May, 2024
May 2024
Paper summary by Marco Donia
Apr 20, 2024, 07:47

Paper summary by Marco Donia

Marco Donia, at the

“TCR Engineered T Cells for Cancer: 37% response rate in Sarcoma (phase II).

Access here (The Lancet, March 27th, 2024 Sandra D’Angelo), Commentary.

The phase 2 SPEARHEAD-1 trial presented compelling results for afamitresgene autoleucel (afami-cel), a T cell receptor (TCR)-engineered T cell therapy, for HLA-A2+ patients with MAGE-A4+ advanced, treatment-resistant synovial sarcoma or myxoid round cell liposarcoma.

Key Results (Cohort 1):

  • Response Rate: 37% (19/52) response rate.
  • Manageable Toxicity: Cytokine release syndrome (CRS) in 71% (37/52) of patients, with only one case of grade 3 CRS. 19 patients received Tocilizumab (anti-IL6, typically used to treat CRS).
  • Overall Survival: Median OS reached 15.4 months.
  • Patient Population: 28% (105/373) of patients were positive for HLA-A2 and MAGE-A4. 52 patients received treatment, median manufacturing time 40 days. Median three lines of previous treatments.
  • Both engineered CD4+ and CD8+ T cells infused: Median 8.7×10^9 transduced cells infused.

Take Home Message:

  •  High Response Rate in rare, treatment-resistant sarcomas with scarce therapeutic options, with manageable toxicities, building on durable responses from a previous phase 1 (Nature Medicine 2023).
  • Potential First Approval: Biologics license application filed with the US FDA. Could be the first engineered T cell therapy approved for solid tumors.

About TCR-Engineered T Cell Therapy:

  • Personalised Cell Therapy: A one-time treatment, involving the collection of a patient’s own T cells, which are engineered in the lab to express specific T-cell receptors (TCRs) recognizing and attacking cancer cells; finally, T cells are reinfused after lymphodepleting chemotherapy. Afami-cel targets MAGE-A4, an antigen expressed in many cancer types but not in normal adult tissues (except non-vital, mostly immunologically inaccessible tissues).
  • Most Advanced TCR therapy: Afami-cel is the most advanced TCR engineered T cell therapy by clinical development phase.
  • HLA Restriction: The efficacy of this therapy depends on the patient’s HLA type presenting the target antigen in a form recognizable by the engineered TCR.
  • Challenges: Includes the complexity of manufacturing and related logistics (common with all personalized cell therapies), risk of off-target effects, and severe immune reactions like CRS.
  • Synovial Sarcoma and Myxoid Round Cell Liposarcoma: rare, aggressive tumors especially when metastatic. More here.

This trial was sponsored by Adaptimmune (plots and survival curves available).”

Additional information.
Source: Marco Donia/LinkedIn