‘Gratifying’ results show ‘incredible step forward’ for off-the-shelf T-cell therapies
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The first published results of a phase 3 allogeneic T-cell therapy showed a better than 50% response rate in patients with relapsed or refractory Epstein-Barr virus-positive post-transplant lymphoproliferative disease.
In the open-label ALLELE study, patients whose disease responded to tabelecleucel (tab-cel; Atara Biotherapeutics) had an estimated 1-year OS rate of more than 80% compared with less than 35% for those who did not respond to therapy, according to study results published in The Lancet Oncology.
“The history of treating [Epstein-Barr virus (EBV)] lymphoproliferative disease with adoptive T-cell therapy started over 20 years ago,” Susan Prockop, MD, director of clinical and translational research for the Stem Cell Transplant Program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, told Healio. “This is incredibly gratifying and important.”
Background and results
EBV-positive post-transplant lymphoproliferative disease (PTLD) is a rare but serious complication of hematopoietic and solid organ transplant (SOT). First-line therapy is successful in a majority of patients, but survival time is short for those with disease that is refractory to first-line therapy, according to background information provided by researchers.
“In the hematopoietic setting, first-line therapy is typically rituximab [Rituxan; Genentech, Biogen],” Prockop said.
“For people who have disease that fails to respond to rituximab, the median overall survival is less than 2 months,” she added. “In the solid organ transplant recipient population, some patients receive rituximab alone and are either too frail or have other reasons that multiagent chemotherapy is not appropriate. Some of those patients receive risk-stratified rituximab followed by multiagent chemotherapy. Still, those patients who have disease that fails to respond to that strategy also have a very poor overall survival.”
Researchers focused on overall response rate as the primary endpoint of the multicenter, single-arm trial.
The study cohort consisted of 43 patients (median age, 48.5 years; 56% men; 84% white) with relapsed or refractory EBV-positive PTLD. Of those patients, 14 had previous HSCT and 29 had SOT, and treatments occurred between June 27, 2018, and Nov. 5, 2021.
Of the HSCT recipients, 50% had an objective response to therapy (six complete responses, one partial), with a median time to response of 1 month. Responders had an estimated 1-year OS rate of 100%, whereas nonresponders had a 35.7% estimated 1-year OS rate.
Among SOT recipients, 52% had an objective response to therapy (six complete responses, nine partial), with a median time to response of 1.1 months. Responders had an estimated 1-year OS rate of 75.2%, whereas nonresponders had a 33.6% estimated 1-year OS rate.
The overall study cohort had a median response duration of 23 months.
Grade 3 or worse treatment-emergent adverse events appeared in 53% of patients and fatal events in 12%, although no treatment-related deaths occurred during the trial.
‘Embedded’ saftey and efficacy
“EBV PTLD arises because of defects in EBV-directed T-cell immunity. Investigators first demonstrated that it was possible to treat EBV PTLD in HSCT recipients with an infusion of T cells from their donor — if that donor had previously been infected with EBV and thus had normal EBV-directed immunity,” Prockop said. However, this type of infusion of bulk T cells — called a donor lymphocyte infusion — also contains T cells that recognize the recipient as foreign and cause graft-versus-host disease.”
A group of researchers at Baylor College of Medicine conducted pioneering research that has enabled the selective growth of EBV-specific T cells that can be frozen for future use, Prockop explained.
“These EBV-specific T cells function through their native T-cell receptor by recognizing a specific EBV antigen presented by a specific HLA allele on the surface of EBV-infected cells,” she said.
“Specific to this T-cell product is the characterization of each line,” Prockop added. “Knowing the HLA allele(s) recognized by each T cell line allows them to be selected for use in patients sharing this HLA allele and thus to be used as an off-the-shelf product.”
The “mismatched” T cells work because they recognize EBV through a shared HLA allele,” she said.
“The safety and efficacy are embedded in the process by which these T cells are generated and selected for use,” she said. “Each T-cell line is generated from a normal, healthy EBV sero-positive donors. T cells from the donor are cultured in an autologous system. There’s no allogeneic stimulus in the culture system, which protects against expanding any potentially allogeneic T cells.
“If you can use cells from somebody other than the patient or donor to control this disease and eradicate [it], you have a rapidly available off-the-shelf product,” she added. “To use T cells that are mismatched with the recipient effectively and without concerns for significant toxicity related to graft-versus-host disease or solid organ graft rejection is an incredible step forward.”
Tabelecleucel has been approved by the European Union in patients aged 2 years and older for relapsed or refractory EBV PTLD following HSCT or SOT. Atara is preparing a biologics license applications submission in the second quarter of this year and will work toward an FDA approval, Pascal Touchon, DVM, president/CEO of Atara, said in a press release.
An approval would expand “access to these therapies beyond boutique centers, to the centers [that] are actually performing the bulk of allogeneic stem cell and cell organ transplants,” Prockop said.
Other allogeneic therapies are being developed targeting a variety of malignant conditions, Prockop added, and the success of tabelecleucel could pave the way for more in the future.
“The ability to do these types of multicenter, cell-based therapeutic trials has been transformative in the past 10 years,” she said.
“I’m hopeful that these promising therapies can really get to patients much faster,” she added. “What is most exciting is to have an armamentarium of potentially less toxic novel curative therapies.”
References:
- Atara Biotherapeutics and Pierre Fabre Laboratories announce publication of phase 3 ALLELE Tab-cel data in The Lancet Oncology (press release). Available at: https://investors.atarabio.com/news-events/press-releases/detail/340/atara-biotherapeutics-and-pierre-fabre-laboratories. Posted Jan. 31, 2024. Accessed Feb. 29, 2024.
- Mahadeo KM, et al. Lancet Oncol. 2024;doi:10.1016/S1470-2045(23)00649-6.
For more information:
Susan Prockop, MD, can be reached at susan.prockop@childrens.harvard.edu.
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