERING A HYBRID CELL
The patient�s T-cells are infected with a modified virus that cannot cause disease. The virus contains genetic instructions to make each T-cell grow a new type of receptor on its surface. These hybrid T-cells are called CAR T-cells, for chimeric antigen receptor T-cells.
ACTIVATING A SERIAL KILLER
The virus also contains instructions for other molecules, an activator and aco-stimulator, which put the T-cell into a killing mode. The activated CAR T-cells are multiplied in the lab, then sent back to the hospital and dripped into the patient�s veins.
ATTACKING CANCER CELLS
The cells cause a ferocious immune reaction as they find and destroy the patient�s B-cells, which are covered with a protein called CD19. B-cells are a type of white blood cell involved in some leukemias and lymphomas. CAR T-cells have not yet been proven to treat other kinds of cancer.
Solid tumors are more difficult due to the strong regulatory T cell protection they develop.
A problem with CART cells is they become "exhausted" over time. This is due to the increased regulatory chemicals cancer cells can produce. It stops the immune cells from attacking. If we were able to reprogram the CART T cells by delating those genes that express increased levels of regulator genes such as PD 1 , and others, then the cells would continue to kill cancer cells and not become regulated to stop.
There are side effects. Examples are the reactions in healthy lungs due to a HER2 surface protein that reacted with the CAR. A reaction in the colon due to cross reaction with a CEA protein on healthy colon cells.
Another problem can be the high levels of potent cytokines released by the increased response to the CAR treatment. Cytokine storm. The cytokine mostly responsible is IL-6. An antibody against this , tocilizumab, is used. The reactions are often related to the amount of tumor that needs treatment. This reaction occurs 25-30% of patients but can be treated.
"Safety Switches" have been added to CAR treated T cells. These are ways to increase the destruction of the T cells cells by apoptosis (self destruction) if too active.
The genetically engineered CAR-T cells to carry a "barcode scanner and switchboard "as two separate parts, so they can scan and stick to the target but can�t attack the cell. Only when a special glue is added � in this case, a drug called rapalog � do the parts snap together, completing the circuit and allowing the cell to launch an offensive. By withdrawing the drug doctors can switch off the T cells if things go awry.
The �switchable� CAR-T cells only killed cancer cells in mice when the mice were also given rapalog. In a petri dish, they also showed they could use rapalog to dial the CAR-T cells up or down like a dimmer switch. The more rapalog, the more cancer cells died.
Doctors could one day inject these switchable CAR-T cells to let them roll around the body and �hope they stick to cancer cells like flies on a cake,� as Boyd puts it. Doctors could then slowly ramp up their cancer-killing power by increasing the rapalog dose, while keeping a close eye on any side effects. Should they see excessive fever or signs of cross-reactivity, doctors could stop and the T cells would become inactive. Rapalog is excreted by the body after only a few hours. The plan is to develop a longer acting Rapalog drug.
A big problem in all of this is the fact that as cancer cells divide and grow new mutations and new "drivers" develop. Some of these may not create the original antigen and therefore not attract the CAR T cells. It will be necessary to re valuate new tumors and recurrences for these new proteins, create new CAR-T cells against them and re treat.
The CAR T cells that have been used in hematologic malignancies have in the main been focussed on targeting CD19, which is expressed on B lymphatic cells.
In the latest report, the researchers at the City of Hope developed another type of CAR T cells that target the high-affinity IL-13 receptor IL13Ra2, which is over expressed in a majority of glioblastomas.
They administered the therapy locally in the brain by directly injecting it into the tumor site and/or through infusion in the ventricular system. (By contrast, for hematologic malignancies, the CAR T cells are administered by intravenous infusion.)
This method of administration was associated with a much lower incidence of adverse events, (Cytokine Storm) which have been life-threatening in some of the patients with hematologic malignancies.
In the glioblastoma patient treated with CAR T cells administrated intraventricullarly, the team reports that there was a significant increase in a number of inflammatory cytokines in the cerebrospinal fluid. This increase appeared to correspond with the incidence of grade 1 and 2 symptoms, such as fever, fatigue, and myalgia. The cytokine levels returned to near baseline levels between weekly treatment cycles.
They also note that these immunologic changes were restricted to the cerebrospinal fluid; no notable increases in levels of cytokines and no CAR+ T cells were detectable in the peripheral blood.
"The absence of systemic toxic effects is particularly noteworthy given the severe cytokine release syndrome and neurotoxicity that are often associated with antitumor responses against high disease burden in patients receiving CD19-targeted CAR T-cell therapy," the authors comment.
Monoclonal antibodies are nonspecific and bivalent (contain two identical antigen binding sites and one crystal fragment (Y shape). The bi specific property allows then to bring more then one cell type together. By binding the T cells to the tumor cells and allows an activating signal to occur. This allows the T cell to recognize the cancer cell and to react to it. The purpose is to redirect effector immune cells to antigens that they would not otherwise recognize.
An example is blinatumomab used to treat acute lymphoblastic leukemia. Patients with less then 50% of the bone marrow involved had a 73% response With a greater amount of tumor the % dropped. Overcoming Immune suppression in the tumor environment so our own immune system can act.
Tumor cells , by their actions make themselves susceptible , to the immune cells in our body and the possibility of destroying them. Mutations , as well as inflammations and other causes of abnormal cell metabolism, create abnormal appearing proteins (antigens) on the cancer cell membranes. . The cancer cells have discovered many ways to hide from the powerful immune system. They use the many pathways available in our immune system to do this. The function of self recognition, foreign recognition and regulation of the immune system is constantly changing. It is necessary to change the cancer cells environment from immunosuppressive to one that allows attack by the immune system.
One natural way the body can cause regulation is by creating enzymes that produce proteins that have suppressive actions. One of these pathways is the IDO gene family which is activated when significant dying cells (after chemotherapy) are produced. Increased IDO protection is found in many tumors and protects them from destruction. They affect the function of the dendritic cells and create increased regulation of the immune system and protection of the tumors.
By inhibiting the IDO genes and by increasing the amount of dead tumor cells with chemotherapy and radiation the immune system can be effective in removing the cancer cells. Also, the amounts of antigenes released by these treatments are recognized by the immune system. Fortunately , the IDO inhibitors are well tolerated. They are used with combinations of chemo, radiation, vaccines, (multi antigenic peptides to different tumors) and check point inhibitors.
Tumors often have increased numbers of these T regs that suppress tumor killing. Even those tumors that have many T regs killed can continue to suppress the activity of the immune system.
In 2004, researchers discovered that Treg cells were acting against cancer immunity. They linked higher numbers of these cells to shorter survival in patients. That work led to the failed clinical trial designed to eliminate the Treg cells.
It turns out, this new study finds, that when Treg cells die, they release a lot of small metabolites called ATP. Usually ATP helps supply the body with energy. But dying Tregs quickly convert ATP to adenosine. The adenosine then targets T-cells, binding to a receptor on the T-cell surface. This affects the function of the T-cells, making them unhealthy.
Tregs travel to the tumor from throughout the body, which explains the earlier finding that there are many Tregs in a tumor. But while the Tregs proliferate, at the same time they are dying fast. So there are a many Tregs but also many dying Tregs.
Many cancers have a group of cells , Myeloid derived suppressor cells, (MDSC), that group around the cancer and suppress the immune system from recognizing and attacking the tumor. A molecule from onions, onioninA (ONA), has been shown to stop this effect of the MDSC. This allows the immune system to do its clearing of tumor cell.
Unfortunately there are many patients that do not respond to the inhibitory treatment. After a few days the T cells die and do not attack the tumor. As a tumor develops, slowly, it attracts a special type of cell from the bone marrow, the Myeloid derived suppressor cell (MDSC) . This cell migrates to the tumor site and secretes a molecule, FAS ligand, which binds to a receptor on the T cells at the tumor site and causes them to begin their own cell death (apoptosis). This removes these healing cells from the tumor.
There are developments of a drug to block the action of FAS ligand and stop the destruction of the cancer killing T cells.
A recent study, published in the journal Nature, describes in detail a metabolic mechanism that helps convert one cell type into another. A small molecule can act on the immune cells receptors.
This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body. Converting these cells into regulatory T cells could help reduce the hyperactivity and return balance to the immune system, thus treating the root of the disease.
In addition, the study could improve therapies using stem cells. At least in theory, producing regulatory T cells could promote immune tolerance and prevent the body from rejecting newly-transplanted cells.
"Our work could also contribute to ongoing efforts in immuno-oncology and the treatment of cancer,"This type of therapy doesn't target the cancer directly, but rather works on activating the immune system so it can recognize cancer cells and attack them."
Many cancers take control of regulatory T cells to suppress the immune system, creating an environment where tumors can grow without being detected. In such cases, the team's findings could be used to transform regulatory T cells into effector T cells to strengthen the immune system so it can better recognize and destroy cancer cells.
Tumor cells cause extensive expansion of MDSCs, which are associated with poor prognosis in patients with various types of cancer. Using a state-of-the-art microscopy system to visualize T lymphocytes, the professional killers of cancer cells within the arsenal of the immune system.
They discovered that MDSCs can blunt the immune reaction to cancer by preventing the ability of T lymphocytes to enter lymph nodes, important sites where the immune response to invading cancers becomes ramped up. MDSCs accomplish this by removing a molecule known as L-selectin from the surface of T lymphocytes that is essential for cellular trafficking into lymph nodes. As a result, the protective immune response to cancer is severely compromised.
Given the rapid movement of cells within the circulation, one of the most surprising findings of this investigation was that MDSCs can act directly on T cells within fast-flowing blood to limit their widespread trafficking to lymph nodes. This subversive activity of MDSCs was not restricted only to T lymphocytes but included B lymphocytes, which are responsible for generating protective antibodies against tumor cells. The team's research established for the first time that B lymphocytes are also a target of MDSCs in cancer.
Having established a link between TAMCs (Tumor associated myloid cells) and checkpoint inhibitor resistance, researchers next set out to test the hypothesis that blocking immune suppressor cell activity would improve immunotherapy response. To do this, they used an experimental drug manufactured by Infinity Pharmaceuticals called IPI-549. The drug, which is available for clinical use, blocks a molecule in the suppressor cells called PI3 kinase-gamma. Blocking this molecule changes the balance of these immune suppressor cells in favor of more immune activation.
"We effectively reprogrammed the TAMCs, turning them from bad guys into good guys,"
IPI-549 dramatically improved responses to immune checkpoint blockade (ICB) therapy for tumors with high concentrations of TAMCs. When checkpoint inhibitors were administered to mice with suppressed tumors, only 20% of the animals underwent complete remission. When the same drugs were administered with IPI-549, that number jumped to 80%. IPI-549 provided no benefit to tumors lacking the suppressor cells. As an example of the complexity of these treatments is Prostate cancer. Prostate cancers usually have very few immune cells near the cancer cells. The cancer cells are good at suppressing the signals to attract the immune system. This is done by a molecule PD-L1 that reacts with a receptor on the immune cells (PD1) to stop the immune cells from recognizing the cancer cells. There are drugs to block the PD-L1 from doing this but the cancer cells still are protected. There is a second inhibitor of T cells, VISTA, which may also need to be blocked. Not just one but two inhibitors protecting the cancer.
A scanning electron micrograph of two T cells attached to a cancer cell.
STEVE GSCHMEISSNER / GETTY
Using drugs called checkpoint inhibitors, patients with incurable cancers like advanced melanoma have shown long-term responses.
Forty percent of melanoma patients will still fail to respond to the treatment, however, which means that cancer cells must have other means � ones that are not addressed by checkpoint inhibitors � to disable the immune system�s weaponry.
To discover what they are, a research team led by Nicholas Restifo at the US National Cancer Institute began with human melanoma cells growing in a dish, and systematically disabled every gene in the melanoma cells using the CRISPR gene-editing technique.
They then tested the ability of the T-cells fighters to recognize each one. It turned out about 100 different genes activated by the cancer were able to prevent the attack by the T-cells. This shows the variety of inhibitors that a cancer may use.
Macrophages are very active attack cells and will engulf and destroy cancer cells when signaled. However they have two possible conditions, M1 which is the attack and kill phase or M2 which is the heal and repair stage. The macrophages near prostate cancers ( and probably others) is in the M2 stage which actually helps the cancers. These M2 macrophages showed high levels of regulation PD-L1 and Vista molecules.
There are new methods that will allow us to identify the various "drivers' of different cancers and therefore allow specific antibodies against them, "personalized medical treatment". At this time about 30-40% of cancer patients qualify for this personalized treatment. There are about 5 Antibodies against the immune inhibitors available at this time. By using two or more the results are much better since cancer cells can use more then one type to protect themselves.
It is found that some tumors have many more tumor mutations then others especially in older patients. The more mutations the more targets for the immune system.This means that these tumors would have more foreign appearing targets (mutation proteins) then those with less changes. The immune system would be more likely to recognize these and attack. These increased loads are seen in Melanoma and lung cancers. By using checkpoint inhibitors to block the inhibition of the immune system there would be better results. Stem cells are a major source of cancer . They are found in all organs and constantly divide to replace the adult cells. Each division creates possible damage. When they mature to adult cells they are susceptable to treatment but when they are stem cells they are resistant. "Nests" of these damaged precancer cells are often found when cancer is found. These can cause recurrences later. By promoting their maturity they can then be treated.
Stem cells, and other immature cells, are more resistant to treatment then adult cancer cells. A drug ATRA ( trans-retinoic acid) causes certain leukemic cancer cells (promyelocytic) to stop their uncontrolled growth and mature into normal adult cells. The drug stops the action of an enzyme produced by a mutated gene. Many of the cells would then go back to cancer cells in 3-6 months. By using a drug, arsenic trioxide, that is a known cancer killing drug, they could then kill the mature cancer cells that were more susceptible to the drug then the immature cancer cells. This treatment has a 95% cure rate. This finding has allowed the realization that immature cancer cells, that are resistant to treatment, can be forced to mature and then treated when they are susceptible. It is thought that many different cancers have their own stem cells and these cause the recurrence often seen.
Aggressive breast tumors have a high level of a micro RNA ( controls the messenger RNA from different genes) that reduces the stem cells from recognizing important signals from the immune cells in the tumor. This allows the cancer stem cells to divide and grow more rapidly. This miRNA blocks a protein, LCOR , that allows the signaling to the stem cells from the immune system. The less LCOR the more cancer stem cells grow and divide. A drug to block the miRNA action would be important.
Antibodies can be washed in a solution of Quantum Dots (very small fluorescent balls that vary in size from 2-6 nanometers). The color they emit varies with their size. These nano-antibodies are infused onto a tissue sample from a patients tumor sample and with a microscope it is seen if a dot-antibody has reacted with a protein on the cell. The color is for a specific antibody reaction showing which one of the proteins is driving the cancer. The cell may then be treated with a certain low pH solution, is cleaned and another antibody-dot can be injected. At this time 100 separate biomarkers can be identified in a single cell! When trying drugs to stop cancer it will now be possible to see which proteins are the drivers allowing a specific antibody drug to be developed.
FDG-PET, a method that the University of Pennsylvania helped pioneer, has been used for more than two decades to detect tumors and determine the extent to which cancer has spread. But the newer PET probes now in development and testing target certain tumor markers. This will allow much earlier and more specific detection.
Two new classes of probes that show particular promise are designed to bind to estrogen and HER2 receptors. Breast, uterine, and ovarian tumors often use these receptors to boost their growth, and many cancer drugs target them. Detecting the presence of tumor estrogen or HER2 receptors with PET scans would enable oncologists to examine all sites of cancer for each patient, choose the appropriate drug treatment more quickly, monitor the tumor for changes that would necessitate a switch to another treatment, and even evaluate how well a drug is hitting its receptor targets. Other tumor "markers" are also being evaluated for this technique.
Using an enzyme, originally found in bacteria, to "edit " our genes has produced a amazing new way of diagnosing disease, including cancers, at very early stages. This technique is called CRISPR and allows small amounts of nucleic acids to be identified. Even one molecule of RNA or DNA in a sample can be discovered. Cancers produce specific abnormal types of RNA and DNA which are released into the blood, urine and saliva. These happen during the very early cellular changes before cancer can be seen. Certain cancers have specific types. By using these diagnostic tests the cancer can be discovered early and appropriate treatment started before spread.
A new class of antibodies that are made in the lab, synthetic antibody mimics (SyAM's) scan attach themselves simultaneously to disease cells and immune disease fighting cells. This will give a highly targeted immune response that acts like natural antibodies. They are very stable and may be taken orally. They recognize the protein on a cancer cell or pathogen and bind with it and also bind with an appropriate immune cell making this a very targeted action. These are small molecules but can bring together large cells.
Using a amino acid, selenocysteine, and adding this to a tumor specific antibody ( selenomabs) allows this antibody to attach strongly and specifically to the antigen on the cancer cell surface. This is specific to the cancer cell only. No side effects. 3 of these have been approved by the FDA. It is hoped that some toxic drugs can be attached and then delivered to the cancer cell also. Inserting these antigens into memory immune cells so they can form antibodies can be done in the lab. Getting vital molecules into living cells and causing these to alter abnormal actions is a goal that has been achieved. Silicon and Glass Microchip's that have many channels that gradually narrow until the gap is smaller then the cells allows the flexible living cells to slide through but small micro openings occur on the membrane and various molecules can be inserted. Different chips for different cells and over 500,000 cell can pass in a second.
Using a special microfludic -squeezing device specific antigens can be squeezed into B lymphatic cells to create vaccines against various diseases. Usually the patrolling Dentritic cells recognize antigens and began the antibody process. The B cells are longer lived, and more abundant in the blood. Usually the B cells are restricted by limited receptors to certain antigens on their surface. They ignore others. By squeezing other antigens into the B cells they are now able to "prime" the immune killer T cells to attack the new targets.
This may also be used to put many different molecules into cells as needed. A way to give a cancer vaccination! The hope is to have the device available at the clinics, a single syringe of blood run through the device with specific antigens squeezed, re- injection of the blood , and you have vaccinated the patient . This would allow specific cancer "drivers" to be used to create antibodies against them and the programmed "B" cells injected into the patient.
Adoptive Cell Therapy , which is a process where the patients own immune cells are removed and a genetic change to create a new receptor that targets a tumor is done. The immune cells are cultured and millions produced that are now targeted to the tumor cells (not normals). By culturing the cells in an antioxidant, N-Acetyl-Cystine many more viable adoptive cells are produced. This has been used in melanoma with great success. These are then injected into the patient.
Almost all Cancers have an increase in IL-6. Other inflammatory diseases also have this inflammatory effect. A nanoscale portable device that has antibodies against this protein and can be used at the bedside is being developed. Specific antibodies against almost any antigen could be in the device and testing for many diseases will be possible. Each antibody-antigen binding gives a specific light frequency that can identify the antigen.
A tiny implant is being tested that can detect the early biomarkers of a new cancer that are released into the blood before the tumor is actually formed. This sensor would recognize these and by shining a specific wavelength light onto the skin at the sensor site the cancer markers would be recognized.
Making "designer" viruses that infest cancer cells and then these cells aredestroyed and many cancer specific antigens released that alert the Immune system to make T cells and antibodies to these allow cancer cells to be killed. The main chemical released when the cancer cells are killed is IL-33 , Alarmin, that is a major stimulator of the immune system.
At this time there are many pathways being tried to use our immune system to stop cancer. Usually when a cells DNA is damaged or the cell acquires abnormal changes (like cancer), a protein is produced by a gene P 53 which is the "angel of death" and causes the cell to produce chemicals to self destruct (apoptosis). The cancer danger is removed by stopping the ability of the cell division. However, cancer cells are superb at fooling the cell and can create a protein called MDM 2 which binds with and inactivates the P 53 produced protein. No cell destruction happens and the abnormal cell now proliferates. It becomes immortal. There is active work on developing a drug that will cause the MDM 2 to separate from the P 53 and allow the apoptosis (cell death) to occur. 50% of cancers have inactive P53.
Certain cancers (bladder, lung, melanoma) have increased levels of a protein , PDL1 that is produced by the cancer cells and binds to a cell receptor on T cells that inhibits the T cells from recognizing and attacking the cancer cells. An antibody has been developed that binds with the T cell receptor and prevents the PDL1 from inhibiting the T cell and the cancer cell is destroyed. Not all cancers have high levels of PDL1 but when they do there has been great success. Checkpoint Inhibitors are antibodies ( there are at least 5) that bind with the various cytokines that the cancer cell produces to protect itself from attack by the immune system. In order to get these to just affect the cancer cells and not effect the important functions in normal cells a "mask" has been developed for the antibody.
One approach is the so-called adoptive T-cell therapy, which involves removing immune cells from the body and genetically arming them. The cells are given new structures on the surface that accurately lead them to the cancer cells.
One limitation in this form of therapy is that the binding between the immune cell and the cancer cell is often somewhat weak. "Although this binding can be artificially strengthened, doing so also increases the risk of unwanted binding to healthy structures in the body.
In current work, researchers present a new surface molecule which comprises two halves. On the outside, it preferentially binds to the PD-L1 molecule, which tumor cells often form in order to thwart the attacking immune cells. On the inside of the T-cells, however, this binding does not activate a sleep mode (which the natural protein would do), and instead activates the T-cell's killer program, making it especially aggressive. Experimental models showed that T-cells armed in this way proliferate more strongly in the tumors and destroyed more tumor cells. Using certain biomarkers ( products of the cancer cells) such as MS1-H and dMMR which show failure of DNA repair, allows the choice of certain checkpoint inhibitors which acts to allow the T cells to inhibit the tumors
"Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy,""While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved." There is a normal control of the immune cells attack activity done by the regulating T cells (T regs). . Some immune cells are T regs.They slow down and stop the attacks. These are separate from the PD inhibitors and due to Nf-kB receptors that signal the T cells to regulate the attack T cells. These are important to prevent an out of control immune response and auto immune disease. If only one of the receptors are blocked, c-Rel, then the regulating cells allow the attack on the cancer to continue without whole body effects. This increases the cancer killing by 50-60%.
A drug now in in use for increased blood flow, Pentoxiflline, does this. It is being paired with a PD 1 inhibitor, Opdivo, to increase the effectiveness of the treatment.
PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. "Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer. One way to know that immune inhibitors are probably being used by the cancer is seeing large numbers of macrophages at the site without attack.
Scientists have long sought a way to discover whether patients will respond to new checkpoint inhibitor immunotherapies and to better understand the characteristics that indicate a tumor can be successfully treated with them. A proposed mathematical model, which captures aspects of the tumor's evolution and the underlying interactions of the tumor with the immune system, is more accurate than previous genomic biomarkers in predicting how the tumor will respond to immunotherapy.
Using certain biomarkers for cancer changes that can be found early in the blood, urine and saliva allows a cancer to be recognized and appropriate treatment started. An example is the biomarker MS1-H that is a marker for a abnormal DNA repair system in many cancers. This can be found in melanomas, lung, uterine and other cancers. If it is recognized then a checkpoint inhibitor can be used to allow the immune system to attack the abnormal cancer cells. Remember, it maybe that more then one type of checkpoint inhibitor is active and other checkpoint inhibitors maybe necessary.
The PD1 mechanism is similar to that of another antibody , the antibody that blocks the protein CD47 that also inhibits the immune system. Cancers with PD-L1 decreases the response to pain. Cancers at the primary site (before spreading) secreting PD-L1 blocks pain. It is not until the cancer metastases that the patient experiences pain. As successful treatment progresses and the PD-L1 is blocked and the pain is felt. This maybe a way of seeing if the treatment is working.
The PD-L1 injected into the dorsal neurons of the spine (where pain is sent from the site of injury) causes the neurons to stop "firing"and the pain sensation is stopped. This may be a way to add a new pain medication to help patients.
A problem has been found with the exhaustion of T cells when attacking cancer cells. The cell surface receptors of T cells act like brakes to stop the immune cells and prevent damage to normal cells by overactivity (autoimmune disease). Blocking of PD 1 can allow increased activity but even then the T cells soon become "exhausted". This treatment also decreased the ability of the memory immune cells to function.
These exhausted T cells have a epigenetic profile distinct for the effector and memory T cells. These profiles effect the activity or inactivity of DNA and change the cells behavior. These can last for long times. The epigenetic profile remained even with the PD 1 blockade. This prevented the T cells from changing into the more active effector or memory types of immune cells. This is why using PD 1 blockade (check point inhibitor) does not always work. Most cancer patients respond to PD 1 block at first but then it fails. It seems that we need to reprogram the epigenetic profile to achieve long lasting active T cells against cancer.
The exhaustion process was intrinsic to the T cells. This finding has important implications for immunotherapies in which a patient's T cells are engineered outside the body to supercharge them to fight a cancer and then are reintroduced into the body.
"Now that we have shown this is an intrinsic property of T cells, it means you can pull out the T cells, treat them, and reintroduce them to attack the cancer,"
The researchers found that treating the T cells with a widely used immune-checkpoint inhibitor called PD-1 did not erase the epigenetic exhaustion finding. "This finding shows that, at least for this particular therapy, the therapeutic effect may be inherently transient and prone to relapse,"
However, when researchers treated mice that had tumors with the chemotherapy drug decitabine, their T cells showed properties indicating enhancement. Decitabine acts to thwart the epigenetic DNA methylation off-switch."We found this treatment reversed the exhausted state,
The active killer T cells lose their ability to destroy cancer cells after a while. It has been discovered that a hormone, Leptin, released by increased fat cells in the bone marrow causes this. Blocking this Leptin receptor on the T cells allows them to become active. It is now known that these checkpoint inhibitors bind as an antibody to the PD1 receptors on the attack CD8 T cells. This allows the cells to avoid the regulation. The problem has been that the inhibitors do not last long. New microscopic observations show that the immune systems macrophages recognize this antibody on the T cell surface and remove it, quickly, leaving the T cell to be blocked by the cancer PD1. The removal depends on a reaction of the macrophage with a section of the PD1 antibody (the Fc part). If this were blocked then the inhibitor would be much more effective. Another problem is the the inhibitors blockers are non specific and can cause other parts of the body to be affected by the loss of inhibition. By adding a specific peptide (small protein) that is derived from a placenta protein, so that a combination of inhibitor and protein are then injected into the tumor site. The peptide binds to the extracellular matrix adjacent to the tumor and allows the blocking of the inhibition to only be at the tumor site. This avoid systemic side effects.
A macrophage (red) removing PD-1-blocking antibodies (yellow) from the surfaces of neighboring CD8 T cells (blue), cutting short the drug's activity. Credit: Sean Arlauckas, PhD, Christopher Garris, Mikael Pittet, PhD, and Ralph Weissleder, �more Probody molecules are found throughout the body. However, these are at very high levels adjacent to cancer cells. The probody (protects) is a mask that stops the antibody from combining with the checkpoint protein unless it is removed from the antibody by the high level of protease enzymes at the cancer site. Once removed the antibody is able to block the cancer produced checkpoint inhibitors and the immune system attacks.
There is not a 100% effect of PD1 and other inhibitors on tumors. It has been found that the T regs in the tumor itself have a different membrane protein then T regs in other places. This is Nrp1 that allows the T regs in the tumor to continue expressing immune regulators stopping the attack. By blocking these receptors the T regs in the tumor are upgraded to attack cells. An interferon in the tumor region can also block the suppressive actions of the tumor T regs. This is 1 Fny and if a drug were made it could be used as another T reg blocker. The important thing is that these are produced by T cells in the tumor only so the remaining T regs throughout the body would not be effected.
Cancer creates many new blood vessels to nourish the rapidly growing tumor mass. These vessels can cause WBC's of the immune system to be directed away from the tumor. However if anti angiogenesis antibodies are given to block the vessel formation a new type of vessel is made. This is the High Endothelial Vessels that are found in lymph nodes and are roadways for WBC's. Adding the anti angiogenesis antibodies to the use of the checkpoint inhibitors for PD 1 increases its actions against tumors.
The immune cells involved in destroying the cancer cells include, B cells, T helper cells and T killer cells. The T helper is the one that seems to be inactivated by the cancer cells and it is this cell type that enables the others to be effective. It is also responsible to allow memory so that the cancer antigen can be recognized later by the immune system. By adding a cytokine to the vaccine (IL-33) , the T cells are more active against the cancer antigens. Certain cytokines are signals to specific immune cells for specific actions. It maybe that these can be developed as drugs to activate cancer cell attacks.
An example of the protein blocking treatment is Chronic Myelogenous Leukemia which is caused by a translocation of two chromosomes where a hybrid oncogene (cancer promoting protein) is formed. This gene causes uncontrolled division and cancer. A special protein blocker was discovered that covered the active part of the abnormal oncogene protein and the disease was stopped. The drug is called Gleevec. The idea of a specific drug to block an activity without side effects was a great discovery.
A new drug named ibrutinib is being used to treat chronic lymphatic leukemia (CLL). It blocks the protein BTK found in blood cell tumors. Itbrutinib binds to the BTK receptor stopping the cells from signaling and receiving vital nutrients needed to survive. Eighty three percent of the study group was alive after two years.
The Tyro Kinase Receptors on the surface of cells are receptors for important growth stimulators of the cell. These include , Epidermal Growth factor (EGF), controls cell growth rate and differentiation, Platelet derived GF, same function and Vascular Growth receptor promoting increased blood supply for growth. If a mutation occurs and the protein switch to regulate these receptors is stuck on "ON" then the cell receives increased demand for growth and causes cancer changes. Many tumors have this situation and this allows their growth.
There are about 8 new drugs that inhibit this from acting and the various ones effect different receptors but the result is slowing down or stopping many cancer growths. Normal cells are not effected.
A new monoclonal antibody, duilumab, blocks the action of a immune cytokine, IL-4 which is over expressed in skin eczema. By blocking this signal molecule the disease is stopped. Many chronic inflammatory diseases are due to over expression of these interlukin's and monoclonal antibodies may stop the processes of most of these.
70% of Breast cancer are types that depend on Estrogen receptors on their surface to grow (ER positive). If these sites are blocked the cancer is slowed or stopped. There are drugs to do this blocking but one, fulvestraut (Faslodex), tags and destroys the receptor leaving no more message center for estrogen to act .
Premalignant lesions have a ability to suppress the immune system and allow progression of the possible cancer. Significantly, as premalignant cells develop into cancer , the immune environment switches from stimulatory/inflammatory to immunosuppressive. This change in the tumor microenvironment prevents the immune system from combating the cancer. Prostaglandin may be an important mediator of this switch.
A current study used a novel mouse model of premalignant lesions to determine how inhibition of prostaglandin affects tumor progression. Mice with premalignant lesions were given indomethacin, an NSAID that inhibits the production of prostaglandin. Indomethacin treatment increased the presence of immune cells at the lesion site and led to a systemic activation of the immune system. Specifically, there was an increase in both Th1-associated cytokines (IL-2 and IFN-?) as well as Th2-associated cytokines (IL-10). This allows more "attacking" of the cancer cells.
This activation of the immune system reduced the progression of premalignant lesions to cancer. It may be possible to develop more specific drugs to inhibit the prostaglandins and prevent these lesions from becoming cancer.
Researchers found that, compared to normal breast tissue, breast tissue with benign breast disease had greater numbers of several types of immune cells, especially dendritic cells and macrophages that work together to create an immune response, women who later developed breast cancer showed lower amounts of antibody-producing immune cells, known as B cells, in their breast tissue, which supports the hypothesis that the immune system may play an important role in early breast cancer development.
A cytokine ,LIGHT, when injected into tumors caused a significant increase in the attraction of CD8 killer T cells to the tumor and shrinkage occurred in colon cancer and liver metastases in mice.
Cabozantinib, an FDA-approved drug for patients with certain types of thyroid or kidney cancer, was able to eradicate invasive prostate cancers in mice by causing tumor cells to secrete factors that entice neutrophils -- the first-responders of the immune system -- to infiltrate the tumor. This novel approach, utilizing the innate immune system, produced near-complete clearance of invasive prostate cancers within 48 to 72 hours.
Having a strong immune system is very important. Our Gut bacteria are constantly signaling the immune system and the types of bacteria are important. Using probiotics and increased fiber will help build a stronger system. (See blog on helping our bacteria and Fiber. ) It has been found that certain types of bacteria effect the ability of the immune attack to work. The more diversity of the bacteria allows more success. It maybe that using certain types of bacteria we can improve the treatments.
One of the problems with creating drugs to treat cancer that inactivate the abnormal oncogenes is that cancers may have a significant number of mutations. Which ones and how many need to be stopped? The same type of cancer seen under the microscope from one patient may have different mutations in another. Even a secondary tumor in the same patient can have more than one mutation. Each would need individualized treatment. One drug will not fit all.
Treating a Glioma for 5 years it was discovered that with each recurrence a new "driver " was responsible. At each occurrence the new tumor was evaluated and the new drivers identified and antibodies to inhibit them were created. This allowed a successful treatment at each recurrence.
In mice with a partially functioning immune system that had been transplanted with any of the five types of pediatric brain tumors, treating the mice with anti-CD47 antibodies ( CD-47 is a molecule that cancer cells produce to stop the immune system from recognizing them) antibodies significantly reduced the presence of those tumors.
In mice, the CD-47 antibody crossed the blood-brain barrier in significant amounts after being injected into the peritoneal space. This was an important finding because some other forms of immunotherapy are unable to cross this barrier. In mice transplanted with Group 3 medulloblastoma, anti-CD47 antibodies were more effective at treating the primary tumor if given in the peritoneal space, but better at treating metastases if given directly into the cerebrospinal fluid. The tumors showed many macrophages .
Some failures with antibody treatments is related to the ongoing changes in the mutations of different cancer cells in the same tumor. The genomic search narrowed in on genes that code for the production of antigens, which serve as a source of identification to the immune system. Cancer cells may contain mutations in genes that code for antigens, producing misshapen or otherwise altered antigens that are known to scientists as neoantigens. Such neoantigens are foreign to the immune system, and thus, the cancer cell is flagged for destruction, usually with the help of immunotherapy drugs.
It was found that after some patients developed resistance to immunotherapy, all of their tumors had shed between seven and 18 mutations in neoantigen-coding genes. By getting rid of those mutations, the tumor cells' neoantigens look less foreign to the immune system and may go unrecognized,. As tumors grow they change mutations. Each division of the cell increases the chance of a new mutation.
The researchers found that the tumors had lost these mutations by various means, including immune-mediated elimination (the treatment worked on those cells) of cancer cells containing these mutations, leaving behind cancer cells without the mutations, or by deleting large regions of their chromosomes. The cancer cells are constantly changing as they divide. Treatment will also have to change.
To illustrate the new personalized , precision type approach to treatment for each individual the following study was done.
the PALOMA study, researchers looked at the PAM50 HER2 (drivers of the cancer) subtype as a predictor of response to neoadjuvant lapatinib and trastuzumab (antibodies against these). This is an interesting study in which they took clinically HER2-positive patients and subjected them to PAM50 testing because we know that the molecular and clinical correlations are not one hundred percent, and they looked at just non-chemotherapy, dual HER2 targeting therapy in the neoadjuvant setting. And what they showed that if you are HER2 and with PAM50 you had about a 40 percent pathologic complete response to non-chemotherapy regimens, so it potentially identifies a group of patients that may be able to avoid chemotherapy if they�re HER2-positive.
Follicular Lymphoma often has a mutation of the BCL2 gene which produces a protein that then allows a cell to not die. Usually cells recognize damage and send out signals that cause it to commit suicide (apoptosis). This prevents cancer. If these genes are mutated then this process is stopped. By using a antibody that blocks the BDL2 protein the cancer will die. However, about 50% of these tumors will also have another gene CDK4 that also is mutated and allows the normal cancer suppressing proteins to be stopped. Again treatment with an antibody against this allows cancer death. Some patients have one or the other mutations but some have both.In those cases two, not just one, antibodies are necessary.
As of 2009 a majority of the genomes for all cancers had been discovered with genes mutated in tumors but not in normal tissue. In most cancers, forty to fifty mutations are seen. In Leukemias there are usually five to ten and this may be the reason why drug treatment has more success. Also, the same type of cancers show individual variations of mutations with some having one hundred forty mutations and others forty. Many of the mutations occur on genes that have little effect on the division of the cell and are probably not important for cancer control ( passengers) . The important pathways (the "drivers") probably have ten to fifteen mutations in each cancer. They create pathways that accelerate cell division or fail to stop it (oncogene mutations). Polypeptides are being developed to react with the surface of proteins in the pathways created by the mutant oncogenes blocking their actions. The good news is that many different cancers have similar mutations.
A new way of diagnosis of cancer is now under evaluation. Cancers form unique molecules that are present in cancer cells only. Phosphoproteins. Different cancers may have variations but many of these are similar regardless of the cancer type. These are carried to the cells surface in small durable packets called microvesicles and exosomes. These "waste bags" are then released into the blood. A new method can identify these and over 144 different types associated with cancer. Early detection will be possible as well as following treatments.
A protein, Kindlin-3, normally found in the hematopoetic (blood forming) system is also found in high levels in certain breast cancer tumors. The cells that contain the kindlin at high amounts had more tumor growth, more blood vessel development and were able to metastasize more often. Kindlin-3 is in the top 3% of gene products found elevated in breast cancer cells. An antibody to block this would add significant help to stopping breast cancer growth and spread.
There are a type of T cells that surround some tumors called Tumor Infiltrating Lymphocytes (TIL). These are special cells that recognize a particular gene mutation and when seen will attack and kill the cancer cell. Pancreas and colon cancers often have a mutation, KRAS, that can be presented on the cancer cells surface. The presentation of this depends on the underlying type of immune HLA system the patient has. Certain types will present this mutation on the cell surface and other types will not.
If the tissue immune system is of the type that presents the mutation on the cell surface then the TIL's will attack. By choosing those cancer patients that have the cell presentation, and then taking the TIL's and multiplying them in the lab until billions are available and then putting them into the patients blood and adding an T cell stimulator, IL-2, the cancers were stopped and actually removed.
Recently an old idea is being tried. Salmonella bacteria do well in low oxygen environments and most cancers are hypoxic. By modifying the genes , in a salmonella strain, and causing these to produce a strong immune cell signal, Fla-B, and adding these bacteria to tumors allowed the tumors to be attacked by the immune cells. The tumors had 10,000 X more bacteria then the surrounding normal tissues.
Increasing the ability of the immune system to produce more immune cells to attack cancers is desirable. This is often used with a checkpoint blocker to attract more immune cells and to make sure they are not stopped from attacking the cancer cells. However, this "revved" up system can cause serious side effects such as inflammation in other organs. This must also be treated.
There are some cancers that do not express abnormal proteins on their surface. There are no "targets" to go after. Researchers have found a way to mark the cells using a class of small-molecule sugars called azides. Once metabolized in the cell, they are expressed on the surface, and can be targeted by a molecule called DBCO.
"It's very much like a key in a lock. They are very specific to each other. DBCO and azide react with each other with high specificity. "click chemistry," "The key question is, how do you put azide just on the tumor?"
To make sure the azide would only be expressed on the surface of cancer cells, the researchers added a protective group to the azide sugar that could only be removed by tumor-specific enzymes. In normal tissues, the azide sugar simply travels through. In tumor cells, it is completely metabolized and expressed on the cell surface, creating specific targets for DBCO to deliver a cargo of cancer-treating drugs or imaging agents.
Cancer immunotherapy approaches, designed to harness the body's natural immune defenses to target and kill cancer cells, are showing great promise for cancer treatment and prevention. DNA vaccines can induce immunity through the delivery by an intramuscular injection of a sequence of synthetically designed DNA that contains the instructions for the immune cells in the body to become activated and target a specific antigen against which an immune response is sought. This approach has proven effective in generating strong immunity against some infectious diseases as well as clearing neoplasia in patients with tumors caused by viral infection. The recent identification of tumor-associated antigens, or proteins that are specifically expressed by tumor cells and not by normal cells, has sparked the development of DNA vaccine approaches against some of these promising targets.
Unfortunately, most vaccines targeting tumor-associated antigens have had limited success so far in producing therapeutic effects against most cancers due to poor immunogenicity. Despite being specific for tumor cells, tumor-associated antigens typically trigger weak immune responses because they are recognized as self-antigens and the body has in place natural mechanisms of immune acceptance, or "tolerance", that prevent autoimmunity but also limit the efficacy of cancer vaccines. This is the case of Wilm's tumor gene 1 (WT1), a tumor antigen that is overexpressed in many types of cancer and likely plays a key role in driving tumor development. Vaccine approaches against WT1 so far have not appeared promising due to immune tolerance resulting in poor immune responses against cancers expressing WT1.
Scientists have developed a novel WT1 DNA vaccine using a modified DNA sequence that tags the WT1 as foreign to the host immune system breaking tolerance in animal models. This has allowed a vigorous immune cell response to these cancer cells.
A protein , CD40, attacks cancer cell but not normal cells.This protein stops the ability of the cancers cells to resist self destruction which enables them to keep dividing even though they send out signals for self destruction (apoptosis). Clinical trials are now being done in England.
One of the most important things that we have learned is the role of our stem cells in cancer. Stem cells are probably the source of most Cancers. These are found in all adult tissues and are vital to replace the many cells lost as we age. Some are replaced much more then others, gut cells each 5 days. As these cells divide each time they need to replace adult cells they have an increase in the chance of injury. Cancer is more common in those tissues with rapid turnover.
As we age these chances increase as do the changes causing cancer to the cell. We then have a damaged stem cell replacing the adult cell. This can be the start of the cancer. Since the adult cancer cell is very active it is susceptible to treatment. However, the resting, dormant group of stem cells is not and avoids being effected by the chemo or radiation. Later, these stem cells replace the damaged cancer cells that were killed and we have a new group of cancer cells, recurrence.
The stem potential cancer cells do have specific abnormal protein markers on their surface and antibodies can be made to target these and allow the immune cells to attack. These antibodies are specific for the hidden group of cancer stem cells . Both the adult cancer cells and the dormant stem cancer cells need treatment. It is possible to make a combination of the abnormal proteins from the adult and the stem cells of the cancer , create a vaccine, and allow the immune system to recognize all of the cancer cells. Another factor in immune therapy is the diversity and type of our gut bacteria. These bacteria are known to be associated with many functions of the whole bodies immune cells. In a study looking at why some patients with PD1 inhibitors did not respond and those that did an important observation was made.
The team conducted 16S rRNA sequencing, an analysis of the presence of 16S ribosomal RNA used to identify bacteria.
Among the 93 patients treated with anti-PD1 immune checkpoint blockade, the researchers had gut microbiome samples from 30 responders and 13 non-responders. They found:
A greater diversity of types of bacteria in the responders' microbiomes.
Increased abundance in responders of the Ruminococcaceae family of bacteria within the Clostridiales order.
Increased abundance of Bacteriodales in non-responders and a much lower diversity of bacteria.
The researchers also conducted immune profiling before treatment for the presence of important immune system cells in the tumors. Responders had significantly increased immune infiltrates in their tumors, including the presence of CD8+ killer T cells, correlated to the abundance of a specific bacterium.
Another factor that involves the immune system is STRESS.
Stress is a factor.
In the study, the scientists investigated how stress affects the lymphatic system � the body�s sewerage pipe system, which drains waste such as fluid or dead cells from tissues.
The team imaged the growth of lymphatic vessels around breast cancer tumours in mice. They stressed some of the mice by locking them in a cage to stop them moving around freely for two hours a day over 21 days.
The researcher discovered that stress hormones remodelled the architecture of the lymphatic vessels around the tumours � more vessels grew and were wider, allowing more liquid to flow. This remodelled network also let cancer cells spread to lymph nodes more easily.
�We found that chronic stress signals the sympathetic nervous system � better known as the �fight-or-flight� response � to profoundly impact lymphatic function and the spread of cancer cells,� study author Caroline Le from Melbourne�s Monash University explained.
But there�s good news.
The researchers blocked the mice�s response to stress hormones with a common blood pressure �beta-blocker� drug called propranolol. When they stressed mice, they found the drug reduced the lymphatic remodelling, as well as the spread of metastatic cancer cells.
And looks like it�s not just relevant to mice.
To investigate whether beta-blockers could hold hope for human cancer patients, the authors analyzed clinical data from 956 breast cancer patients.
Sure enough, beta-blocker use significantly reduced the risk of metastasis to the lymph node. During a 78-month follow-up period after cancer diagnosis, 47 lymph node metastases were identified in patients not taking beta-blockers, where only one was diagnosed in those taking the medication.
�Blocking the effects of stress to prevent cancer spread through lymphatic routes may provide a way to improve outcomes for patients with cancer,� said Le.
A research group discovered that an immune signaling molecule called IL-6 was the link between adrenaline-dependent mobilization of NK (T cells) and tumor infiltration. It's known that IL-6 is released from muscle tissue during exercise, but presents the evidence that adrenaline specifically hails IL-6 sensitive NK cells and that the IL-6 molecules helped guide the immune cells to the tumors. Vigorous exercise may aid cancer therapy.
Another factor that compromises the immune system are toxins in the environment.
Acrolein is toxic (found in cigarette smoke and inhaled as "second hand smoke") and damages genetic material. However, it also inhibits our natural immune response via the regulatory T cells, thus accelerating tumour growth. Up until now we did not know that acrolein can suppress the immune response - not only during smoking or passive smoking but also afterwards.
However, acrolein is not only produced by smoking but also when vegetable or animal fats are overheated, for example during cooking or deep-frying. Burning of printing inks, biodiesel or wax also releases acrolein. This is the reason for the typical acrolein smell directly after a candle has been snuffed out.
"Inhalation is not the only relevant incorporation pathway. Acrolein can stick to anything, such as dinner plates, clothing or curtains and so can be incorporated much later on, via the skin, for example. It is therefore particularly important to protect children and pregnant women, especially in the domestic situation - and this can only be done by completely eliminating any contact with cigarette smoke or its residues."
We can help our body fight cancer by certain life actions. Diet is showing that compounds in food can effect the abnormalities of cancer. Remember these are all chemical changes.
A super cocktail of six natural compounds found in fruits, spices, vegetables and plant roots killed 100% of a sample of breast cancer cells without affecting normal cells. The cancers often have an undifferentiated group of stem cells which evade therapy. The compounds were; Curcumin (Tumeric), isoflavone from soy, Indo-Carbinol from cruciferous plants (Broccli family), C-phycocyanin from spirulima, Reservatrol from grapes and Quercetin which is a flavonoid present in most fruits, vegetables and teas. They were ineffective individually but had 100% effect when combined.
The drug cocktail suppressed cancer growth, inhibited migration (metastases) and caused cell death to 100% of the cancer cells. These compounds are known to affect the genes BRCA 1 and 2 mutations that occur in cancer. Two of the compounds also caused death to ovary cancer cells. By correcting the BRCA genes they were able to suppress the cancer.
The compound, sulforaphane, found in broccoli , cauliflower and cabbage and other vegetables is a potent anticancer phytochemical. It affects a epigenetic methylation in metastasized prostrate cancer cells. A enzyme, SUV39H1, is effected by this.
Another way the immune system will be used is to allow bone marrow transplants to be done in a much easier way. At this time the bone marrow is destroyed with chemotherapy or radiation , a procedure with many side effects, in order to rid the body of dangerous cancerous , abnormal immune cells produced in the bone marrow. There are two proteins on the surfaces of the bone marrow stem cells, c-kit a marker of blood stem cells and CD-47 which sends out a "do not eat or attack me" signals to the immune system. This protects these cells from our own immune attack systems. When antibodies to these two surface protein markers are added they are blocked and the patients own immune system attacks and destroys the bone marrow stem cells,
Some recent results from the use of these Immune drugs.
At the 100-milligram dose, melanoma patients treated with the Opdivo and epacadostat combination saw a 75% response rate and a 100% disease control rate,
Merck's top response rate was 47% in kidney cancer with its best disease control rate at 63% in bladder cancer. The results were released ahead of the American Society of Clinical Oncology meeting next month in Chicago. In total, Merck tested Keytruda and epacadostat in six types of cancer at varying doses.
In head and neck cancer, Opdivo plus epacadostat achieved a 70% disease control rate. Merck's Keytruda with epacadostat hit a 62% disease control rate in patients who had already undergone two prior therapies, and 43% in patients who'd already been treated three times.
Neratinib is a potent, irreversible, pan-HER inhibitor that results in sustained inhibition of the epidermal growth factor receptor (HER1), HER2, and HER4 signaling by binding irreversibly to the intracellular signaling domain of these receptors in breast cancer.
Inhibition of HER receptor phosphorylation by neratinib inhibits several downstream HER signaling pathways, leading to decreased proliferation and increased cell death. Suppression of HER-mediated growth signals and can overcome resistance mechanisms from current HER2-targeted therapies.
Neratinib can be given conveniently with once-daily oral administration. The pivotal ExteNET study in patients with HER2-positive breast cancer demonstrated that extended adjuvant neratinib therapy after up to 1 year of trastuzumab therapy improved invasive disease-free survival significantly, sparing half of patients from invasive tumor recurrence 2 years after randomization.
There is ongoing research to discover what "drivers" will best respond to different drugs or groups of drugs. This is a necessary step to allow the right drugs to be used for the different tumor "Drivers".
The cancers targeted by this new checkpoint inhibitor drug have a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). MSI-H/dMMR tumors are most often found in colorectal, endometrial, or gastrointestinal cancers, the FDA said. About 5 percent of patients with metastatic colorectal cancer have this biomarker.
Of 149 individuals with such tumors who took Keytruda in clinical trials, nearly 40 percent had a complete or partial remission. And for 78 percent of those patients, the drug's effects lasted six months or more, the FDA said. The drug's most common side effects included fatigue, pruritus, diarrhea, loss of appetite, rash, pyrexia, cough, and dyspnea.
The real "killer" in cancer is the ability of the cancer to spread throughout the body. The immune signals are involved in this.
There at least two key drivers of metastasis, the cancer cells' tendency to reproduce at a rapid rate and their ability to move through surrounding tissue until they reach the bloodstream, where they can then hitch a ride to spread the disease to other parts of the body.
By studying tumor cells in a three-dimensional environment that resembles human tissue, the researchers were able to determine how these activities begin. The research team discovered that as two types of cancer cells reproduced and created more crowded conditions in the test site, these cells secreted certain proteins that encouraged migration. The researchers identified these proteins as Interleukin 6 (IL-6) and Interleukin 8 (IL-8).
"IL-6 and IL-8 seem to deliver a message to cancer cells, telling them to move away from the densely populated primary tumor,"
In the team's animal studies, the researchers found that applying two existing antibody drugs--Tocilizumab and Reparaxin--blocked the receptors that enable cancer cells to get their relocation orders. Tocilizumab is an approved medication for rheumatoid arthritis and is in trials for use in ovarian cancer cases. Reparaxin is being evaluated as a possible treatment for breast cancer.
"In our eight-week experiment, when we used these two drugs together, the growth of the primary tumor itself was not stopped, but the spread of the cancer cells was significantly decreased," "We discovered a new signaling pathway that, when blocked, could potentially curb cancer's ability to metastasize."
One day the miracles won't be miracles at all, they will simply be just what happens on a regular basis.
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