Immunotherapy Shows Early Promise in Advanced Sarcomas

Arun Singh, MD

Early research has shown promise for adoptive cellular therapy with autologous lymphocytes genetically modified to express an NY-ESO-1-specific T-cell receptor and dendritic cell vaccination in combination with ipilimumab (Yervoy) in patients with advanced sarcomas. The data were presented at the 2015 Connective Tissue Oncology Society (CTOS) Annual Meeting.

“This [study] is expanding the role of NY-ESO-1 adoptive cellular therapy. This type of therapy has been used at the National Cancer Institute, and…there have been efforts to do this type of work at other institutions and bring this therapy to other patients,” said lead author Arun Singh, MD, of the Division of Hematology-Oncology at UCLA, in an interview with OncLive.

At the meeting, Singh discussed results of the safety and antitumor efficacy feasibility part of the research, in which investigators used a previously developed, short (1-week) ex vivo protocol to manufacture NY-ESO-1 antigen-specific T cells.

“The way the people make the immune cells is actually a little cumbersome. It can take weeks to do sometimes, and our project was also trying to see if we could shorten that and make it a much more feasible protocol to do,” said Singh. “Also, we think that combining immunotherapies is better than giving either of them alone.”

The research involved 4 patients with synovial sarcoma and 1 patient each with dedifferentiated liposarcoma, malignant peripheral nerve sheath tumors, and melanoma.

Autologous peripheral blood mononuclear cells were transduced with a retroviral vector, encoding an NY-ESO-1—specific TCR and expanded over 2 days in the presence of IL-2. Fresh cells were infused into patients who were HLA-A2.1-positive on day 0 after a regimen of 60 mg/kg of cyclophosphamide (day -5, -4) and 25 mg/m²/day (day -4 to -1) of fludarabine.

NY-ESO-1_157-165 —peptide-pulsed DC vaccinations were administered on days +1, +14, and +30 and IL-2 was administered at 500,000 IU/m² subcutaneously twice daily for 7 to 14 days. Ipilimumab at 1 mg/kg was given on day 0 or 1 every 3 weeks, for a maximum of 4 doses.

Six of the 7 enrolled patients received 1 x 10⁹ transgenic cells. Mean NY-ESO-1—specific TCR was 55.6% (range, 34.1-71.2). Five of seven patients received 3 DC vaccinations. One of 7 patients received 2 vaccinations and one of seven patients received 2 vaccinations. Six patients received 18 to 28 doses of IL-2 (mean 22), and 1 patient received 14/14 doses upon amendment.

The median follow-up was 18.7 weeks. Four of 6 evaluable patients showed evidence of a transient response at an early day-30 PET scan. One patient had stable disease (SD) and 1 patient had progressive disease (PD). At day 90, 1 of 6 patients had partial response, 1 of 6 had SD, and 4 of 6 had PD by RECIST 1.1 criteria. At 36 weeks, 1 patient had a complete response CR.

Adverse events attributed to NY-ESO-1 TCR included anemia (1 patient), rash (1), eosinophilia (1), and one patient experienced a cytokine storm that required hospitalization.

Singh thinks the next steps for this research would be to add a PD-1-inhibiting agent, such as nivolumab (Opdivo) to NY-ESO-1 adoptive cellular therapy, because of some of the resistance mechanisms that can occur in the tumor microenvironment.

“It’s baby steps; you have to look at all the toxicities and weigh them very carefully to see what makes sense for patients,” said Singh.

Singh A, Chmielowski B, Berent-Maoz B, et al. Adoptive cellular therapy with autologous lymphocytes genetically modified to express an NY-ESO-1 Specific T-cell receptor and dendritic cell vaccination with or without ipilimumab in patients with advanced sarcomas and melanoma. Presented at: The 2015 Annual Meeting of the Connective Tissue Oncology Society; November 5, 2015; Salt Lake City, UT. Abstract 010.