among uninfected cells (blue)
Image by Benjamin
NEW YORK—Type 2 Epstein-Barr virus (EBV) tumors, such as Hodgkin and non-Hodgkin lymphomas, are challenging to treat with virus-specific T (VST) cells, according to researchers.
These lymphomas express a more restricted array of EBV antigens that are not particularly immunogenic.
Nevertheless, researchers are devising an approach using peptide mixtures to activate EBV VSTs for use in these patients.
Helen Heslop, MD, of Baylor College of Medicine in Houston, Texas, described this work at the inaugural CRI-CIMT-EATI-AACR International Immunotherapy of Cancer Conference. She also described the researchers’ efforts to create off-the-shelf VSTs.
Dr Heslop explained that, in addition to the more restricted array of EBV antigens, EBV-associated tumors often produce inhibitory cytokines that can impede the activity of T cells.
So the researchers devised a strategy to expand these low-frequency clones by stimulating responding T cells with dendritic cells genetically modified with an ADV viral vector to overexpress LMP1 and LMP2. After multiple stimulations, they obtained an autologous product from the patient.
The team then tested the cytotoxic T cells in 21 patients with relapsed disease and in 29 patients as adjuvant therapy after stem cell transplant (n=14) or chemotherapy (n=15).
In the adjuvant arm, all patients but 1 remain in remission up to 5 years later.
In the relapsed arm, 11 had a complete response (CR), 2 had a partial response (PR), and 8 had progressive disease within 2 to 8 weeks.
“Importantly, there was no toxicity,” Dr Heslop said. “[A]ll were heavily pretreated with multiple lines of therapy for lymphoma, so I think the response rate is encouraging.”
An alternative approach: Pepmix-activated EBV VSTs
Although the antitumor effects of the above approach were encouraging, “we had a very complex manufacturing methodology that we didn’t think was sufficiently scaleable and robust for clinical studies,” Dr Heslop said.
“We also thought there would be potential regulatory issues with live EBV virus and the adenoviral vector,” she added.
And the researchers were concerned about the competition from the EBV/Ad-LMP dominant antigens.
So they devised an alternative approach using peptide mixture (pepmix)-activated EBVSTs.
This approach used autologous monocyte-derived dendritic cells as the antigen-presenting cells for the first stimulation.
The researchers pulsed them with overlapping peptides derived from 4 EBV antigens expressed in the tumors (EBV-LMP1, LMP2, EBNA1, and BARF1). They then expanded and opsonized the cells with IL-7 and IL-15.
For the second stimulation, the team used the T cells pulsed with the peptides and a K562 line pulsed with co-stimulatory molecules. And this process took 23 days, as opposed to the 2-3 months with the previous product.
The researchers have treated 9 patients with these EBVSTs as adjuvant therapy after autologous stem cell transplant. All patients remain in remission.
They also treated 6 patients with active disease. Two are in CR, 2 are in PR, and 2 have progressed.
This trial is ongoing, but the researchers believe that targeting the more challenging type 2 latency tumors with autologous cells can overcome T-cell anergy by using IL-7 and IL-15.
“Obviously, we need more numbers to know what the range of response is,” Dr Heslop said, although, at this early stage, it appears pepmix-activated T cells can produce antitumor responses. .