Adoptive Cell Therapy in Solid Tumors Demonstrates Robust Antitumor Effects

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Autologous T cells engineered to recognize a dominant immunogenic antigen in incurable metastatic synovial sarcoma produced lasting antitumor responses.
Autologous T cells engineered to recognize a dominant immunogenic antigen in incurable metastatic synovial sarcoma produced lasting antitumor responses.

Administration of an affinity-enhanced T-cell receptor (TCR) construct targeting NY-ESO-1/LAGE1a, an antigen found in 70% to 80% of metastatic synovial sarcoma cases, had a robust antitumor response in patients with these solid malignancies, leading to a complete response in 1 patient, according to a study published in Cancer Discovery.1

Though engineered T-cell therapies have shown striking responses in numerous blood cancers, there has been limited evidence that this tailored immunotherapy approach could work in solid tumors. Results from a trial (ClinicalTrials.gov Identifier: NCT01343043) found that many patients had responses to their investigational affinity-enhanced TCR. In addition to seeing patient tumors shrink, the researchers demonstrated that expansion of the NY-ESO1c259T cells occurred after infusion and persisted for 6 months in all responders and in 1 of 6 nonresponders.

Building on prior results that showed adoptive transfer of NY-ESO1c259T cells plus IL2 produced a clinical response in synovial sarcoma,2 researchers enrolled 15 patients with recurrent synovial sarcoma, with 12 eligible to receive treatment following leukapheresis and a lymphodepleting regimen of fludarabine and cyclophosphamide. Of the 12 patients who received treatment, 10 were infused with the protocol-specified dose (2 received a subtarget cell dose).

Overall response rate to the cell therapy was 50% and included 1 complete response and 5 partial responses. Five patients were alive as of March 30, 2017, the data cutoff date. Those who received the treatment at lower cell doses progressed within 12 weeks. Seven patients experienced decreases in tumor burden following the 4-week evaluation point, suggesting the decreases were not solely due to treatment with chemotherapy.

Antitumor responses continued to occur in 4 patients more than 3 months after initial administration with NY-ESO1c259T cells. No fatal adverse effects were observed during the trial, and 11 patients experienced grade 3 or higher treatment-related events. Though the researchers specifically eliminated IL2 from the treatment regimen, cytokine release syndrome occurred in 5 patients.

“Demonstration of transient increase in the size of metastatic lesions consistent with lymphocyte-induced inflammation followed by regression, trafficking of NY-ESO-1c259 T cells into the tumor bed, and a prolonged progressive clinical response in several patients confirms that the antitumor effects observed were immune-mediated,” the researchers concluded, with responders demonstrating significantly enhanced NY-ESO-1c259T-cell expansion compared with nonresponders (P = .0411).1 Postrelapse biopsy in 1 patient with high persistence of engineered cells confirmed that NY-ESO-1 continued to be expressed as long as 28 months after infusion.

The researchers also found that post-infusion, the phenotypic profile of the T-cell subsets included all types of T cells in varying stages of differentiation. The persistence of the engineered T cells relies heavily on the manufacturing parameters used to make them, wrote the investigators, and certain subsets of T cells may have enhanced regenerative capabilities. Thus, isolating selected populations of T cells based on phenotype in future trials has the potential to “enable dose reduction and potentially enhance efficacy,” they wrote.1

Though the researchers remained optimistic about the treatment approach, they also acknowledged that it has been difficult to establish a cause-and-effect relationship between clinical response and administration of the adoptive cell therapy, pointing to other trials examining NY-ESO1c259T cells in multiple myeloma:2,3 “Although clinical response appeared greater than would be expected with transplant alone in the 20 patients studied, antitumor activity attributable to the infused cell product was difficult to definitively distinguish from the chemotherapy effect.”1

The researchers added that a follow-on study (ClinicalTrials.gov Identifier: NCT03168438) investigating the effect of NY-ESP-1 SPEAR T cells (NY-ESO1c259T cells) alone and in combination with pembrolizumab in multiple myeloma will address this concern surrounding transplantation. The sponsor of that early phase 1 trial is also Adaptimmune; the company is running the trial in collaboration with Merck Sharp & Dohme Corp. and GlaxoSmithKline.

In an accompanying editorial, authors outlined why previous efforts to treat synovial sarcoma through PD-1 blockade have failed, and why adoptive cell therapies could work well in sarcoma. “The remarkable responses observed in this study are in stark contrast to the lack of therapeutic efficacy of checkpoint blockade in this malignancy, highlighting the fact that the defect in the immune response appears less dependent on T-cell exhaustion or the immunosuppressive microenvironment and more likely to be at the level of immune recognition and evasion.”4

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. Please refer to the original paper for a complete list of disclosures.

References

  1. D'Angelo SP, Melchiori L, Merchant MS, et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1c259T cells in synovial sarcoma. Cancer Discov. 2018;8(8):944-957.
  2. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917-924.
  3. Robbins PF, Kassim SH, Tran TLN, et al. A pilot trial using tumor lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin Cancer Res. 2015;21(5):1019-1027.
  4. Keung EZ and Tawbi HA. Engineered T cells in synovial sarcoma: persistence pays off! Cancer Discov. 2018;8(8):914-917.

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