Striking Effect of Adoptive Cell Therapy in Sarcoma Treatment

Synovial sarcoma, usually in the arms and legs and often very close to joint capsules and tendon sheaths, is a rare cancer type. It is a soft tissue sarcoma, accounting for %5-10 of all sarcomas.

Discovered in the early 1900s, this cancer was named "synovial sarcoma" because its cells resemble those in synovium, the joint capsule fluid. Its actual cells of origin are unknown and are not necessarily synovial.

A Study of Adoptive T-Cell Therapy, a Type of Immunotherapy, in Synovial Sarcoma

In metastatic (stage 4) synovial sarcoma, % 70 to % 80 of cancer cells carry an antigen called NY-ESO-1 / LAGE1a.

An antigenis a toxin or other foreign substance that can trigger the immune system, particularly antibody production.

Designed to target this antigen, a T-cell receptor was used to modify T cells, producing a strong antitumor response in synovial cancer patients. This striking study, resulting in 1 patient's complete response, was published in Cancer Discoveryon 11 June 2018.

Although adoptive T-cell treatments have produced striking examples in many blood cancers, evidence that this particular immunotherapy could work in solid (organ) tumors has been limited. This trial found good responses to T-cell treatment with enhanced affinity for cancer cells. Alongside tumor shrinkage, researchers observed modified T cells continuing to increase after infusion. This increase occurred in all responders and, among the 6 nonresponders, in 1 patient.

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NY-ESO-1c259T cells were the name of these modified immune cells, given with another immune stimulant, interleukin-2 (IL2), to 12 patients with recurrent synovial sarcoma. T cells were collected by leukapheresis. Before modification and administration, patients underwent lymphodepletion (immune suppression) with fludarabine and cyclophosphamide chemotherapy. Of the 12 treated patients, 10 received the protocol-specified T-cell dose and 2 a lower dose.

Results

• The overall response rate to adoptive cell treatment was % 50 (1 complete response and 5 partial responses)
• As of the data analysis on 30 March 2017, five patients were alive.
• Cancer progressed within 12 weeks in patients receiving low-dose treatment.
• Seven patients showed tumor burden reduction relatively rapidly, within 4 weeks of administration, suggesting shrinkage was not due solely to chemotherapy.
• After the first NY-ESO-1c259T-cell administration, 4 patients continued to show antitumor responses for more than 3 months.
• No fatal adverse effects occurred during the trial, and 11 patients reported severe (grade 3 or higher) adverse effects. Although researchers removed IL2 from the regimen because they considered it responsible for adverse effect intensity, 5 patients developed cytokine release syndrome.
• Modified T-cell numbers increased significantly after administration in responders compared with nonresponders.
• Transport of NY-ESO-1c259T cells to the tumor bed temporarily increased metastatic tumor sizes in several patients.
• In 1 patient's biopsy after cancer recurrence, these modified T cells were still being produced 28 months later.

Researchers also found that post-infusion T cells included all subtypes at different differentiation stages. Modified T-cell persistence depends largely on manufacturing parameters, and some subsets may have enhanced regenerative abilities. Selecting certain T cells in future studies may therefore allow lower doses and potentially greater effectiveness.

Although optimistic about the results, researchers pointed to studies of NY-ESO-1c259T cells in multiple myeloma and acknowledged the difficulty of establishing a causal relationship between clinical response and adoptive cell therapy. In other words, although the response appears greater than expected from stem cell transplantation alone, it is difficult to distinguish it definitively from chemotherapy effects.

So, immune checkpoint inhibitor treatments, namely anti-PD-1 immunotherapies, why did they previously fail in synovial sarcoma, while adoptive cell therapies worked well? A possible explanation is:

In sarcoma's cancer–immune system relationship,the main issue may be immune evasion and lack of recognition rather than T-cell inactivity or an immunosuppressive tumor microenvironment.

The figure below illustrates how T-cell receptors with enhanced affinity target cancer cells:

• What Is the Immune System and How Does It Work? The Body's Defense Mechanism