, Sharon Reynolds
For some people with aggressive blood cancers, such as certain types of leukemia, a treatment called an allogeneic stem cell transplant can provide the most desired outcome in cancer treatment: a cure.
But sometimes the process leads to a long-term, debilitating condition known asgraft versus host disease(GVHD). GVHD occurs whencells of the immune systemfrom donors who have contributedStem cellsduring transplantation, they attack the healthy tissue in the recipient's body along with the cancer cells.
A new study reports that there may be a way to prevent chronic GVHD after astem cell transplant: by removing the so-called naïve immune cellsT. stationfrom donor cells before transplantation. The researchers found that this significantly reduced the risk of chronic GVHD among study participants without significantly increasing the chance ofrelapse.
"It's a strategy that seems to hit the sweet spot" between maintaining the supply of helper immune cells and preventing chronic GVHD, explained Marie Bleakley, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center, who led the of study.
It's three o'clockClinical tests,only 7% of 138 patients who received past T cells–the exhausted graft developed chronic GVHDcompared with more than 40% of a cohort of similar patients who had previously received a standard transplant at the same cancer center. Of the cases of chronic GVHD that developed in patients who receivedexperimentaltransplants, none were difficult.
The trial results were published together on January 10 in the journalJournal of Clinical Oncology.
All trials were non-randomised phase 2 trials, meaning that all participants received the experimental treatment. Dr. Bleakley and her colleagues currently present tworandomizedstudies to confirm these early findings.
Randomized studies are needed before changes to the standard transplant regimen can be approved, explained Steven Pavletic, M.D., of the NCI.Cancer Research Center. “But if we canhalogentransplant without patients suffering from [chronic] GVHD, that's huge,” he said.
Stem cell transplantation: the initial immunotherapy for cancer
Blood cancer arises from stem cellsMarvbenproduced by the body's blood cells, includingWBCsnecessary to fight infections. As part of treatment for some aggressive types of blood cancer, people may receive an allogeneic stem cell transplant.
This procedure destroys the bone marrow, which contains the stem cells, with high doses of chemotherapy and sometimes radiation therapy. The patient then receives an infusion of healthy stem cells from a donor, often a family member,coordinated to reduce the risk of graft rejection and GVHD.
These stem cells travel to the bone marrow and eventually give the patient brand new blood cells. In addition, the immune system cells injected with the stem cells will hopefully recognize and kill any remaining cancer cells in the body, a phenomenon called the graft-versus-leukemia effect.
"Allogeneic stem cell transplantation is a form of cancer immunotherapy," said Dr. Pavletich. "It's been around for over 50 years, but it's actually a precursor to [things like]CAR T-cell therapyas we have today".
T cells are among the many types of immune cells that can attack cancer cells. But there are many subsets of T cells. Naïve T cells have never encountered santigen— protein or other molecule that can cause aimmune response. For reasons that are not yet fully understood, they are more likely to respond to healthy cells in the transplant recipient.
If immune cells attack and destroy these healthy tissues, GVHD can occur. GVHD can develop within months after the transplant, which is called acute GVHD. The most commonly damaged organs in acute GVHD are the skin, liver, and intestines.
For some people, acute GVHD can be resolved with the use of immunosuppressive drugs. GVHD that develops later and has certain distinctive features — including specific changes in the skin, mouth, eyes and joints — is considered chronic GVHD, explained Dr. Bleakley.
"Chronic GVHD is often a really serious condition and can last from months to years," said Dr. Bleakley. "It is the leading cause of disability and chronic disease in [stem cell] transplant recipients," he added. In some people, the condition can be fatal.
And if someone develops chronic GVHD, they may need to take drugs that suppress their immune system for many years.
Immunosuppressive drugs can have side effects and increase the risk of infection. They can also cause problems if the cancer comes back, explained Dr. Bleakley. People generally can't get immunotherapies like CAR T cells while taking these drugs, but they can't stop taking them without risking worsening GVHD. "Then we're in a Catch-22 situation," he said.
Targeted T cell depletion: Targets only precursor T cells
The researchers previously tried to remove all T cells from the donor cells before the transplant, a strategy called T-cell depletion. But not all T cells are created equal. For example, without memory T cells that have been previously exposed to certain pathogens and can remember them, many people develop serious or fatal infections after transplantation.
The idea of removing only naïve T cells originated nearly two decades ago, explained Warren Shlomchik, M.D., director of hematopoietic stem cell transplantation and cell therapy at UPMC Hillman Cancer Center in Pittsburgh, the study's senior investigator.
At that time, while working at Yale University, Dr. Shlomchik and his colleaguesthe difference between contributionsnaiveand memory T cells in GHVD. "When we realized that memory cells cause less GVHD, we saw an opportunity to take [this discovery] from the bench to the bedside," he said.
To extract specific types of T cells from donor grafts, they adapted a laboratory technique for separating cells that usesantibodiesbound with tiny iron balls. Antibodies are made to bind to proteins found only on certain types of T cells. The donor's blood is then passed through a magnet, which snaps onto iron balls and removes only the unwanted T cells from the graft.
His team quickly saw the potential for using this technique in the clinic. In 2005 they joined the NCIDevelopmental therapy programThe Rapid Access to Intervention Development (RAID) program, which is designed to translate ideas from basic research into proven treatments.
They then teamed up with Fred Hutchinson, who has one of the largest stem cell transplant programs in the United States, and brought in a biotech company partner to make the product needed for the selective T cells.–exhaustion method.
Over the next decade, Fred Hutchinson's clinical team tested the strategy in three early trials. They began using high doses of chemotherapy and radiation therapy before the transplant - known asconditioning treatment— which limited participation to younger, healthier people.
Over time, researchers discovered that less intense regimens could also be used. This allowed the team to raise the upper age limit for participation from 55 to 60 for the third Test.
Between 2009 and 2020, 138 people with acute leukemia received past T cells–exhausted cuttings. All participants also received standard drugs administered immediately after transplantation to prevent GVHD. By the time the results were published, the surviving study participants had been followed for an average of 4 years.
Go directly against the standard of care
Almost three-quarters of participants developed mild acute GVHD, mainly affecting the upper extremityof the gastrointestinal tract. Participants who developed acute GVHD were less likely to have their cancer return or die, Dr. Bleakley attributed the graft versus leukemia effect.
Of the 7% of participants who developed chronic GVHD, symptoms were mild in almost all cases and none were severe. By comparison, between 42% and 45% of people who previously received standard stem cell transplants at Fred Hutchinson developed chronic GVHD.
Slightly more than 20% of participants who received past T cells–depleted grafts had cancer recurrence similar to that seen in historical comparison groups. This, and the similar chance of survival compared to people who received standard transplants, suggests that the graft-versus-leukemia effect was not compromised by the removal of past T cells, explained Dr. Bleakley.
Two small randomized trials - onein adultsand oneto the children- now directly compares the rate of chronic GVHD in people randomized to receive one of three types of transplants: naïve transplants without T-cells, standard transplants, or a newly widely used type of transplant. Patients receiving this latter type will receive the chemotherapy drug cyclophosphamide immediately after the transplant, which can suppress T cells that can attack the recipient's tissues.
In addition to the goal of reducing the rate of chronic GVHD with naïve T-cell-free transplants, "we [also] want high survival rates and low relapse rates," he continued. "Is what we developed really better than the standard of care? We think so, but we won't know until we actually do randomized trials."
Ongoing trials will also determine whether this method of depleting naïve T cells can be replicated in other hospitals. The first experience in a pediatric trial showing the reproducibility of the technique was encouraging, explained Dr. Bleakley.
"We've trained half a dozen other centers and they've had very good results on naïve T-cell depletion [so far]," he said.
If the results of ongoing trials are as expected, the new technique should also be tested in older adults, said Dr. Pavletich. All participants in the ongoing randomized trials are 60 or younger, but "about 80% of [blood] cancers occur in patients over 60," he explained. Currently, stem cell transplants are rarely used in people over 75, he added.
Fred Hutchinson's team began testing a combination of less intense treatments used in elderly patients and naive T-cell depletion as part of a recently published study, said Dr. Bleakley.
When she and her colleagues first started these trials, she explained, they weren't sure whether the intense treatment regimens were a necessary condition for the grafts to work — that is, to settle in the bone marrow and start making healthy blood cells, known as as an implant.
"But in the last trial, we had half the patients get a less intensive regimen and their transplant was fine. So we think we can dial back [the intensity even more]," he said.
FAQs
What is the role of T cells in GVHD? ›
Overall, T cells are indispensable mediators of aGVHD pathogenesis since GVHD rarely develops after syngeneic or T cell-depleted transplants (3–7). Both aGVHD and GVT have been found to be initiated by antigen presenting cells (APCs) derived from the donor and from host activating donor T cells (8, 9).
Do T cells cause GVHD? ›Naive T cells have never encountered an antigen—a protein or other molecule that can provoke an immune response. For reasons that are not yet fully understood, they are more likely to react to healthy cells in the transplant recipient. If immune cells attack and damage those healthy tissues, GVHD can result.
How can GVHD be prevented? ›To prevent GVHD, transplant recipients can be treated early after transplant with a drug called cyclophosphamide. This commonly used drug has long been thought to work by eliminating the disease-fighting T cells that turn against the recipient's body.
What type of T cell is GVHD? ›GVHD is primarily a donor T cell-mediated syndrome whereby T cells in the graft elicit an immune response, resulting in host tissue damage (Korngold and Sprent, 1978).
Why T cells are responsible for graft rejection? ›The ability of recipient T cells to recognize donor-derived antigens, called allorecognition, initiates allograft rejection. Once recipient T cells become activated, they undergo clonal expansion, differentiate into effector cells, and migrate into the graft where they promote tissue destruction.
What is the role of T cells and B cells in transplant rejection? ›B cells contribute to allograft rejection after differentiating into antibody-secreting plasma cells (blue). Additionally, B cells shape the T-cell response through a combination of antigen presentation, cytokine production, and costimulation (green).
How do you remove T cells? ›The CAR T Therapy Process
Collecting the T Cells: We draw blood from a vein in your arm. The blood flows through a tube into an apheresis machine, which removes T cells. The machine returns the rest of the blood back into your body through a different tube.
T cell depletion methods can be broadly categorized into either physical or immunological. Examples of physical separation include using counterflow centrifugal elutriation, fractionation on density gradients, or the differential agglutination with lectins followed by rosetting with sheep red blood cells.
What cells are responsible for GvHD? ›Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells.
Can chronic GvHD go away? ›A lot of people see a gradual improvement over a few months, but for some it can last longer. The average length of time you have chronic GvHD is between 1 and 3 years. Some people can have it for longer.
Can you get GvHD from your own stem cells? ›
GVHD does not occur when people receive their own cells. This type of transplant is called autologous. Before a transplant, tissue and cells from possible donors are checked to see how closely they match the recipient.
What drug prevents GvHD? ›Methotrexate is a type of chemotherapy drug. It stops T cells from dividing and so keeps the numbers down. You often have low doses of methotrexate after your transplant to try to prevent GvHD.
Can you transplant T cells? ›There are two main types of T-cell transfer therapy: tumor-infiltrating lymphocytes (or TIL) therapy and CAR T-cell therapy. Both involve collecting your own immune cells, growing large numbers of these cells in the lab, and then giving the cells back to you through a needle in your vein.
Can you get GVHD from car T? ›CAR T-cell therapies made with donor cells can potentially be given more quickly and affordably than autologous therapies that are currently available, but allogeneic CAR T-cell therapies, like allogeneic hematopoietic stem cell transplants, can cause graft-vs-host disease (GVHD).
What is T-cell depletion of stem cells? ›The T-cells are removed when there is a strong possibility that GvHD may occur after an HSCT. The removal process is called T-cell depletion. A possible side effect of an HSCT occurs when the donated cells do not recognise that they should be in the patient and try to reject the patient's cells, resulting in GvHD.
Can your body reject allograft? ›There are three major types of allograft rejection: Hyperacute, acute, and chronic rejection.
What is T cell rejection? ›In kidney allografts, T cell mediated rejection (TCMR) is characterized by infiltration of the interstitium by T cells and macrophages, intense IFNG and TGFB effects, and epithelial deterioration. Recent experimental and clinical studies provide the basis for a provisional model for TCMR.
What immunity is mainly responsible for graft rejection? ›In most cases, adaptive immune responses to the grafted tissues are the major impediment to successful transplantation. Rejection is caused by immune responses to alloantigens on the graft, which are proteins that vary from individual to individual within a species, and are thus perceived as foreign by the recipient.
What is the treatment for T-cell rejection? ›Rejection Treatment
Borderline and Banff I TCMR are typically treated with steroid pulse. Treatment includes dexamethasone 100 mg the first day, 50 mg the second day‚ and then gradual taper of prednisone from 180 to 10 mg daily.
Abatacept is a drug form of CTLA-4. By using this medication, we are able to turn off the T cell immune response.
What cells are T cells? ›
A type of white blood cell. T cells are part of the immune system and develop from stem cells in the bone marrow. They help protect the body from infection and may help fight cancer. Also called T lymphocyte and thymocyte.
Can you live without T cells? ›Without them, we can't survive. T cells protect us from infection. In our daily lives, we're constantly exposed to pathogens, such as bacteria, viruses and fungi. Without T lymphocytes, also called T cells, every exposure could be life-threatening.
Do T cells grow back? ›T cell production by the thymus naturally wanes with age, but stress, toxic chemotherapy, radiation or infection can also torpedo thymic output. “But the thymus actually has this remarkable capacity to regenerate itself,” Dudakov said.
Do T cells destroy infected body cells? ›Killer T cells are called “cytotoxic” or “cytolytic” because they possess special molecular weapons that enable them to directly attack and destroy other cells displaying targets they recognize, for example, a virus-infected cell or even a cancerous cell.
How do T cells get rid of viruses? ›When the perfectly shaped virus antigen on an infected cell fits into the Killer T-cell receptor, the T-cell releases perforin and cytotoxins. Perforin first makes a pore, or hole, in the membrane of the infected cell. Cytotoxins go directly inside the cell through this pore, destroying it and any viruses inside.
What happens to your T cells after Covid? ›Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19.
What are the consequences of T-cell depleted individual? ›Progressive T-cell depletion in HIV infection is induced, in part, by a state of chronic immune activation, which also contributes to noninfectious complications, such as cardiovascular disease.
Who is at the greatest risk for GVHD? ›Who is at the greatest risk for GvHD? The most important risk factor is donor/recipient HLA match. You're at an increased risk of developing GvHD if you've: Received stem cells from an HLA-mismatched donor who is related to you.
What increases the risk of GVHD? ›The risk of GvHD increases if an HLA-matched second- or third-degree relative (such as a cousin) is recruited as a donor, or if the matched donor is unrelated. 5 And, in some cases, the doctor may have no option but to use an HLA-mismatched donor if the benefits outweigh the risks.
What is the most common GVHD? ›Acute GVHD usually involves the skin, gastrointestinal tract, and liver, and is seen in 70%, 74%, and 44%, respectively. It can also involve the lungs, kidneys, eyes, and hematopoietic system. It may also result in decreased responsiveness to active immunization.
What is the death rate of chronic GVHD? ›
Chronic graft-v-host disease (chronic GVHD) is a frequent cause of late morbidity and death after bone marrow transplantation (BMT). The actuarial survival after onset of chronic GVHD in 85 patients was 42% (95%Cl = 29%, 54%) at 10 years.
What is the most organ affected in chronic GVHD? ›The most frequently involved organs in patients with chronic GVHD are skin, mouth, and liver, with less frequent involvement of eye, lung, GI tract, joint/fascia, and genital tract.
How many people survive GVHD? ›The 12-month overall mortality rate after acute GVHD diagnosis was 35.2%, while the nonrelapse mortality rate was 25.5%.
What is the most common organ transplant to cause GVHD? ›SOT-GVHD most often occurs in patients receiving small bowel or liver transplants.
How long does GVHD last after stem cell transplant? ›Chronic GVHD usually starts 100 or more days after an allogeneic stem cell transplant. It can last a few months or a lifetime. Chronic GVHD can happen right after you have had acute GVHD or after a time with no symptoms.
How common is GVHD after stem cell transplant? ›Between 20% and 70% of patients who receive an allogeneic stem cell transplant as a part of their cancer treatment will develop at least a mild case of a condition called graft vs. host disease, or GVHD. But what is graft vs. host disease, exactly, and why does it happen?
What is the first line treatment for chronic GVHD? ›Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation. Corticosteroids have been the standard first-line treatment for cGVHD, but their long-term use contributes to morbidity.
What is the second line treatment for chronic GVHD? ›Ruxolitinib effective as second-line therapy for chronic GVHD.
What is the target organ for GVHD? ›The unusual cluster of GVHD target organs (skin, gut, and liver) is inadequately explained by the systemic release of cytokines.
How long does it take for T cells to regenerate? ›Results: The extensive T-cell lymphopenia observed particularly in patients with severe COVID-19 during acute infection had recovered 6 months after infection, which was accompanied by a normalization of functional T-cell responses to common viral antigens.
How can I increase my T cells naturally? ›
- Get some sun. The same t-cells that benefit from sleep form part of the body's response to viruses and bacteria, and one of the key ingredients that 'primes' those t-cells for action is vitamin D. ...
- Reach for vitamin C foods. ...
- Incorporate garlic in your diet.
Virtually all patients with T-ALL will start treatment immediately. The main exception would be if a patient is very ill with other medical problems and is not fit enough to receive treatment. Acute leukaemia is often curable with standard treatments, in younger and/or fitter patients.
What is the best way to prevent GVHD? ›To prevent GVHD, transplant recipients can be treated early after transplant with a drug called cyclophosphamide. This commonly used drug has long been thought to work by eliminating the disease-fighting T cells that turn against the recipient's body.
Why do T cells cause GVHD? ›T Cells Inducers of GVHD. T cells differentiation is initiated when naïve T cells are stimulated by antigens in the presence of MHC molecules under a particular milieu of cytokines their corresponding signaling pathways to develop into different T cell subsets that acquire specialized effector cell phenotypes (17).
What happens when T cells are exhausted? ›Describes a condition in which T cells (a type of immune cell) lose their ability to kill certain cells, such as cancer cells or cells infected with a virus. This can happen when cancer, chronic infection, or other conditions cause the body's immune system to stay active for a long time.
How long can'T cells survive? ›The lifespan of a human memory T cell is of the order of 30–160 days [12,13,15,16], in contrast to the typical half-life of human T cell memory of 8–15 years [1,4,5]. Longevity thus does not seem to be an intrinsic characteristic of circulating memory T cells.
Can exhausted T cells recover? ›However, new insights from University of Pittsburgh and UPMC researchers suggest that even the most fatigued T cells can be revived. In a study, published today in Science Immunology, the team profiled molecular features of T cells as they progressed from early to terminal exhaustion in a mouse model of melanoma.
Are B cells or T cells involved in GVHD? ›Both acute and chronic GVHD are accompanied by a lower B-cell generation from B-cell progenitors in the bone marrow. In addition, donor T cells can contribute to GVHD-associated B-cell deficiency by Fas ligand–mediated cytotoxicity or release of cytokines such as interferon-gamma, which inhibit B-cell lymphopoiesis.
What cells are responsible for GVHD? ›Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells.
What is the role of T cells in the body's response to infectious agents? ›T cells express a receptor with the potential to recognize diverse antigens from pathogens, tumors, and the environment, and also maintain immunological memory and self-tolerance. T cells are also implicated as major drivers of many inflammatory and autoimmune diseases.
What cells are involved in GVHD? ›
Graft-versus-host disease includes acute graft-versus-host disease and chronic graft-versus-host disease. Host APCs (e.g., dendritic cells and macrophages), effector T cells (e.g., Th1, Th17, and abnormal Th17:regulatory T cell ratio), B cells, and NK cells are implicated in graft-versus-host disease physiopathology.
How T cells and B cells work against viral infection? ›T cells can wipe out infected or cancerous cells. They also direct the immune response by helping B lymphocytes to eliminate invading pathogens. B cells create antibodies. B lymphocytes, also called B cells, create a type of protein called an antibody.
Are B cells and T cells immunosuppressant? ›CD4+ T cells are documented targets of immune suppression by B cells, but many of the mechanisms described also have effects on NKT cells, CD8+ T cells, APCs and other lymphoid and nonlymphoid cells.
What are the three requirements for GvHD to occur? ›In 1966, Billingham formulated three requirements for the development of GVHD: the graft must contain immunologically competent cells; the recipient must express tissue antigens that are not present in the transplant donor; and the recipient must be incapable of mounting an effective response to eliminate the ...
What causes chronic GvHD? ›GVHD may occur after a bone marrow, or stem cell, transplant in which someone receives bone marrow tissue or cells from a donor. This type of transplant is called allogeneic. The new, transplanted cells regard the recipient's body as foreign.
Who is at the greatest risk for GvHD? ›Who is at the greatest risk for GvHD? The most important risk factor is donor/recipient HLA match. You're at an increased risk of developing GvHD if you've: Received stem cells from an HLA-mismatched donor who is related to you.
Do T cells destroy virus infected cells? ›Killer T cells are called “cytotoxic” or “cytolytic” because they possess special molecular weapons that enable them to directly attack and destroy other cells displaying targets they recognize, for example, a virus-infected cell or even a cancerous cell.
Do T cells destroy a virus infected cell directly? ›Armed effector cytotoxic CD8 T cells are essential in host defense against pathogens that live in the cytosol, the commonest of which are viruses. These cytotoxic T cells can kill any cell harboring such pathogens by recognizing foreign peptides that are transported to the cell surface bound to MHC class I molecules.
How long does chronic GVHD last? ›How long does chronic GvHD last? The length of time you have chronic GvHD can vary. A lot of people see a gradual improvement over a few months, but for some it can last longer. The average length of time you have chronic GvHD is between 1 and 3 years.