UCLA

Cancer immunotherapy has become the new medicine for cancer patients providing curative hopes. The adoptive cell transfer of engineered T cells has demonstrated promising clinical response rates, especially for chimeric antigen receptor (CAR) therapies and T cell receptor (TCR) engineered therapies. This dissertation aims to extend the findings of previous engineered T cell therapies focusing on TCR-engineered T cells. Two TCRs are studied here: NY-ESO-1-specific TCR (esoTCR) and invariant natural killer T (iNKT) cell TCR. Towards the “off-the-shelf” T cell immunotherapy, we demonstrated the efforts in developing the TCR toolbox, the ex vivo allogeneic T cell generation platform, combination engineering methods for next-generation allogeneic T cell product, and nanomaterials for T cell activation and expansion.

NY-ESO-1 attracts wide attention for developing targeted cancer therapies for its broad aberrant expression across tumor types and strong ability to elicit immune responses. Due to the MHC restriction nature of TCR, a toolbox of esoTCRs with various NY-ESO-1 epitope specificity and MHC restriction is in great need to expand the patient pool and prevent tumor evasion through the loss of MHC heterozygosity. Chapter 2 of this dissertation will present the work on isolation and characterization of NY-ESO-1-specific TCRs restricted on various MHCs.

Most current engineered T cell therapies, including CAR and TCR therapies, fall under autologous cell therapy. The autologous approach has demonstrated its feasibility and effectiveness. The personalized nature of autologous therapies has also greatly limited the further extended use of engineered T cells in the clinic. In Chapters 3 and 4, we established a novel ex vivo HSC-based TCR-engineered T cell generation platform for allogeneic “off-the-shelf” T cell therapies for cancer. In two separate works, we demonstrated the use of esoTCR and iNKT TCR in this platform. The combinational uses of CAR, CRISPR-Cas9 gene editing, and other enhancement genes were also explored in these two chapters.

T cell activation and expansion is an essential step required for all T cell-based immunotherapies. The developmental path of T cell activating methods starts from the simple addition of anti-CD3 antibodies to magnetic antibody-conjugated beads that are commercially available nowadays. Striving to mimic the natural cell-cell interaction and immunological synapse relating to T cell activation, in Chapter 5, we present a novel nanomaterial-based method for ultrahigh T cell activation and expansion.

Collectively, the work described here advances the field of T cell therapies by enriching the toolbox of TCRs restricted on various MHC, establishing an ex vivo HSC-based TCR-engineered T cell generation platform which provides new allogeneic T cell sources towards the “off-the-shelf” T cell therapies for cancer patients, and providing a new nanomaterial-based method for ultrahigh T cell activation and expansion.