An “off-the-shelf” allogeneic T-cell product, tabelecleucel, may effectively treat patients who develop Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder with central nervous system (CNS) involvement, researchers from Memorial Sloan Kettering Cancer Center reported at the 2019 Transplantation & Cellular Therapy Meetings in Houston.1
We found responses that are very encouraging in a group whose expected survival is very poor. The 1-year overall survival for responders was 91.7%, and for nonresponders, it was 14.3%.— Susan Prockop, MD
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Susan Prockop, MD, described a subset analysis of two, phase II studies that were previously presented at the 2018 European Hematology Association Annual Congress.2 The investigators reported that treatment with tabelecleucel for patients developing EBV-associated posttransplant lymphoproliferative disorder following transplantation resulted in a median overall survival that was 21.3 months in the recipients of solid organ transplantation and was not reached in recipients of hematopoietic cell transplantation (HCT) after 23.3 months of follow-up. Among responders to tabelecleucel, the overall survival at 2 years was 83% in the HCT group (n = 24) and 86% in the solid organ transplant group (n = 7). These results represent significant improvements over historical outcomes of patients who failed to respond to rituximab, the investigators pointed out.
In the current subset analysis, Dr. Prockop said, “We looked at patients with CNS involvement specifically because they are an especially high-risk population. We found responses that are very encouraging in a group whose expected survival is very poor. The 1-year overall survival for responders was 91.7%, and for nonresponders, it was 14.3%,” she said.
EBV can cause multiple lymphoproliferative disorders. When it develops in immunocompromised individuals, such as patients who have received allogeneic HCT or solid organ transplant, the virus can quickly become life-threatening in the form of EBV-associated posttransplant lymphoproliferative disorder. For these patients, rituximab is the first-line treatment, but it is effective in only about half of patients. Tabelecleucel may offer a new alternative, and as an off-the-shelf product, it should be relatively simple to obtain and deliver (within 3 to 5 days).
The off-the-shelf product uses allogeneic T cells that are bioengineered from healthy donors (in a process that takes about 10 weeks) and designed to recognize particular targets, in this case the EBV antigen. The donor cell line is matched to the patient’s tumor based on the human leukocyte antigen (HLA) allele through which the T cells recognize EBV. “Unlike transplantation, the cell lines do not need to be a perfect match,” according to Dr. Prockop. In the administration of these T cells to the patient, the infusion is rapid, and no lymphodepletion is required beforehand.
In addition to EBV, the manufacturer of tabelecleucel is also creating T cells that will recognize cytomegalovirus antigens and other viruses as well as the tumor-associated antigen Wilms tumor 1. It may be possible, said Dr. Prockop, to expand T cells against self-antigens, but they are less plentiful than virus-specific T cells in the circulation of healthy donors.
One important difference between T-cell therapies that depend on T-cell receptor recognition vs chimeric antigen receptor T-cell therapies is their ability to see antigens that are intracellular, and not on the cell surface.
Current Study Findings
Dr. Prockop presented findings for 19 patients who developed EBV-associated posttransplant lymphoproliferative disorder with CNS involvement: 12 after HCT and 7 after solid organ transplantation. A total of 7 patients received T cells from a primary donor, and 11 received them from a third-party donor (tabelecleucel); 1 patient had both donor types. Primary donor T cells were generated from EBV-seropositive HCT donors at the time of, or after, patients underwent transplantation. Third-party tabelecleucel lines were selected from a bank of 330 lines generated at the laboratory from normal HCT donors. Selection of third-party tabelecleucel lines was made on the basis of HLA restriction by at least a single HLA allele shared by the patient’s tumor and the HCT donor and matching for at least 2 of 10 recipient alleles.
Nine patients were treated for isolated CNS disease, whereas 10 had CNS and systemic disease. Of the 19 patients, 17 had received prior therapy, which included rituximab, radiation therapy, and/or systemic chemotherapy.
Responses were assessed 3 to 4 weeks after the start of each cycle. Patients not achieving a complete response to an initial cycle of T cells were eligible to receive a subsequent cycle.
1-Year Survival Among -Responders Almost 92%
Of the 19 patients treated, 12 achieved responses in the CNS, including 6 complete responses and 4 durable partial responses, lasting at least 2 years. Two patients responded but received concomitant radiotherapy; therefore, for them, it is unclear whether the T-cell therapy or the radiotherapy is most responsible for the response.
Tabelecleucel is currently being evaluated in two phase III trials (MATCH and ALLELE).— Susan Prockop, MD
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The overall response rate in the CNS was 53%, and responses were more likely with third-party tabelecleucel (73%) than with primary donor T cells (29%), Dr. Prockop reported. The 1-year overall survival for the 19 patients was 60%; it was 91.7% in the group that responded and just 14.3% in nonresponders.
Of the 10 patients with isolated CNS disease, 8 responded to adoptive EBV-directed T-cell therapy, for a 1-year survival rate of 70%. For patients with CNS and systemic disease, the 1-year survival rate was 55.6%.
Adverse events associated with this treatment were observed in 8 patients experiencing serious adverse events of grade ≥ 3 in severity; one grade 3 event was deemed possibly related to treatment. There were no infusion-related toxicities and no evidence of cytokine-release syndrome.
Phase III Trials Underway
The investigators are now looking for biomarkers of response and working on ways to enhance the immunogenicity of tumors in nonresponders. Tabelecleucel is currently being evaluated in two phase III trials (MATCH and ALLELE): one in HCT and one in solid organ transplantation. Results from the first tabelecleucel phase III study and submission of a European Union conditional marketing authorization application are expected in 2019. ■
DISCLOSURE: Dr. Prockop is an inventor on technology referenced in this work; she has waived rights to revenue generated from these inventions. Memorial Sloan Kettering Cancer Center (MSK), which owns the technology, has licensed this technology to the company Atara, and MSK has interests in Atara through this licensing arrangement and has received support for trials sponsored by Atara Biotherapeutics (the manufacturer of tabelecleucel) and Mesoblast.
1. Prockop SE, Saser SE, Doubrovina E, et al: Efficacy of donor and ‘third-party’ (tabelecleucel) EBV-specific T cells for treatment of central nervous system EBV-PTLD. 2019 Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR. Abstract 92. Presented February 23, 2019.
2. Prockop S, Doubrovina E, Feng A, et al: Long-term outcomes of tabelecleucel (allogeneic third-party EBV-targeted cytotoxic T lymphocytes) for rituximab-refractory post-transplant EBV+ lymphomas: A single center experience. 2018 European Hematology Association Annual Congress. Abstract PF401. Presented June 15, 2018.
Marcie L. Riches, MD, MS
Marcie L. Riches, MD, MS, Director of Clinical Research and Data Quality and Bone Marrow Transplant Clinic Medical Director, and Clinical Associate Chief of Hematology/Oncology at the University of North Carolina at Chapel Hill, commented on the study of...!-->!-->