This article is more than 5 years old. Information may no longer be current.
T-cell immunotherapy appears effective in post-HSCT lymphoproliferative disorder
Click Here to Manage Email Alerts
PHILADELPHIA — A new type of T cell-based immunotherapy induced response in a majority of patients with Epstein-Barr virus-associated lymphoproliferative disorder who did not respond to standard treatment, according to study results presented at the American Association for Cancer Research Annual Meeting.
The responses associated with Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs; Atara Biotherapeutics, Memorial Sloan Kettering Cancer Center) were durable, and no patient who achieved complete response to treatment relapsed by data cut-off, results showed.
Richard J. O'Reilly
“The EBV paradigm in marrow transplants is one which is really very problematic,” Richard J. O’Reilly, MD, chairman of the department of pediatrics and chief of the Pediatric Bone Marrow Transplantation Service at Memorial Sloan Kettering Cancer Center, said during a press conference. “About 30% to 60% of patients who want to go on marrow transplant for myelomas or other diseases like leukemia will actually activate with this virus. There is a proportion of these patients, who, by virtue of the fact that they’re very immunosuppressed, will develop an EBV lymphoproliferative disorder.”
Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) that develop after allogeneic hematopoietic stem cell transplant typically present as high-grade diffuse large B-cell lymphomas (DLBCL). The median survival for these patients with conventional treatment is normally less than 31 days, O’Reilly said.
“We’ve known since 1995 … that you can administer immune T cells from the transplant donor, and they can in fact induce durable remissions of disease,” O’Reilly said. “Since then several groups … have also shown that EBV-specific T cells generated from the transplant donor can be used to effectively deal with these disorders. The limitation that we have found is that unfortunately takes about 60 days or more to actually generate these T cells. What we wanted to do was to develop an approach which would allow for the development of these T cells and the use of these T cells in the rapid order which is really required because the median survival is only 31 days.”
O’Reilly and colleagues developed a bank of 330 transplant donor-derived EBV-specific T cell lines consented for use in an individual other than the individual to whom they gave the transplant. The cells are defined in terms of their HLA typing, EBV specificity and HLA restriction and can be used within 24 hours of diagnosing EBV-LPD. So far, 98.6% of patients referred for potential therapy have had a match in the bank.
Researchers conducted two trials to evaluate the use of EBV-CTLs in 57 allogeneic hematopoietic stem cell transplantation recipients with EBV-positive disease. Fifty-one (89.4%) patients had monomorphic DLBCL, whereas three had polymorphic DLBCL, two had viremia alone and one had natural killer/T-cell lymphoma.
The first trial included 39 patients (median age, 21 years; 58% men), the majority (71.9%) of whom failed rituximab (Rituxan; Genentech, Biogen Idec). Twenty-six of these patients received EBV-CTLs derived from primary stem cell donors, and 13 received EBV-CTLs derived from unrelated third-party donors.
The second trial included 18 patients (median age 52 years; 55.6% women), all of whom had failed rituximab. All patients in this trial received EBV-CTLs derived from unrelated third-party donors.
Patients in both trials received up to five cycles of EBV-CTL infusions. Each cycle consisted of infusion with 1 x 106 cells/kg or 2 x 106 cells/kg weekly for 3 weeks.
In the first trial, researchers reported a 62% response rate and a 69% non-progression rate. Twenty-three patients (58.9%) achieved complete response, one (2.5%) achieved a partial response and three (7.6%) achieved stable disease.
In the second trial, researchers reported a 67% response rate and a 72% non-progression rate. Nine patients (50%) achieved complete response, three (16.6%) achieved a partial response and one (5.5%) achieved stable disease.
The median duration of complete responses and partial responses was 318 days. Researchers reported a 1-year PFS rate of 66.7%, and OS was 71.8% at 1 year and 2 years.
Among all rituximab-refractory patients in both trials, 1-year OS was 50% for those treated with third-party–derived EBV-CTLs and 49% for those treated with transplant donor-derived EBV-CTLs.
Overall, 10 patients (17.5%) died within 2 months of their first infusion, although no deaths appeared related to treatment. Six died due to progression of EBV-LPD, two died due to leukemic relapse and two died due to other causes.
Treatment with EBV-CTLs appeared well tolerated. No patients developed cytokine release syndrome or graft-versus-host disease that required systemic therapy, according to the researchers.
“The EBV-CTLs work well for the majority of recipients,” O’Reilly said in a press release. “However, the responses became clinically evident only after the T cells expanded in vivo, which took about seven to 14 days. We are rigorously pursuing the development of biomarkers and other tests to predict response earlier.”
In March, the FDA granted breakthrough therapy designation to the use of EBV-CTLs generated from the blood of third-party donors for the treatment of patients with rituximab-refractory EBV-LPD.
“We are looking forward to working with our collaborators at Atara Biotherapeutics and regulators to plan the next steps,” O’Reilly said in a press release. – by Mark Leiser
Reference: Prockop SE, et al. Abstract 8841. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.
Disclosure: O’Reilly reports no relevant financial disclosures. See the full study for all other researchers’ relevant financial disclosures.
Perspective
Back to Top
Suzanne L. Topalian, MD
Adoptive T-cell transfer as a form of cancer therapy has been around for decades. Most of what we’re familiar with is individualized preparation of cells for each patient which can only be done in very specialized medical centers. Even though the number of these medical centers is growing, it’s still a relatively limited number of laboratories that can do this. Here is an off-the-shelf free agent for a devastating complication of bone marrow transplantation.
Click Here to Manage Email Alerts