Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation

Abstract

BACKGROUND. Adoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBVassociated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients. METHODS.We developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation. RESULTS.EBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles. CONCLUSION.Third-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBVassociated lymphoma after transplantation.Authorship note: SP and ED contributed equally to this work. Conflict of interest: ED and ROR had consultancy agreements with Atara Biotherapeutics. ED and ROR are inventors on technology referenced in this work (SK2013-71 [patient ID], Proprietary Cell Banks for Use in 3rd-Party EBV-Specific T Cell Therapy; and SK2018-122 [patient ID], Methods of Selecting T Cell Lines for Adoptive Cellular Therapy). SP is an inventor on technology referenced in this work (SK2013-71 and SK2018-122) and has waived rights to revenue generated from these inventions. Memorial Sloan Kettering Cancer Center (MSK), which owns the technology, has licensed this technology to Atara, and MSK has interests in Atara through this licensing arrangement.

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“…In addition to therapeutic approaches using Treg cell infusion, another three clinical trials are underway with the aim of evaluating treatment using specific SARS-CoV-2 T cells isolated from individuals who recovered from COVID-19 (290)(291)(292). The use of virus-specific T cells for off-the-shelf treatment has been used in several viral infections, such as cytomegalovirus, HHV6, adenoviruses, Ebola virus, and BK virus (293)(294)(295)(296). Although vaccination provides T cells-based virus-specific immunity, the path to its development is long, so the use of adoptive cell transfer techniques from healthy individuals who recovered from COVID-19 and developed an effective cell response is probably the fastest way to treat critically ill individuals (297).…”

T-Cell Therapeutics Targeting Human Parainfluenza Virus 3 Are Broadly Epitope Specific and Are Cross Reactive With Human Parainfluenza Virus 1

“…Although our products were manufactured from a diverse group of donors, a limitation to this study is that we cannot evaluate for all possible HLA restricted responses. However, we and others have shown that even knowing a relatively restricted number of class I and class II restricted virus-specific responses provides important clinical information when evaluating virus-specific T cell products in a third party “off the shelf” setting ( 16 , 23 ).…”

COVID-19 in Kidney Transplantation: Epidemiology, Management Considerations, and the Impact on Kidney Transplant Practice

“… 78 , 79 Other directions in future therapeutics include the use of monoclonal antibodies against the viral spike protein 80 and adoptive T cell therapy. Adoptive T cells with a chimeric antigen receptor or a T-cell receptor have been successfully developed against other viruses like Epstein barr virus 81 and severe acute respiratory syndrome coronavirus-1. 82 Use of adoptive T cell therapy may be particularly helpful in SOT recipients with COVID-19 in reducing the risk of serious complications and are in the developmental stage ( https://www.fiercebiotech.com/research/scientists-explore-using-engineered-t-cells-to-target-covid-19 ).…”