Nicolas Thiault, Ph.D.

What if there is a new immune cell that could be engineered to safely kill tumor cells and cure cancer?

FUNDED: JANUARY 2021
FUNDED BY: the generosity of Larry & Tiki Spitcaufsky

Cancer is a leading cause of death but impressive successes of immunotherapies have brought hope and greatly enhanced the quality and life expectancy for cancer patients. A very promising immunotherapy uses engineered immune-cells that express an artificial receptor that senses cancer cells and signals the immune cell to kill them.

Currently, these engineered immune-cells originate in the patients’ own blood to minimize attacks on patients’ own healthy cells. However, this requires a custom-made manufacturing process for each individual, which is extremely costly and time-consuming. In addition, many patients’ immune cells function sub-optimally or are dysfunctional due to previous heavy anti-cancer treatments (i.e radiotherapy). The advanced use of donor cells from healthy people allows for cheaper, scaled-up production of readily available and more effective engineered immune-cells. But unfortunately, foreign immune-cells may also aggressively attack the patients’ healthy cells, or, because they are foreign, they may be rapidly eliminated by the patients’ immune system. Thus, there is a critical need for off-the-shelf and highly effective engineered anti-tumor immune-cells, that will persist in the patient and kill tumor cells but leave healthy tissues intact.

As part of my research I believe I’ve discovered the perfect candidate. Although this immune cell had been known for decades, it was continually overlooked and left uncharacterized. I fully characterized this cell, determined its function and found it to be a potent killer-cell that does not operate by distinguishing self from non-self. This implies that it might not attack the healthy cells of cancer patients. Based on my findings, I predict that this cell might be the ideal donor immune-cell to be engineered for an effective and safe anti-tumor therapy. SPARK funding will allow me to provide proof-of-concept for my hypothesis using a straight forward experimental approach and a well-established mouse tumor model.

Six-Month Project Update

Engineering chimeric antigen receptor (CAR) T cells represent one of the most promising immunotherapies against cancer. Unfortunately, CAR T cells are often associated with severe toxicity and a high failure rate in certain types of cancers. I’m aiming to apply the existing CAR T cell technology to new immune cells, discovered at La Jolla Institute for Immunology, called double negative T (DNT) cells. These cells harbor more effective killing capacity with lower toxic potential.

So far, I have focused on establishing methods to generate CAR DNT cells and their appropriate tumor targets. I also genetically modified tumor cells to allow their recognition by the engineered CAR DNT cells and provide the proof-of-concept for my hypothesis. These steps are essential for conducting upcoming in vitro and in vivo experiments. In fact, such characterization of the DNT cell biology has never been described in fundamental nor translational research and would be worth considering for future publications or grant submission.

I will now start the in vitro experiments to validate these protocols and address DNT efficiency against tumor cells. At the same time, I will confirm that our tumor model can grow in mice. Then I will address whether engineered DNT cells can safely kill tumors and cure cancer in vivo.