Jon Silk talks about our next generation research

By: Jon Silk | April 25, 2019

Last month, Jon Silk, who leads our Cell Research team, spoke at the Proimmune 'Mastering #immunity Europe Conference' (bit.ly/2FpBJ2g), about our next generation approaches to improve our SPEAR T-cells for cancer patients.

In the video below, you can watch his presentation (N.B.: the video lasts 18.52 minutes) in which he discussed how we are looking at ways to:

  1. Overcome the tumor micro-environment
  2. Enhance persistence of our SPEAR T-cells
  3. Induce a broader immune response
  4. Improve T-cell functions

Jon focused on two specific approaches that we were working on in partnership with GSK. We have also recently announced that we have had a patent application published, based on work from Garth Hamilton, Claire Gueguen and Jon Silk, as a PCT application WO/2019/034703, “T-Cell Modification”, on enhancing the persistence of our T-cells through expression of IL-7, and potentially activating endogenous tumor-specific T-cells (known as tumor infiltrating lymphocytes or TILs). Adaptimmune have also had a US patent application allowed (US15/713464) based upon the work of Bruno Laugel and Kathrin Skibbe on making our T-cells resistant to the immunosuppressive environment of solid tumors.

The microenvironment of tumors is a hostile environment for T cells and often contains a number of immunomodulatory metabolites including adenosine and prostaglandin E2 which inhibit the activity of tumor-reactive T-cells.

Our ongoing research covers many potential approaches to enhance our SPEAR T-cells.

Co-expression of CD8α

The first next generation approach Jon described uses co-expression of CD8α to enhance the activity of CD4 positive T-cells. Co-expression of CD8α is anticipated to broaden the immune response against solid tumors, by promoting interaction with antigen presenting cells, as well as increasing the antitumor activity by converting CD4+ helper cells into CD8+ killer or cytotoxic T-cells. We have also presented pre-clinical data during the recent AACR meeting (you can read the press release here and the see the poster here) about a next generation SPEAR T-cell product, known as ADP-A2M4CD8, expressing the CD8α co-receptor alongside our engineered TCR that targets MAGE-A4.

“Our next generation programs are designed to enhance our existing SPEAR T-cells, to improve their ability to target and kill solid tumors. The preclinical data we presented at AACR indicate that adding CD8a to our ADP-A2M4 candidate may help broaden the antitumor immune response against additional tumor antigens. Further, the CD8a co-receptor may enhance the ability of CD4+ SPEAR T-cells to kill cancer cells through the engineered TCR targeting MAGE-A4,” said Rafael Amado, Adaptimmune’s President of Research & Development.

Overcoming inhibition by TGF-β through expression of dnTGFβRII

The second next generation program that Jon discussed is the expression of dnTGFβRII to overcome T-cell inhibition in the tumor micro-environment. Our research, conducted in partnership with GSK, shows that TGFβ and associated gene signatures are commonly expressed in different cancer types. The analysis of patient’s tumor signatures will determine whether TGFβ associated pathways are important for resistance to SPEAR T-cell therapies.