NY-ESO-1 TCR Produces Positive Results in Patients With Multiple Myeloma

Rafael Amado, MD

Rafael Amado, MD

Data from a phase I/II single-arm trial of the NY-ESO-1 T-Cell Receptor (TCR) therapy, recently published inNature Medicine, is the first to show feasibility and antitumor responses with TCR-specific therapy in patients who have multiple myeloma. Close to 70% of patients showed signs of complete response 3 months after treatment, which is 30% better than expected in patients who do not have a high-risk disease following an autologous stem cell transplant (ASCT).

“Engineered T cells can expand in patients, traffic to the bone marrow, and induce antitumor responses. Unlike other modalities such as chimeric antigen receptors (CAR) that are restricted to proteins present in the cell surface (a small fraction of all possible antigens), TCRs can target any protein, and therefore may have broader applications in the treatment of cancer,” said Rafael Amado, MD, chief medical officer of Adaptimmune, in an interview withTargeted Oncology.

The study was conducted to explore the feasibility of this particular TCR technology, as well as its potential antitumor activity. The trial was conducted in 24 patients who have myeloma with symptoms, active disease despite previous therapies, or a high risk of recurrence based on molecular analyses of cancer cells. Twenty patients were given high-dose chemotherapy and an autologous stem cell transplant, followed by gene-modified T cells.

“This is the first report of lentiviral vector-mediated TCR therapy to be published that shows a continuation beyond 1 month,” said Carl H. June, MD, Richard W. Vague professor in Immunotherapy, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, in aPenn Medicinenews release. This study has proven the safety of TCR-specific T cells, as well as their feasibility in patients who express NY-ESO-1, according to June. Amado also explained that the cells persisted in the bloodstream for long periods of time, which was not previously observed with TCR technology.

Patients involved in the study were given an average of 2.4 billion NY-ESO-engineered CD3 T cells 2 days following an ASCT. The T cells were removed and then reprogrammed using a cell production process first developed by Penn’s Clinical Cell and Vaccine Production Facility. The newly built cells were then infused back into the patients to multiply and seek out a peptide expressed by NY-ESO-1 and LAGE-1 antigens, which is found in the cancer cells of multiple myeloma.

“They [TCRs] are naturally occurring proteins, expressed on the surface of T-lymphocytes, which allow these T cells to recognize and destroy cells that express foreign (non-self) antigens,” said Amado. These antigens are fragments of foreign proteins, most commonly expressed in cells as a result of infections.” Scientists engineered the NY-ESO TCR to recognize and bind with a high affinity to the peptide fragment of the NY-ESO protein. It can be found in multiple cancers, myeloma being one of them.

In the NY-ESO trial, TCRs showed high efficacy. After 21 months, 15/20 patients were surviving. Of the 20 patients undergoing treatment, 14 had near complete responses, two had a very positive partial response, while two others had a partial response, one had a stable disease, and the final patient had progressive disease. In April of 2015, just after 30 months, the median progression-free survival (PFS) was 19.1 months, and the median overall survival (OS) increased to 32.1 months.

In addition, not a single patient underwent macrophage activate syndrome or cytokine release syndrome. The study did not produce a fatality related to treatment. Amado mentioned that the major adverse events were diarrhea, rash, fatigue, fever, and graft-versus-host disease, which can be described as an immune reaction that affects the bowel and skin.

Amado and his team are now considering the results and data, and they will soon decide what steps to take in future trials.

Penn Medicine. Investigational T-cell receptor therapy achieves encouraging clinical responses in multiple myeloma patients, Penn-led study finds.http://www.uphs.upenn.edu/news/News_Releases/2015/07/june/. Accessed July 21, 2015.