Adoptive Cell Therapy Improves Outcomes for Select Patients With Advanced Synovial Sarcoma

Adoptive Cell Therapy Improves Outcomes for Select Patients With Advanced Synovial Sarcoma

The adoptive cell therapy afamitresgene autoleucel (afami-cel) demonstrated a favorable response and duration of response in select patients with metastatic synovial sarcoma, according to results from an international phase 2 clinical trial published recently in The Lancet.

The SPEARHEAD-1 trial evaluated a single-arm cohort of 52 patients ages 16 to 75 with metastatic or unresectable synovial sarcoma (44 patients) or myxoid/round cell liposarcoma (MRCLS) (8 patients) with specific features. (1) Adaptimmune developed afami-cel and funded the ongoing study conducted at Memorial Sloan Kettering Cancer Center (MSK) and more than 25 other specialist sites worldwide (NCT04044768).

Highlights of the study findings are as follows: (1)

  • The overall response rate (ORR) was 39% for patients with synovial sarcoma and 25% for patients with MRCLS.
  • The median duration of response was 11.6 months for patients with synovial sarcoma and 4.2 months for patients with MRCLS.
  • Cytokine release syndrome (CRS) occurred in 71% of patients but was mainly grade 1 and managed with tocilizumab. Cytopenias were the most common grade 3 or higher adverse events.

“At MSK, we probably have the most experience in the country identifying eligible patients, implementing bridging therapy when required, and getting patients safely to T cell therapy,” says medical oncologist Sandra D’Angelo, MD, a specialist in treating sarcomas and lead author of the paper. “The results from the SPEARHEAD-1 trial suggest that a onetime treatment with afami-cel has the potential to extend life while allowing responders to go off chemotherapy.”

Synovial Sarcoma and Myxoid/Round Cell Liposarcoma

Synovial sarcoma and MRCLS are ultrarare malignancies, comprising 5% to 10% of all soft tissue sarcomas. Standard care includes surgical resection and chemotherapy. Despite initial response to chemotherapy, metastatic tumors are associated with a dismal five-year overall survival. (2) (3)

These distinct sarcoma subtypes share clinical and biological features, (4) including unique chromosomal translocations (5) (6) (7) limited T cells and antigen-presenting cells in their immune microenvironments; and a low PD-L1 expression, explaining the limited effectiveness of checkpoint inhibitors. (8) (9) Both also highly express cancer testis antigens, such as New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and melanoma antigen family A4 (MAGE-A4). (10) (11)

MSK has been pioneering an adoptive cell therapy approach for patients with synovial sarcoma and MRCLS since 2014. In studies led by Dr. D’Angelo, engineered T cells targeting NY-ESO-1 showed promising efficacy in patients with synovial sarcoma and MRCLS, highlighting the potential for a targeted therapy approach. (10) (11)

Afami-Cel Targets MAGE-A4

MAGE-A4 is expressed in solid tumors, including synovial sarcoma; MRCLS; non-small cell lung cancer; head and neck squamous cell carcinoma; melanoma; and ovarian, urothelial, and gastroesophageal cancers.

Afami-cel is an autologous CD4-negative and CD8-positive T cell product engineered with a self-inactivating lentiviral vector to express a high-affinity MAGE-A4-specific T cell receptor. (12) “Afami-cel works differently than chimeric antigen receptor (CAR) T cell therapy, which binds to molecules on the surface of cancer cells,” says Dr. D’Angelo. “The mechanism of action is more complex: Afami-cel identifies proteins found inside cancer cells, requiring more involvement by the immune system to bring the protein inside the tumor to the immune cell’s surface.”

In the previous phase 1 study (NCT03132922), afami-cel showed promising efficacy in 16 heavily pretreated patients with MAGE-A4-positive metastatic synovial sarcoma, with an overall response rate of 44%, a disease control rate of 94%, and a median duration of response of 28 weeks. (13)

Study Design

Patients eligible for the SPEARHEAD-1 trial were human leukocyte antigen (HLA)-A*O2-positive, had tumors with a high level of MAGE-A4, and had received at least one prior line of anthracycline- and/or ifosfamide-containing chemotherapy. (1)

Baseline MAGE-A4 expression at or above the predefined level were observed in 61% and 47% of tumors of patients with synovial sarcoma and MRCLS, respectively. Patients were heavily pretreated with a median of three prior lines of therapy, and 38.5% received bridging therapy, which was permitted by the protocol for maintaining disease control between leukapheresis and lymphodepletion. (1) 

In the present analysis, 44 patients with synovial sarcoma and 8 patients with MRCLS underwent leukaphersis and lymphodepletion before receiving a single infusion of afami-cel between August 2019 and November 2021. The period from leukapheresis to infusion was about four to six weeks. (1) 

The primary end point was the ORR as determined by a blinded independent review. Secondary end points were the duration of response and safety, including the incidence of immune-related events of particular interest, such as CRS. (1)

Results and Implications

Among all patients, the ORR was 37%, including 39% for 44 patients with synovial sarcoma and 25% for 8 patients with MRCLS. The median duration of response was 11.6 months and 4.2 months for the synovial sarcoma and MRCLS subgroups, respectively. (1)

Treatment response was rapid — within five weeks. Higher responses were observed in patients who had a lower disease burden and synovial sarcoma expressing higher MAGE-A4, were female, and did not require bridging therapy. (1)

The pro-inflammatory cytokine interferon-gamma was associated with anti-tumor response. However, the study authors noted there is an ongoing need to identify biomarkers of resistance to afami-cel. (1)

As anticipated for a patient population with a heavy prior history of systemic chemotherapy, cytopenias were the most common grade 3 or higher adverse events, including lymphopenia (96%), neutropenia (85%), and leukopenia (81%). CRS occurred in 71.2% of patients, with grade 3 or higher events occurring in only 1.9%. (1)

There were no grade 5 adverse events. A total of 28 patients (54%) who received afami-cel died during the trial. However, no deaths occurred within the first month after afami-cel infusion and all deaths were attributed to disease progression. (1)

The investigators observed an exposure-response relationship between afami-cel cellular persistence and overall survival over three months post-infusion. At data cutoff, median progression-free survival was 3.7 months in patients with synovial sarcoma and 2.4 months in patients with MRCLS. (1)

Overall, these phase 2 trial results confirm the benefits observed in the phase  1 trial of afami-cel in synovial sarcoma and indicate a need for further investigation in MRCLS.

Advancing Care for Patients With Sarcoma

MSK is committed to researching new therapies for common cancers as well as rare and ultrarare tumors.

Learn more about MSK’s clinical trials for patients with sarcoma, including the present phase 2 afami-cel trial, which is still open and recruiting.

Dr. D’Angelo partnered with MSK Kids to ensure eligible young patients with synovial sarcoma can access afami-cel. As a result, MSK Kids has opened a phase 1/2 trial of afami-cel (NCT05642455) for pediatric, adolescent, and young adult patients ages 2 to 21 with advanced sarcomas, called the SPEARHEAD-3 Pediatric Study.

The SPEARHEAD-1 phase 2 clinical trial was sponsored and funded by Adaptimmune. Access disclosures for Dr. D’Angelo.

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  1. D’Angelo SP, Razak AR, Agulnik, M, et. al. SPEARHEAD-1: A single-arm phase 2 trial of afamitresgene autoleucel (afami-cel) in advanced synovial sarcoma and myxoid/round cell sarcoma. Lancet. 2024.
  2. Pollack SM, Somaiah N, Araujo DM, et al. Clinical outcomes of patients with advanced synovial sarcoma or myxoid/round cell liposarcoma treated at major cancer centers in the United States. Cancer Med. 2020;9(13):4593-4602.
  3. MF Murray, Antonescu CR, Alektia KM, Maki RG. Management of Soft Tissue Sarcoma: Springer, 2016.
  4. WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. 5 ed: IARC Publications, 2020.
  5. Jones KB, Barrott JJ, Xie M, et al. The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis. Oncogene. 2016;35(38):5021-5032.
  6. Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer. 1992;5(4):278-285.
  7. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature. 1993;363(6430):640-644.
  8. Pollack SM, He Q, Yearley JH, et al. T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer. 2017;123(17):3291-3304.
  9. Tawbi H. A promising start for checkpoint inhibitors in childhood malignancies. Lancet Oncol. 2020;21(1):13-14.
  10. SP D’Angelo, Druta M, Tine BAV, et al. Safety and efficacy of letetresgene autoleucel (lete-cel; GSK3377794) in advanced myxoid/round cell liposarcoma (MRCLS) following high lymphodepletion (Cohort 2): Interim analysis. J Clin Oncol. 2021;39: suppl. 15, 11521.
  11. D’Angelo SP, Melchiori L, Merchant MS, et al. Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1 c259T Cells in Synovial Sarcoma. Cancer Discov. 2018;8(8):944-957.
  12. Sanderson JP, Crowley DJ, Wiedermann GE, et al. Preclinical evaluation of an affinity-enhanced MAGE-A4-specific T-cell receptor for adoptive T-cell therapy. Oncoimmunology. 2020;9(1):1682381.
  13. Hong DS, Van Tine BA, Biswas S, et al. Autologous T cell therapy for MAGE-A4+solid cancers in HLA-A*02+ patients: a phase 1 trial. Nat Med. 2023;29(1):104-114.