A novel approach to adoptive T cell immunotherapy holds promise for some patients who develop acute, possibly deadly viral infections after undergoing allogeneic hematopoietic stem cell transplant (HSCT).
Physicians at The University of Texas MD Anderson Cancer Center are using T cells that target BK virus, JC virus, and cytomegalovirus (CMV) to successfully treat infections in HSCT patients. The T cells were developed in the institution’s Good Manufacturing Practice and Cellular Therapy Facility by Katy Rezvani, M.D., Ph.D., and Elizabeth Shpall, M.D., both professors in the Department of Stem Cell Transplantation and Cellular Therapy.
“Viral infections are major causes of morbidity and mortality in HSCT patients,” Dr. Rezvani said. “We’re showing that we can immediately treat some of these potentially fatal infections with banked virus-specific T cells from healthy donors.”
Potentially fatal infections
People with healthy immune systems may harbor BK virus, JC virus, or CMV and never experience symptoms of infection. But in people with extremely weakened immune systems—such as HSCT patients—these viruses can wreak havoc. The conditions resulting from these infections can be debilitating or even deadly, and conventional treatments to fight the infections are severely lacking. BK virus infection can cause BK hemorrhagic cystitis, which occurs in about 20% of all HSCT patients, depending on how high-risk the transplant is. BK hemorrhagic cystitis can be very painful, and patients with the condition may develop bladder hemorrhage and/or renal failure. For years, the standard of care has been limited to supportive measures, including analgesics, continuous bladder irrigation, hyperhydration, and forced diuresis.
JC virus infection can cause progressive multifocal leukoencephalopathy (PML), a rare, demethylating disease of the central nervous system that is marked by a sudden and severe loss of coordination and language ability. Treatment for PML is virtually nonexistent, and most patients who are diagnosed with it die within 6 months.
CMV infection can cause multi-organ disease that includes hepatitis, gastroenteritis, pneumonia, and encephalitis. Drugs to treat the infection are toxic and expensive.
The right cells at the right time
Previous efforts to use virus-specific T cells to treat viral infections in immune-deficient patients were hampered by the duration and complexity of cell production. Cell lines were generated on a patient-by-patient basis, which precluded their use in emergent situations.
“If we were to generate the T cells for each patient individually, then the patient would have to sit there for 2 weeks and suffer,” Dr. Rezvani said. To overcome these limitations, Dr. Rezvani and her colleagues established a cell bank of virus-specific T cells.
BK virus–specific T cells
For BK virus–specific T cells, an in-house procedure is used to generate the cells and expand them ex vivo. Peripheral blood mononuclear cells from healthy donors are cultured with five peptides from the immunodominant capsid proteins of the BK virus (VP1, VP2, VP3, large T antigen, and small T antigen) in the presence of cytokines (interleukin-2, -7, and -5) for 10–14 days. The expanded BK virus–specific T cells are then harvested and frozen.
BK virus–specific T cells can be used to treat both BK hemorrhagic cystitis and PML because the BK and JC viruses have 95% homology. When eligible HSCT patients present with BK hemorrhagic cystitis or PML, they are given BK virus–specific T cells from the most closely HLA (human leukocyte antigen)-matched donor. The cell bank is steadily increasing its number of donors and currently has BK virus–specific T cells from 15 donors covering the most common HLA types.
“From the moment a patient comes in with a viral infection, we can administer T cells within 24 hours because all we have to do is find the best donor, thaw the cells, and give them to the patient intravenously, just like a blood or platelet transfusion,” Dr. Rezvani said.
Once the virus-specific T cells are given, the patient is observed for a response. If no response is apparent within 2 weeks, T cells from another donor are given.
About 85% of the HSCT patients with BK hemorrhagic cystitis who have been treated with the cells have responded to the therapy. Dr. Rezvani believes that the other patients did not respond because they had graft-versus-host disease (GVHD) and were receiving corticosteroids, which are lymphotoxic and thus kill the T cells before the cells can act. On the basis of these findings, Dr. Rezvani and her colleagues no longer administer virus-specific T cells to patients who are receiving a high dose of steroids.
“Using virus-specific T cells, we’ve successfully treated more than 20 patients who had BK hemorrhagic cystitis and two who had PML,” Dr. Rezvani said, “One of these patients with PML, a 32-year-old woman who had a cord blood transplant, couldn’t walk and couldn’t talk properly when she came to our clinic. When we gave her these cells, she had an amazing response, and now she can walk and talk again. She’s even back to work now, 11 months after first presenting with PML; and the virus is no longer detectable in her blood or cerebrospinal fluid.” Given that PML is almost universally fatal, the patient’s response to the therapy was particularly encouraging, Dr. Rezvani said.
Although the BK virus–specific T cells are most often used in the post-transplant setting, Dr. Rezvani said that she has also used them to treat leukemia patients who develop BK hemorrhagic cystitis after chemotherapy. She noted that, because patients must be highly immunosuppressed to develop the condition, BK hemorrhagic cystitis is rare in non-transplant settings.
CMV-specific T cells
Unlike BK virus–specific T cells, which must be cultured, manipulated, and expanded over a dozen days or more, CMV-specific T cells, which are substantially more abundant than BK virus–specific T cells in healthy individuals, can be generated in a matter of hours. Donor cells are stimulated with a mix of peptides of the virus’s immunodominant proteins overnight. The cells start secreting interferon gamma, which allows their detection and isolation by a cytokine capture device. The T cells are immediately harvested and infused into the patient, where they start growing and mediate an antiviral response. So far, the response rate to CMV-specific T cells has been greater than 80%, and 20 patients have been successfully treated.
Dr. Rezvani said that although treatment with the virus-specific T cells has been safe and effective overall, it is not without potential limitations.
“There’s always the theoretical risk that T cells from an allogeneic source could increase the risk of GVHD, although we haven’t noticed a higher-than-average incidence of GVHD in the patients we’ve treated,” Dr. Rezvani said. “There’s also a theoretical risk that T cells from an allogeneic source could contribute to graft rejection, but we haven’t seen any cases of this in our patients.”
There is also a small risk that a good donor match would be unavailable or that even well-matched cells may not work, as was the case in patients who were receiving corticosteroids for GVHD.
Future directions and broader applications
The next step, Dr. Rezvani said, is to make virus-specific T cells available to additional patients. “At the moment, this is a boutique strategy at major transplant centers that have the technology to modify T cells, but we’d like to see the treatment become available to patients at other institutions,” she said. She also mentioned that steps are being taken to make virus-specific T cells more effective.
Other uses for virus-specific T cells are also being explored. For example, CMV-specific T cells are being used in combination with temozolomide in a clinical trial to treat recurrent glioblastoma, which expresses CMV antigens (see “Immunotherapy for Glioblastoma,” p. 1). Dr. Rezvani said that early findings suggest that virus-specific T cells could also be used to treat other cancers in which viruses play a role (e.g., human papillomavirus–associated head and neck cancers). More broadly, Dr. Rezvani pointed to the work of Ala Abudayyeh, M.D., an assistant professor in the Department of Nephrology, who is investigating the use of BK virus–specific T cells to prevent graft rejection in kidney transplant patients.
Dr. Rezvani predicts that off-the-shelf, virus-specific T cells will become commercially available within a few years but will likely be expensive. Currently, the in-house generation of the virus-specific T cells used at MD Anderson is supported by the institution’s Moon Shot Program, so there is no cost to the patient. With this support, Dr. Rezvani said, she continues to see the therapy elicit dramatic responses in HSCT patients with infections that once were debilitating and deadly.
“Where we used to have these patients in the hospital for weeks on end, now we give them these T cells, and most patients respond within a week of receiving them,” Dr. Rezvani said. “The therapy has made a huge difference in these patients’ quality of life.”
For more information, call Dr. Katy Rezvani at 713-794-4260.
OncoLog, March 2017, Volume 62, Issue 3