T-cell Reprogramming: A Strategy to Super-Charge TIL Therapy for Cancer

ASPIRE Award (2021-Present)

Claire Roddie, MD, PhD (Principal) and Tariq Enver, PhD, University College London (United Kingdom)

Claire Roddie, MD, PhD

Tariq Enver, PhD

In many solid tumors, there is a suite of reactive T cells which recognize tumor specific antigens and represent a huge opportunity for harnessing anti-tumor activity. Indeed, these existing tumor infiltrating lymphocytes (TILs) act as crucial effectors during immune checkpoint blockade. In the therapeutic modality known as adoptive cell transfer, TILs are extracted from a resected tumor, expanded ex vivo, and then reintroduced to the patient to attack the cancerous cells. However, there are still limitations in using expanded TILs, which has seen variable success in treating solid tumors. The process of expansion is complex, time-consuming, and often does not generate enough T cells for patients to receive doses associated with efficacy. Enriched T cells are often heterogenous and contain many clones which are not tumor reactive. Moreover, the reactive TILs which are enriched tend to exhibit high levels of terminal differentiation and exhaustion, which makes these cells less cytotoxic to tumor cells, and prone to senescence and cell death, which limits their overall effectiveness.

To overcome the limitations of conventional TIL therapy, Claire Roddie and her collaborators are employing T-cell reprogramming technology to create self-renewing T-induced pluripotent stem cells (T-iPSCs) from patient TILs isolated from renal cell carcinoma (RCC). Drawing on the seminal work of cellular reprogramming by expression of exogenous transcription factors, they aim to use T-iPSC technology to create banks of “rejuvenated” T-iPSC-derived TILs with: (1) better functionality compared with conventional TILs; (2) preservation of tumor reactive clonotypes for better tumor targeting and (3) an absence of exhaustion/senescence markers. While this project aims to demonstrate proof-of-principle in RCC, the findings should be broadly applicable across other immunogenic solid tumors. T-iPSC banks may provide a potentially unlimited supply of rejuvenated patient TILs, such that patients could receive multiple doses in the event of multiple relapse events, and could be an attractive therapeutic alternative to conventional TILs in the future.