Week 5: The Alloimmune Defense Receptor System

Hello! I’m Sidharth, and this week I’ll explain and evaluate a new method of creating “Off-the-Shelf” CAR T-cells that was first proposed two years ago by Dr. Maksim Mamonkin.

In July 2020, scientists at Baylor University published an intriguing paper detailing a novel way to create “Off-the-Shelf” CAR T-cells. Can these cells surmount the adversities presented by T cell receptors (TCR) and NK cells? I’ll discuss that and more below.

A Crucial Receptor (CD137)

CD137 is a protein that is expressed on CD4+ (helper) and CD8+ (cytotoxic) T cells after exposure to a target antigen. When expressed, it also activates the TCR and delivers co-stimulatory signals to other T cells resulting in T cell proliferation, survival, memory formation, and stronger effector function for cytotoxicity and cytokine production. (Ugolini & Nuti, 2021) One problem with CAR T-cell therapy is that the engineered cells don’t last long in the body. However, CAR T-cells with CD137 expression can solve this issue for it is responsible for T cell memory formation and survival. Furthermore, this model of CAR T-cells has already been tested and is in development. (Milone et al., 2009)

Interestingly, Dr. Mamonkin’s “Off-the-Shelf” CAR T-cells use CD137 (also known as 4-1BB) in a completely different way with the hopes of eliminating T cell and NK cell responses. His team hypothesized that the selective elimination of T and NK cells expressing CD137 would result in the suppression of cellular rejection.

The Alloimmune Defense Receptor (ADR)

Mamonkin’s team engineered a chimeric 4-1BB Alloimmune Defense Receptor (ADR) that enables the engineered T cells to selectively target activated T and NK cells. The ADR is co-expressed with the chimeric antigen receptors (CARs). One potential problem with this approach is the complete suppression of the immune system, which can lead a patient to be susceptible to a whole host of other diseases. However, the ADR only selects for activated T cells, and thus resting T cells will be spared. (Mo et al., 2021) While the immune system will still be drastically compromised, this may not be an issue in a clinical setting.

Mouse Models

Mamonkin’s “Off-the-Shelf” approach has been successful in mouse models. The team examined the ability of ADR T cells to eliminate alloreactive cytotoxic lymphocytes (activated T/NK cells) and resist immune rejection. The donor cells were also HLA mismatched; however, it is unclear the extent of HLA matching that existed, if any. The ADR expression ultimately protected the donor T cells from elimination and promoted their expansion. (Mo et al., 2021)

Delving Into The Unknown

As with everything regarding the immune system, nothing is exactly what it seems. There are other immune cells that express 4-1BB – what impact will ADR expression have on those cells? Furthermore, if the ADR-modified cells persist in the body and continue to resist rejection, what will occur? There are many unknowns when it comes to ADR CAR T-cells; however, hopefully my research and the research of other scientists will help to bring this method to light. Will this method be more effective and feasible as compared to HLA-banked induced pluripotent stem cells? I hope to compare and contrast these approaches in my final paper.

Thanks for reading! Be sure to tune in next week as I continue my quest to “Off-the-Shelf” CAR T-cells.

Sidharth