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Virus-specific T cells attack infections after hematopoietic stem cell transplantation
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An “off-the-shelf” approach using virus-directed virus-specific T cells safely and effectively treated patients with severe viral infections following allogeneic hematopoietic stem cell transplantation, according to phase 2 trial results published in Journal of Clinical Oncology.
Viral infections — a major cause of morbidity and mortality following allogeneic HSCT — add substantial clinical and financial burden to transplantation.
The adoptive transfer of stem cell donor-derived virus-specific T cells to treat viral pathogens appears effective; however, broader implementation is limited.
“[The approach] is limited by the cost and complexity of individualized product manufacture; the time needed for custom manufacturing, which may preclude the immediate availability of virus-specific T cells for urgent medical need; and the requirement for seropositive donors — an issue of growing importance given the increasing use of younger, virus-naive donors and cord blood as a source of stem cells,” Bilal Omer, MD, instructor at the Center for Cell and Gene Therapy at Baylor College of Medicine, and colleagues wrote.
However, these limitations may be overcome by preparing and cryopreserving banks of virus-specific T-cell lines from healthy seropositive donors to be available for immediate use as an “off-the-shelf” product. This approach has shown promise for the treatment of Epstein-Barr virus posttransplantation proliferative disorder, cytomegalovirus and adenovirus.
Still, it is unknown if this approach would also be effective for the treatment of human herpesvirus 6 and BK virus, and whether additional T-cell specificities for these two viruses could be incorporated into a multiple virus-specific cell product.
Omer and colleagues generated a bank of virus-specific T-cell lines for 12 viral antigens and administered them to 38 allogeneic HSCT recipients with 45 drug-refractory infections or diseases associated with Epstein-Barr virus, adenovirus, cytomegalovirus, human herpesvirus 6 and BK virus.
Among 37 evaluable patients, cumulative clinical response occurred in 91.9% (95% CI, 78.1-98.3) after one infusion by week 6.
Seventeen patients who received virus-specific T-cell lines for persistent cytomegalovirus demonstrated a cumulative response rate of 94.1% (95% CI, 71.3-99.9) by week 6. Of these patients, six showed a complete response and 10 patients had partial responses.
Both patients treated for Epstein-Barr virus achieved a virologic complete response by week 6.
Seven patients received infusions for adenovirus, which resulted in four complete responses, one partial response and two nonresponses, for a cumulative response rate of 71.4%.
Two of the three patients infused to treat human herpesvirus 6 reactivations achieved partial responses for a cumulative response rate of 67%. The other patient was not evaluable.
Clinical benefit occurred in all 16 patients (95% CI, 79.4-100) who presented with tissue disease, including 14 patients with BK virus-associated hemorrhagic cystitis and two patients with BK virus-associated nephritis. Patients demonstrated a median 85.5% decrease in urinary viral load by week 6, which increased to 96% by week 12. In addition, 13 of the patients treated for BK virus-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6.
A single infusion controlled dual infections in seven patients.
Seven of the 34 patients who achieved a partial or complete response had subsequent recurrence after a median of 10 weeks. Six of those patients were successfully treated, and one patient required additional infusions.
Fifteen patients with no response, partial response or recurrence also received a second infusion. The second infusion led to clinical benefit in 10 patients (77%).
To evaluate in vivo T-cell persistence, Omer and colleagues discriminated between infused vs. endogenous cells on the basis of peptide-epitope specificity in 16 clinical responders. Researchers confirmed the persistence of virus-specific T-cells from the infused line for up to 12 weeks in 11 patients.
The infusions appeared well tolerated. One patient developed recurrent grade 3 gastrointestinal graft-versus-host disease and five patients developed recurrent or de novo grade 1 or grade 2 skin GVHD.
The researchers noted a randomized trial will be required to definitively assess the value of banked virus-specific T cells.
“These virus-specific T cells can be rapidly and cost-effectively produced in scalable quantities with excellent long-term stability, which facilitates the broad implementation of this therapy,” Omer and colleagues wrote. “More widespread and earlier use of this modality could minimize both drug-related and virus-associated complications and, thereby, decrease treatment-related mortality in recipients of allogeneic HSCT.” – by Kristie L. Kahl
Disclosures: Omer reports one patent pending in the field of cell therapy. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
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Navneet Majhail
Viral infections — especially if they are treatment refractory — are the scourge of HSCT and cause significant morbidity and mortality in transplant recipients. Mostly, drug treatment options have limited efficacy, are logistically challenging to administer and/or have debilitating toxicities. Because these infections are primarily a manifestation of impaired immune response, adoptive transfer of stem-cell donor-derived virus-specific T cells has been evaluated as a treatment and has been shown to be highly efficacious.
However, several challenges have restricted the wider application of this approach, including the need for seropositive stem-cell donors, as well as the logistics, time, cost and complexity of generating virus-specific T cells. Tzannou and colleagues report a phase 2 trial of off-the-shelf virus-specific T cells and show a remarkable 92% overall response rate in treatment-refractory BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus and adenovirus infections in allogeneic HSCT recipients.
Researchers identified a suitable virus-specific T-cell line for the majority of patients. Further, most patients received partially HLA-matched cells, responded to one infusion and generally tolerated the infusion well without any appreciable risk for GVHD.
With the disclaimer that further confirmatory trials are needed, the ability of recipient HLA-agnostic off-the-shelf virus-specific T cells to efficaciously and safely treat refractory highly morbid viral infections can definitely be classified as a major breakthrough in transplantation. As science and evidence for this innovation evolves, it is also critical that regulatory and reimbursement issues be addressed simultaneously to maximize its generalizability and impact.
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