Many thanks to my faculty advisor Mr. Davoren and my on-site advisor Dr. Hans Snoeck for all their support in this project. You can view my future work (including my podcast) by visiting and subscribing to my personal blog, Brooklyn Musings. You can also follow me on Twitter @SidR73. Thank you!
“Off-the-Shelf” CAR T-cells (CAR T-cells made from cells not from the patient) are the future of cancer immunotherapy. Aside from being easier to mass produce, “Off-the-Shelf” therapies may be more affordable, safe, and accessible than existing immunotherapies.
Finding the Optimal Cell Type
There exist many different options to create “Off-the-Shelf” therapies. First, there are many cytotoxic cell types that can be used in building CAR modulations including αβ T cells, iPSCs, γδ T cells, NK cells, and iNKT cells. Induced pluripotent stem cells (iPSCs) may be the easiest option to manufacture “Off-the-Shelf” CAR T-cells as they can be used to create a banks of homozygous HLA cell lines. Additionally, cord blood banks already exist, and the cord blood cells can be reprogrammed into iPSCs which can be transformed into CAR T-cells. There is one major hurdle, however: differentiating iPSCs into T cells is not an easy process. NK cells and other cell types must also be investigated in lab experiments and clinical trials as they may be more effective than iPSCs and αβ T cells. Furthermore, the optimal CAR cell may differ with the type of cancer that a patient has and how advanced it is.
Evading Rejection and Graft v. Host Disease
As “Off-the-Shelf” CAR T-cells are developed from allogeneic cells, it is critical that they evade immune rejection and Graft v. Host disease. Deleting TCRs on the surface of CAR T-cells is essential for the mitigation of GVHD. There are many important steps to overcoming rejection of allogeneic CAR T-cells. First, PD-1 must be knocked out on engineered cells to prevent PD-1/PD-L1 interactions that deactivate T cells.
There are many ways of dealing with HLA disparities. It’s much safer to create banked homozygous HLA cell lines that match HLA genes at several different locations. However, it’s unclear how much HLA matching is needed, and diverse populations will require a greater number of banked cell lines. Cells with HLA/MHC deletion may be more feasible but come with additional risks. It is critical that the persistence of CAR T-cells with knocked out MHC complexes be examined in a clinical setting. Suicide genes for therapies that utilize these hypoimmune manipulations may be a way of regulating cell persistence. While CAR T-cells are “living drugs”, they must be engineered to act as non-living drugs so that they are predictable and can be easily adapted to a patient.
The Bigger Picture
My senior project was more than research on “Off-the-Shelf” CAR T-cells, it was an investigation into the present and future of cancer immunotherapy treatments which are set to change the course of medicine. CAR T-cells themselves are extremely versatile; they could one day treat HIV/AIDS, Diabetes, Lupus, and solid tumors. As new immunotherapy treatments are being discovered every year and the depths of our immune system continue to be unraveled, I’m optimistic that one day we will finally find a cure for cancer.