Patients with metastatic synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCL) urgently need better treatment options. Therapies that employ anti-cancer immune T cells are proving effective against certain other malignancies, and SS and MRCL are ideal targets for this very promising approach. Both sarcoma types consistently express the NY-ESO-1 protein (AKA: antigen).
Our group and others have shown that NY-ESO-1-specific T cells can attack SS and MRCL tumors in patients, but we need to further improve this therapy to produce more consistent, complete and durable responses. Most T cell therapies use CD8+ T cells, but CD4+ T cells might also be critical for effective treatment of these diseases. CD4+ T cells directly support CD8+ T cells and activate the ‘antigen-presenting’ cells (APC) that help CD8+ cells recognize tumor antigens.
We can genetically engineer T cells to recognize NY-ESO-1 by engineering them to express a T cell receptor (TCR). We isolated the genes for two highly active TCRs specific for NY-ESO-1, one to be used in CD4+ cells and one to be used in CD8+ T cells. These TCRs were discovered in a very unique way, by using mice that had been engineered to have human immune system components. We are now ready, for the first time, to combine both genetically engineered CD4+ and CD8+ T cells.
We will also precisely irradiate tumors to damage them and help our infused T cells recognize the tumor. We propose a first-in-human, first-in-class clinical trial for SS and MRCL patients addressing a fundamental question in cancer immunotherapy, i.e., are both CD8+ and CD4+ T-cell functions necessary for optimal response? This trial will evaluate the safety and efficacy of the engineered T cells and using biopsy samples, we will analyze the changes that occur in the tumor following the treatment.
If successful, the proposed studies could transform the treatment paradigm for patients with SS and MRCL and address fundamental questions in immunology, potentially advancing novel strategies that can broadly improve immunotherapy efficacy and patient outcomes.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Wendy Walk.