Investigators Report the Successful Allogeneic Transfer of Cytotoxic T Lymphocytes in Progressive Multifocal Leukoencephalopathy
The T cells that were modified ex vivo were made to fight the BK polyomavirus, a genetically similar, immunologic epitope of the JC polyomavirus.
Patient 1 remained asymptomatic for 27 months after the first infusion and 24 months after the last infusion. Meanwhile, patients 2 and 3 showed MRI evidence of immune reconstitution inflammatory syndrome following treatment. Patient 2 eventually died, which the investigators hypothesized was either related to the irreversible damage to her CNS or to the inadequate effect of treatment with the engineered T cells.
The slight mismatch in HLA cells used in patient 1 (HLA-Bw6-negative cells in transplantation compared with HLA-Bw6-positive cells to make the virus-specific T cells) allowed the researchers to confirm that the engineered cells were successfully trafficked to the CSF: approximately 20% of the patient's CD3 cells in the CSF were of donor origin. And, effector memory T cells persisted post-transfer for at least 250 days, suggesting that activated T cells could “cross the blood-brain barrier, proliferate, and putatively mediate an antiviral response.”1
Despite this small mismatch in HLA, graft-versus-host disease was not observed, which the researchers explained was partially due to the immunocompromised state of the patients. Because of this immunosuppression, they wrote, the patients who underwent this type of allogeneic ACT may not have been good candidates for autologous ACT, as this approach relies on the successful generation of a patient's own T cells. But the immunosuppression actually may have served to enhance the utility of the investigators' approach: “The lack of major rejection of cells is probably because patients who are sufficiently immunosuppressed to develop PML may also be unable to reject partially matched T cells due to their severely immunocompromised state,” Dr Rezvani wrote in an email to Cancer Therapy Advisor.
Donor T cells were found to be predominantly of the CD4 variety, and were able to expand and differentiate in vivo.
And, unlike some other adoptive cell therapies, no viral vectors were used to produce the investigational allogeneic product. Instead, the product "was made by culturing the cells from the donor with a mixture of peptides derived from the viral protein and cytokines," Dr Rezvani said. "This process preferentially expands the T cells that are reactive against the virus."
The patient with AML who had a cord blood transplant can now be considered cured of her leukemia, according to Dr Rezvani. “She does not require any additional therapy for the leukemia; however, in the unlikely event that she needs additional therapy, she could be treated as any other patient. Having received the CTLs does not preclude her from receiving any form of therapy in the future,” she added.
The current study was not funded by any pharmaceutical company and according to authors, there was no industry involvement at all. Nonetheless, a pharmaceutical company is already showing interest in the approach, noted Dr Rezvani. "A company called Optera is interested in licensing the product, but they were not involved in the design or execution of this study." The research was supported, however, by MD Anderson's Moon Shots Program and the National Institutes of Health.
- Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK virus–specific T cells for progressive multifocal leukoencephalopathy [published online October 10, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801540
- Cancer patients with rare deadly brain infection treated successfully with off-the-shelf adoptive T-cell therapy in clinical trial [press release]. Houston, TX: MD Anderson Cancer Center; October 10, 2018.