ISTOCK, BIOGEEK I Immunotherapy, which involves the adaptation of immune cells to destroy specific cellular targets, has made a name for itself in treating cancer. But in recent years, a handful of research groups have advanced T cell therapies for viral infections, and are now at the peak of commercialization. "Using T cells to attack infectious diseases is not a new field," says immunologist Michael Keller of Children's National Hospital in Washington, DC, "but it's something that is expanding a lot."
A handful of groups in the US offer donated T cells designed internally as antiviral therapies for bone marrow transplant patients, who are vulnerable to common virus infections. The treatments are still experimental, reaching only a small number of patients so far. But nearly 50,000 people a year receive blood stem cell transplants and could potentially be helped by such intervention. Keller is among those who try to advance with antiviral immunotherapy. At Children's National, for example, he and his colleagues have several ongoing Phase 1 and 2 trials that can help set the standard for bone marrow transplantation.
For now, such treatments are limited by the number of available bone marrow donors and the diversity of their blood types and history of viral exposure. But when used, between 70 and 90 percent of the recipients can fight infections, depending on compatibility with the donor. Researchers are looking for a combination of strategies to store T cells from donors who have already experienced viral infections or train virgin T cells taken from unexposed tissues such as umbilical cord blood to help make antiviral immunotherapies more robust and more widely available. available.
The early days of antiviral immunotherapies
In recent decades, most research on antiviral T cells has focused on people undergoing bone marrow transplants for blood cancers, such as the leukemia. These transplants restore the immune system of the receptors, making them vulnerable to common viruses such as cytomegalovirus (CMV), adenovirus, Epstein-Barr, BK virus and herpesvirus. Because most people have natural defenses against these pathogens, medical treatments are scarce, and patients with immunosuppressed transplants are easy victims of deadly viral infections.
I think that as a doctor and researcher it is very satisfying because you really see very high response rates and it directly impacts the lives of patients. -Katy Rezvani,
MD Anderson Cancer Center at the University of Texas
In the 1990s, immunologists began to explore whether the same tricks that fight tumors could also help against the viruses that afflict transplant recipients. In 1995, immunologist Stan Riddell of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle showed that transfer of T cells from donors already exposed to CMV to a patient with a bone marrow transplant could overcome an infection.
Transplanting the immune system of patients often struggled with other factors in the donor's blood, however, causing graft disease against the host. In a more specific approach developed in recent years, researchers have attempted to modify and amplify the desired T cells from the donor's blood. In one approach, they infect B cells grown in the laboratory with viruses. The B cells then present unique antigens for the viruses, stimulating the production of the appropriate T cells.
But these methods can take eight to 12 weeks and, in some cases, require working with dangerous live viruses. In 2014, a team reported a more secure and faster direct access: using a library of peptides, they could push the donated T cells to replicate in vitro in just 10 days. Other groups have used fragments of viruses, proteins or viral vectors to create several antigen presenting cells to activate T cell production.
Keller's group is now using the peptide library method in a Phase 1 clinical trial which tests the protection against multiple viruses. But the activity of overlapping therapies, which act on so many different pathogens at once, may be difficult for companies to define enough to get regulatory approval, warns hematologist David Gottlieb of the University of Sydney, Australia, who studies the cells and the cells after the transplant. Genetic therapies Instead, it may make sense to develop more direct separate therapies that protect against fewer viruses.
See "Acceleration of antiviral T cell production"
To deposit or to compile
All these methods involve modifying the donated T cells. using external stimuli, which requires institutions to maintain T-cell volumes by hand. But "it's not always easy to get donors who have sufficient amounts of [desired] virus-specific T cells," says hematologist Jiri Pavlu of Hammersmith Hospital in London.
Several institutions are conducting experimental therapies and discovering the mechanics of banking T cells for antiviral therapy. Immunologist Katy Rezvani of the MD Anderson Cancer Center at the University of Texas at Houston says her institution began depositing T cells three years ago and has since treated two or three patients with stem cell transplant a month for virus infections. CMV, BK and John Cunningham. Now they can begin treatment within 24 hours after identifying the need, using frozen T cells from donors previously exposed to viruses that are semi-paired with the patient's immune system.
Those semi-coincidentally donated T cells that have been exposed to virus are detectable for approximately two or three months after the transplant, when the patient's own immune system recovers from the transplant and shows the donated T cells at the door . "If you use a partially compatible donor, you are joining them to fight off any infections that are happening until the new immune system has fully emerged," says Keller.
One drawback is that donated T cells vary in their effectiveness against viruses, and researchers suspect that it may have to do with the donor's exposure history to the viruses and T cell types involved. Therefore, Children's National researchers have begun to experiment with training T cells from blood sources called virgins, such as the umbilical cord or peripheral blood. Cells can offer more predictable protection with fewer side effects.
Several institutions are carrying out experimental therapies and deciphering the mechanics of banking T cells for antiviral therapy.
Although it is even slower than a cumulative product, T without virus Cellular immunotherapy can occur in about eight weeks, the team reported this year. The idea is interesting, says Rezvani, but its effectiveness is even less understood and the process is cumbersome.
Another intriguing possibility in the field of antiviral immunotherapy is to modify donated T cells using the same genetic interventions that have made chimeric antigen receptors. (CAR) such a blow against cancer targets. Essentially, T cells are genetically modified to produce a receptor, the CAR, which recognizes a particular protein in a cancer cell, or in this case, a virus. "The use of CAR T cell technology would ensure that you had cells targeting specific viruses," says Pavlu. In fact, last year, a Chinese-American collaboration redirected T cells using CAR to target several viruses in addition to treating acute myeloid leukemia (AML), reported in Leukemia Research .
See "FDA Approves Second CAR T-Cell Therapy"
Pharmaceutical companies have invested billions of dollars in immunotherapies for cancer in recent years, and the United States Food and Drug Administration (FDA) ) began to approve such therapies in recent months. But the investment boom has yet to affect T cell antiviral therapy. Although a handful of companies, including Atara, Viracyte, Tessa and Cell Medica, have partnered with university researchers and have conducted Phase 2 trials, the largest Part of the work on antiviral T cell therapy continues to be funded by governments and private philanthropy, says Keller.
However, antiviral T cell therapy is "very exciting," says Rezvani, "and I think that as a doctor and researcher it is very satisfying because really very high response rates are obtained and it impacts the lives of patients. directly. "