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Helen Heslop, MD
Photo courtesy of Baylor
College of Medicine

NEW YORK—Researchers are creating virus-specific T cells (VST) to treat and prevent viral infections in patients who undergo hematopoietic stem cell transplant.

Thus far, the group has modified T cells with 5 viral vectors—Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (ADV), BK virus (BKV), and human herpesvirus 6 (HHV6)—and are devising methods whereby these VSTs can be made readily available, off-the-shelf products.

Helen Heslop, MD, of Baylor College of Medicine in Houston, Texas, described the efforts of the Baylor research team at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.

The team’s tri-virus and 5-virus VST approaches have been described previously. Here, we focus on the team’s efforts to create an off-the-shelf product.

A companion story describes the team’s VST approach to treating type 2 EBV-associated lymphomas.

Despite promising results with these earlier methodologies both as prophylaxis and treatment after stem cell transplant, problems existed with the approaches that would impede broader implementation of VSTs.

“Most of these initial methodologies were complex,” Dr Heslop said.

And even though the production time of the 5-virus VSTs is only 10 days, it does not allow for urgent use.

To solve this problem, the researchers are developing VSTs as off-the-shelf, third-party banked cells for patients who don’t have the time to wait for donor-specific cells to be made.

“The strategy here is that we make lines that are well-characterized but are HLA-restricted and tied to specific viruses,” Dr Heslop said.

The cells are then cryopreserved so that they’re available, and patients receive VSTs according to their HLA type and the line that has suitable activity for their infections.

“We initially evaluated this approach through a multicenter study sponsored by the NHLBI [National Heart, Lung, and Blood Institute],” Dr Heslop said.

Tri-virus approach

The researchers used the original tri-virus methodology, which was lengthy, “but, in this case, because the cells were already available, the time was not a major issue,” Dr Heslop said.

The team also made some new lines for donors with common alleles. In all, they had 32 lines available while the study was running.

They treated 50 patients: 23 received VSTs for CMV, 18 for ADV, and 9 for EBV.

One patient who had CMV colitis received the VSTs and had a complete response (CR), as evidenced by a normal endoscopy with no viral inclusions.

Another patient had EBV persistent after 6 doses of rituximab. One month after receiving the VST infusion, the patient had a CR, even though the cell line had only 1 class 2 allele. And the patient has sustained the CR for several years.

The overall response rate for the study is 74.0% at day 42 after infusion.

The response rate was not significantly different for each virus, Dr Heslop pointed out. Patients with CMV had a 73.9% response rate, those with EBV had a 66.7% response rate, and those with ADV had a 77.8% response rate.

“This is a little bit lower than with the donor-specific T cells, but I think it’s still a promising approach,” she added.

5-virus peptide mix

The researchers are now evaluating the more rapid, 5-virus peptide mix method for creating off-the-shelf VSTs.

This method replaced live viruses with overlapping peptide pools and added immunogenic antigens for 5 viruses, including BKV and HHV6. The process takes only 10 days to produce VSTs.

The team has identified a line for over 90% of the patients screened.

“That’s because we will accept a line that’s only matched at 1 HLA allele, as long as we have activity against the infecting virus through the shared allele,” Dr Heslop explained.

So they’re conducting a clinical trial using this method, and thus far, they have enrolled 22 patients. Sixteen patients have had 1 infusion, and 6 patients have had multiple infusions.

The 22 patients had 25 infections: 10 CMV, 10 BKV, 2 EBV, 2 ADV, and 1 HHV6.

The overall response rate is 88%. Nine of 10 responses in patients with BKV were partial because BK is difficult to clear from urine. However, the BK patients who had hemorrhagic cystitis all had symptomatic improvement.

Dr Heslop pointed out that these results are similar to those at other centers using EBV third-party T cells.

The initial third-party studies were done in Scotland and had a response rate of about 60%, which increased to around 80% in follow-up studies, where they characterized the T cells more extensively.

Both donor-specific and third-party VSTs have low toxicity, sustained response rates, and activity confirmed by studies in multiple centers.

Dr Heslop believes the rapid manufacturing methodologies will facilitate definitive clinical trials.

She said Cell Medica provided support for some of the trials with EBV tumors. end hematology article


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