Increasing immunotherapeutic efficacy through manipulation of hypoxic response

In this project we will build on the previous support we have received from Vetenskapsrådet that has allowed us to establish that increasing the capacity for hypoxic response in cytotoxic T cells in turn increases their immunotherapeutic efficacy.

We have shown that increased expression of the transcription factor HIF via both retroviral vectors in mouse cells and CAR T vectors in human donor T cells can increase the capacity of CD8+ T cells to kill target tumor cells and reduce tumor growth in vivo.

In the case of the CAR vectors, this increase can even be curative.We propose to continue these studies so as to prepare for a clinical trial of our findings.

As part of this preparation, we describe work to characterise the metabolic effects of the alterations in T cells induced by overexpression of HIF vectors, wherein we will correlate those changes with metabolic aspects of central memory and effector T cells. We will use this information to establish how HIF acts to improve cytotoxic efficacy and T cell persistence in vivo.

We also propose to study how hypoxic culture of T cells ex vivo, or treatment with inducers of HIF expression, could act to improve efficacy of current CAR therapies being used in the clinic today.

Finally, we propose to characterise the broader relevance of our findings to solid tumors beyond lymphomas, and ask whether increasing HIF can increase the potential use of CAR and other immunotherapies in a wider range of malignancies.