For patients who experience severe viral infections after hematopoietic stem cell transplant (HSCT), there is high promise from a novel T-cell therapy. This approach, which uses off-the shelf “educated” T cells, showed a cumulative response rate of 92%, with a corresponding decrease in viral load and the resolution of disease in most patients.
The study is from researchers at Houston’s Center for Cell and Gene Therapy at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children’s Hospital in Texas. The report was published online August 7 in the Journal of Clinical Oncology.
Viral infections are a major problem after HSCT and can add substantially to the clinical and financial burden of transplantation, the authors write. Although antiviral agents are available for some of the viruses that are clinically challenging, they are not always effective and can result in significant adverse effects, they note. For other viruses, no drugs are available.
In previous studies, adoptive transfer of stem-cell donor-derived virus-specific T cells (VSTs) have shown efficacy, but earlier products were aimed at only one or two viruses. The Baylor researchers developed an off-the-shelf product that is active against five viruses commonly associated with infections after HSCT.
The team generated pentavalent T-cell lines that were specific for 12 viral antigens against five viruses that typically cause infections in HSCT recipients ― Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpesvirus–6 (HHV-6).
These pentavalent VSTs were generated from healthy seropositive donors and were cryopreserved in aliquots that were available for immediate use in patients with refractory viral infections who were partially human leukocyte antigen (HLA)–matched with the VST donors.
“Most similar studies have been done on a smaller scale and targeted a single virus,” corresponding author Bilal Omer, MD, of the Center for Cell and Gene Therapy at Baylor College of Medicine/Houston Methodist Hospital/Texas Children’s Hospital, told Medscape Medical News. “With the pentavalent T cells, we are ready to roll this out on a broader scale and actually try to get a broader application,” he added.
The Baylor Study
In their phase 2 study, which was approved by the US Food and Drug Administration and the institution’s review board, the researchers treated 38 recipients of allogeneic HSCT with these off-the shelf T cells.
Thirty-two of the recipients had received HSCTs for hematologic malignancies; six had received HSCTs for nonmalignant disorders. Transplants included both matched and mismatched bone marrow cells, as well as umbilical cord cells.
In 37 evaluable patients who underwent a single infusion of VSTs, the cumulative response rate (complete + partial) was 91.9%.
A complete response was defined as a return to normal range, as defined by polymerase chain reaction–specific assay, and clinical signs and symptoms. A partial response was defined as a decrease in viral load of at least 50% from baseline or 50% improvement of clinical signs and symptoms.
The approach was effective across all the five viral infections tested. Cumulative response rates were 94.1%, 100%, 71.4%, 67%, and 100% for CMV (n = 17), EBV (n = 2), AdV (n = 7), HHV-6 (n = 3), and BKV (n = 16) infections, respectively.
That’s not all. Recurrence, which occurred in 7 of 34 patients, was successfully treated with an additional infusion of off-the-shelf T cells. In cases in which patients did not initially respond, a second infusion or an infusion of a different VST line from the bank of T cells provided clinical benefit in 77% of patients.
In contrast, among 18 patients who were screened but who did not receive VSTs, progressive disease was reported in 12 patients.
None of the patients who received VSTs developed cytokine release syndrome (which is seen with another T-cell therapy, chimeric antigen receptor T-cell therapy). Five patients developed recurrent or de novo graft-vs-host disease (grade 1 or 2), which resolved with steroid treatment.
In a subset of patients, the partially HLA-matched (third-party) VSTs persisted for several weeks and were not associated with alloreactivity. The number of third-party VSTs subsequently declined as the viral infection resolved and endogenous T-cell recovery occurred.
The Promise for Clinical Practice
“With the pentavalent T cells, we have the possibility of treating multiple viral infections simultaneously,” Dr Omer told Medscape Medical News.
Indeed, in their study, seven patients underwent treatment with VSTs for two viral infections. Both infections were controlled with a single infusion of VSTs.
“CMV, AdV, and EBV were cleared in all cases, and all patients with BKV HC [hemorrhagic cystitis] and the patient with HHV-6 encephalitis had clinical improvement or disease resolution,” Dr Omer and colleagues note.
Disease resolution was reported in most patients. Patients with CMV infections that were refractory to approved therapies, such as ganciclovir and foscarnet, responded to VSTs.
Dr Omer and colleagues give details on one patient with drug-resistant CMV. In this patient, CMV inclusions occurred on numerous ulcers in the ileum and colon. The patient was being treated with cidofovir. CMV titers were increasing, which caused worsened abdominal cramping that required opioid therapy. After a VST infusion, viral titers decreased, as did the severe symptoms. The patient did not require narcotics by week 4 post infusion.
Another patient, who had refractory HHV-6 encephalitis and BKV HC and who showed decreased alertness and responsiveness, showed a remarkable response with one infusion of VST. “Within 24 hours, the patient exhibited improved alertness and sustained normalization of mental status,” the team reports.
Dr Omer pointed out that in no case is there a greater unmet need than in BKV infections, for which there are no treatment options, unlike other viral infections. BKV-associated hemorrhagic cystitis in HSCT recipients is associated with incapacitating pain, significant blood loss, clot retention, and renal failure.
Dr Omer shared his own experience. “A patient is frankly miserable, in pain, bleeding from the bladder. As early as 2 days after the VST infusion, the patient may feel better, does not have pain, does not have to go to the bathroom every 15 minutes, and the bleeding gets better,” he told Medscape Medical News.
Next Steps Toward Commercialization
Dr Omer indicated that on July 18, the intellectual property for VST was licensed to ViraCyte, a company that was cofounded by some of the Baylor researchers.
Ann M. Leen, PhD, the chief scientific officer of ViraCyte, who is also a coauthor on the Baylor study, said that the company is planning a larger-scale multicenter study of this approach and is hoping to commercialize the product.
What products will ViraCyte commercialize? The ViraCyte pipeline consists of Viralym-M (pentavalent to treat AdV, BKV, CMV, EBV, and HHV-6), Viralym-C (for CMV), Viralym-A (for AdV), and Viralym-B (for BKV).
“We hope to provide the first allogeneic off-the-shelf T-cell therapy to treat viral infections,” Dr Leen told Medscape Medical News. “We are manufacturing cells from a carefully chosen pool of donors whose HLA profile will allow us to provide an effective VST product to the majority of allogeneic HSCT recipients,” she added.
She explained that ViraCyte has the capacity to manufacture such a cell therapy product on a robust scale. “Large volume of cells are cryopreserved in batches to allow for the treatment of thousands of patients,” she pointed out.
Viralym products are initially obtained from highly screened donors, whose T cells are expanded, educated, frozen, and stored for use when needed (see figure below). The manufacturing processes do not alter the genetic makeup of the T cells, nor do they expose T cells to the viruses, the company points out.
Dr Omer told Medscape Medical News that they will next undertake a phase 3 study for BKV-associated hemorrhagic cystitis. The study is planned in cooperation with the BMT Clinical Trials Network, which he will be leading. “The protocol is close to completion and will have similar exclusion/inclusion criteria as the reported phase 2 study,” he said. For this study, the same pentavalent T cells (Viralym-M) will be used. “After much debate, it was felt that it was a good idea to provide prophylaxis for other potential viral infections in addition to treating BKV infections,” he said.
“The T-cell therapy for viral infections can be used for all refractory infections and ones that do not have approved antiviral agents,” Dr Leen indicated. He added that trials for AdV and CMV infections will follow.
“Our pentavalent VSTs allow us to do sequential or multiple trials in tandem,” she noted.
Several study authors have received fees, support, and grants from industry sponsors, as detailed in the published article. Dr Omer has a patent pending in the field of cell therapy. Several authors, including Dr Leen, also hold patents, receive royalties for intellectual properties in the field of cellular immunotherapy, and have stock or hold ownership in several start-up companies, including ViraCyte, which is licensed to use the intellectual property from Baylor. Dr Leen is also the chief scientific officer of ViraCyte.
J Clin Oncol. Published online August 7, 2017. Abstract
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