Comparison of the impact of CART19 Therapy and
Stem Cell Transplantation on Acute Lymphoblastic Leukemia
Abstract
Two major ways to treat acute lymphoblastic leukemia are CART19 Therapy and Stem Cell Transplantation. In CART19, the patient’s T cells are reengineered to recognize the MHC Molecules on the surface of cancerous B cells and attack them. The basic Stem Cell Transplantation method is to use chemo or radiation therapy to stop the patient’s cancer cell mitosis and then give the patient the donor’s stem cells, which will produce blood cells that kill cancer cell. However, in the process of Stem Cell Transplantation, the patient might receive new cancer cells from the stem cells, get infection, have graft-versus-host disease, or the stem cells will not work at all. As a result, compared to Stem Cell Transplantation, CART19 Therapy is a better choice in treating acute lymphoblastic leukemia although studies on this treatment is still in progress.
Introduction
About 80 percent of all childhood leukemia is acute lymphoblastic leukemia (ALL), also called acute lymphocyte or lymphoid leukemia. There are two basic types of lymphocytes, B-lymphocytes and T-lymphocytes. Their job is to identify and combat foreign substances, bacteria and viruses in the body. However, in ALL, the bone marrow makes immature lymphocytes (called lymphoblasts) that do not have the ability to fight infection and overproduce and crowd out normal blood-forming cells.The immature forms of B-lymphocytes and T-lymphocytes are the sources of the two corresponding subsets of ALL, T-ALL and B- ALL or pre-B ALL (The Children’s Hospital of Philadelphia, 1996). Most signs and symptoms of ALL result from shortages of normal blood cells, which happen when the leukemia cells crowd out the normal blood-making cells in the bone marrow. These shortages show up on blood tests, but they can also cause symptoms, including: Feeling tired, Feeling dizzy or lightheaded, Shortness of breath, Fever, Recurring infections, Bruising easily and Bleeding (American Cancer Society, 2014).
To cure ALL, there are all kinds of treatments. In this paper, I will be comparing the advantages and disadvantages of CART19 Therapy and the stem cell transplantation treatment.
Body
Before comparing the two types of treatments, here are some informations on how the two treatments work.
1. CART19
In the CART19 treatment, T cells are reengineered to kill cancerous B cells. B cells and T cells are the main types of lymphocytes. B cells work chiefly by secreting substances called antibodies, which ambush foreign antigens circulating in the bloodstream, into the body’s fluids. They are powerless, however, to penetrate cells. The job of attacking target cells—either cells that have been infected by viruses or cells that have been distorted by cancer—is left to T cells or other immune cells (National Institute of Allergy and Infectious Disease, 2012).
Each B cell is programmed to make one specific antibody. For example, one B cell will make an antibody that blocks a virus that causes the common cold, while another produces an antibody that attacks a bacterium that causes pneumonia. When a B cell encounters the kind of antigen that triggers it to become active, it gives rise to many large cells known as plasma cells, which produce antibodies (National Institute of Allergy and Infectious Disease, 2012).
Unlike B cells, T cells do not recognize free-floating antigens. Rather, their surfaces contain specialized antibody-like receptors that see fragments of antigens on the surfaces of infected or cancerous cells. T cells contribute to immune defenses in two major ways: Some direct and regulate immune responses, whereas others directly attack infected or cancerous cells (National Institute of Allergy and Infectious Disease, 2012).
Another type of T cell, Helper T cells, or Th cells, coordinate immune responses by communicating with other cells. Some stimulate nearby B cells to produce antibodies, others call in microbe-gobbling cells called phagocytes, and still others activate other T cells. Cytotoxic T lymphocytes (CTLs)—also called killer T cells—perform a different function. These cells directly attack other cells carrying certain foreign or abnormal molecules on their surfaces. CTLs are especially useful for attacking viruses because viruses often hide from other parts of the immune system while they grow inside infected cells. CTLs recognize small fragments of these viruses peeking out from the cell membrane and launch an attack to kill the infected cell (National Institute of Allergy and Infectious Disease, 2012).
Natural killer (NK) cells are another kind of lethal white cell, or lymphocyte. Like CTLs, NK cells are armed with granules filled with potent chemicals . But CTLs look for antigen fragments bound to self-MHC molecules, whereas NK cells recognize cells lacking self-MHC molecules. Thus, NK cells have the potential to attack many types of foreign cells (National Institute of Allergy and Infectious Disease, 2012).
T cells aid the normal processes of the immune system. If NK T cells fail to function properly, asthma, certain autoimmune diseases—including Type 1 diabetes—or the growth of cancers may result (National Institute of Allergy and Infectious Disease, 2012).
In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body’s own major histocompatibility complex, or MHC, molecules. MHC molecules are proteins recognized by T cells when they distinguish between self and nonself. A self-MHC molecule provides a recognizable scaffolding to present a foreign antigen to the T cell (National Institute of Allergy and Infectious Disease, 2012).
In CART19 Therapy, T cells are taken from a patient's own blood and genetically modified to express a protein which will recognize and bind to a MHC molecule target called CD19, which is found on cancerous B cells (The Children’s Hospital of Philadelphia, 1996).
This is how T cell therapy works:
- B cells, which are found in the immune system, become cancerous in certain leukemias and lymphomas.
- Cancerous B cells fly under the radar of immune surveillance, evading detection by T cells.
- T cells are collected from a patient, then reengineered in a lab to recognize and attached to a protein that is found only on the surface of B cells. After this reengineering, T cells are called chimeric antigen receptor T cells. The cells are put back into the patient where they disperse to find cancerous B cells.
- As the reengineered cells multiply in the body, they attach to and kill the rapidly dividing, cancerous B cells. They remain in the body long after to continue fighting any new cancerous B cells. (The Children’s Hospital of Philadelphia, 1996).
2. Cell Transplantation
In a typical stem cell transplant for cancer, very high doses of chemo are used, often along with radiation therapy, to try to destroy all the cancer cells. This treatment also kills the stem cells in the bone marrow. Soon after treatment, stem cells are given to replace those that were destroyed. These stem cells are given into a vein, much like a blood transfusion. Over time they settle in the bone marrow and begin to grow and make healthy blood cells
There are 3 basic types of transplants: Autologous, Allogeneic and Syngeneic. They are named based on who gives the stem cells (American Cancer Society, 2014).
I. Autologous stem cell transplants
These stem cells come from the patient. In this type of transplant, the patient’s stem cells are taken before he gets cancer treatment that destroys them. His stem cells are removed, or harvested, from either his bone marrow or his blood and then frozen. After the patient gets high doses of chemo and/or radiation the stem cells are thawed and given back to him (American Cancer Society, 2014).
II. Tandem transplants
Doing 2 autologous transplants in a row is known as a tandem transplant or a double autologous transplant. In this type of transplant, the patient gets 2 courses of high-dose chemo, each followed by a transplant of his own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each transplant. Most often both courses of chemo are given within 6 months, with the second one given after the patient recovers from the first one (American Cancer Society, 2014).
III. Allogeneic stem cell transplants
In the most common type of allogeneic transplant, the stem cells come from a donor whose tissue type closely matches the patient’s. The best donor is a close family member, usually a brother or sister. If the patient does not have a good match in his family, a donor might be found in the general public through a national registry. This is sometimes called a MUD (matched unrelated donor) transplant (American Cancer Society, 2014).
Blood taken from the placenta and umbilical cord of newborns is a newer source of stem cells for allogeneic transplant. Called cord blood, this small volume of blood has a high number of stem cells that tend to multiply quickly. But the number of stem cells in a unit of cord blood is often too low for large adults, so this source of stem cells is limited to small adults and children. Doctors are now looking at different ways to use cord blood for transplant in larger adults, such as using cord blood from 2 donors (American Cancer Society, 2014).
For some people, age or certain health conditions make it more risky to wipe out all of their bone marrow before a transplant. For those people, doctors can use a type of allogeneic transplant that’s sometimes called a mini-transplant. Compared with a standard allogeneic transplant, this one uses less chemo and/or radiation to get the patient ready for the transplant. The idea is to kill some of the cancer cells along with some of the bone marrow, and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow (American Cancer Society, 2014).
Unlike the standard allogeneic transplant, in mini-transplant, cells from both the donor and the patient exist together in the patient’s body for some time. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patient’s own bone marrow cells. These new cells can then develop an immune response to the cancer and help kill off the patient’s cancer cells — the graft-versus-cancer effect (American Cancer Society, 2014).
One advantage of a mini-transplant is the lower doses of chemotherapy and/or radiation, and because the stem cells aren’t all killed, blood cell counts don’t drop as low while waiting for the new stem cells to start making normal blood cells. This makes it especially useful in older patients and those with other health problems who aren’t strong enough for a standard allogeneic stem cell transplant (American Cancer Society, 2014).
Mini-transplants treat some cancers better than others. They may not work well for patients with a lot of cancer in their body or those with fast-growing cancers. Also, although side effects from chemo and radiation may be less than those from a standard allogeneic transplant, the risk of graft-versus-host disease is not (American Cancer Society, 2014).
This procedure has only been used since the late 1990s and long-term patient outcomes are not yet clear. There are lower risks of some complications, but the cancer may be more likely to relapse. Ways to improve outcomes are still being studied (American Cancer Society, 2014).
IV. Syngeneic stem cell transplants – for those with an identical sibling
This is a special kind of allogeneic transplant that can only be used when the recipient has an identical sibling (twin or triplet) who will have the same tissue type.
V. Half-matched transplants
Some centers are doing half-match (haploidentical) transplants for people who don’t have closely matching family members. This technique is most often used in children, usually with a parent as the donor, though a child can also donate to a parent. Half of the HLA factors will match perfectly, and the other half typically don’t match at all, so the procedure requires a special way to get rid of a certain white blood cells that can cause graft-versus-host disease. It’s still rarely done, but it’s being studied in a few centers in the United States. Researchers are continuing to learn new ways to make haploidentical transplants more successful (American Cancer Society, 2014).
Advantages and disadvantages of CART19 Therapy and Stem Cell Transplantation:
CART19 Therapy
A lot of problems in cancer treatments are caused by MHC Molecules. Although MHC molecules are required for T cell responses against foreign invaders, they also create problems during organ transplantations. Virtually every cell in the body is covered with MHC proteins, but each person has a different set of these proteins on his or her cells. If a T cell recognizes a nonself-MHC molecule on another cell, it will destroy the cell. Therefore, doctors must match organ recipients with donors who have the closest MHC makeup. Otherwise the recipient’s T cells will likely attack the transplanted organ, leading to graft rejection.The biggest advantage of CART19 Therapy in the treatment of Acute Lymphoblastic Leukemia is that it reengineered the patient’s own T cell to recognize the MHC Molecules on cancerous blood cells and attack them. Therefore, CART19 Therapy will not cause graft rejection. However, according to Dr. Michel Sadelain who studies CART19 Therapy at Memorial Sloan-Kettering Cancer Center, the technology now only allow the reengineered T cells to recognize the outer structure of cancerous cells, while cancerous cells oftentimes share similar exterior structure with many other non-cancerous cells. As a result, reengineered T cells will attack those benevolent cells as well.
Stem Cell Transplantation
I. Autologous stem cell transplants
One advantage of autologous stem cell transplant is that the patient is getting his own cells back. When the patient donates his own stem cells, he does not have to worry about the graft attacking his body or about getting a new infection from another person. But there can still be graft failure and autologous transplants can’t produce the “graft-versus-cancer" effect, in which the donor stem cells make their own immune cells, which could help destroy any cancer cells that remain after high-dose treatment (American Cancer Society, 2014).
A possible disadvantage of an autologous transplant is that cancer cells may be picked up along with the stem cells and then put back into the patient’s body later. Another disadvantage is that the patient’s immune system is still the same as before when his stem cells engraft. The cancer cells were able to grow despite his immune cells before, and may be able to do so again (American Cancer Society, 2014).
To prevent this, doctors may give the patient anti-cancer drugs or treat his stem cells in other ways to reduce the number of cancer cells that may be present. Some centers treat the stem cells to try to remove any cancer cells before they are given back to the patient. This is sometimes called “purging.” It isn’t clear that this really helps, as it has not yet been proven to reduce the risk of cancer recurrence (American Cancer Society, 2014).
A possible downside of purging is that some normal stem cells can be lost during this process, causing the patient to take longer to begin making normal blood cells and have unsafe levels of white blood cells or platelets for a longer time. This could increase the risk of infections or bleeding problems (American Cancer Society, 2014).
One popular method now is to give the stem cells without treating them. Then, after transplant, the patient gets a medicine to get rid of cancer cells that may be in the body. This is called in vivo purging. Rituximab, a monoclonal antibody drug, may be used for this in certain lymphomas and leukemias, and other drugs are being tested. The need to remove cancer cells from transplants or transplant patients and the best way to do it is being researched (American Cancer Society, 2014).
II. Tandem transplants
Doctors do not always agree that Tandem transplant is really better than a single transplant for certain cancers. Because this involves 2 transplants, the risk of serious outcomes is higher than for a single transplant. Tandem transplants are still being studied to find out when they might be best used (American Cancer Society, 2014).
III. Allogeneic stem cell transplants
Transplants with a MUD are usually riskier than those with a relative who is a good match. The advantage of allogeneic stem cell transplant is that the donor stem cells make their own immune cells, which could help destroy any cancer cells that remain after high-dose treatment. This is called the graft-versus-cancer effect. Other advantages are that the donor can often be asked to donate more stem cells or even white blood cells if needed, and stem cells from healthy donors are free of cancer cells (American Cancer Society, 2014).
The disadvantage is that the donor cells could die or be destroyed by the patient’s body before settling in the bone marrow. Another risk is that the immune cells from the donor may not just attack the cancer cells -- they could attack healthy cells in the patient’s body. This is called graft-versus-host disease. There is also a very small risk of certain infections from the donor cells, even though donors are tested before they donate. A higher risk comes from infections the patient has had, and which his immune system has under control. These infections often surface after allogeneic transplant because his immune system is held in check by medicines called immunosuppressive drugs. These infections can cause serious problems and even death (American Cancer Society, 2014).
One advantage of a mini-transplant is the lower doses of chemotherapy and/or radiation, and because the stem cells aren’t all killed, blood cell counts don’t drop as low while waiting for the new stem cells to start making normal blood cells. This makes it especially useful in older patients and those with other health problems who aren’t strong enough for a standard allogeneic stem cell transplant (American Cancer Society, 2014).
Mini-transplants treat some cancers better than others. They may not work well for patients with a lot of cancer in their body or those with fast-growing cancers. Also, although side effects from chemo and radiation may be less than those from a standard allogeneic transplant, the risk of graft-versus-host disease is not.
This procedure has only been used since the late 1990s and long-term patient outcomes are not yet clear. There are lower risks of some complications, but the cancer may be more likely to relapse. Ways to improve outcomes are still being studied (American Cancer Society, 2014).
An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. There are no cancer cells in the transplant, either, as there would be in an autologous transplant (American Cancer Society, 2014).
A disadvantage is that because the new immune system is so much like the recipient’s immune system, there is no graft-versus-cancer effect, either. Every effort must be made to destroy all the cancer cells before the transplant is done to help keep the cancer from relapsing (American Cancer Society, 2014).
Conclusion
In all, it seems that CART19 Therapy has a higher chance of healing cancer because the patient’s own T cell will not cause graft-versus-host disease, and there is no chance for the patient to get his own cancer for using his own T cell since the cancerous cells in ALL are B cells. Furthermore, the reengineered T cells can attack cancer cells while the patient’s immune system does not react to them. Additionally, patients will not need to undergo the painful chemotherapy in CART19 treatment. It is true that reengineered T cells attack healthy cells as well, but further study should be able to fix that problem.
Work Cited List
American Cancer Society. 2014. web.
National Institute of Allergy and Infectious Disease. 2012. web. http://www.niaid.nih.gov/topics/immuneSystem/immuneCells/Pages/bcells.aspx
Sadelain, Michel. Interview by Cynthia Fox. “Training T Cells to Fight Their Own Cancers” Jan. 15, 2014. web.
The Children’s Hospital of Philadelphia. 1996. web.
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