Gene Editing for Safer CAR T-Cell Therapy in Large B-Cell Lymphoma

The investigational allogeneic chimeric antigen receptor (CAR) T-cell therapy cemacabtagene ansegedleucel (cema-cel; Allogene Therapeutics) is being evaluated in the ALPHA (NCT03939026) and ALPHA2 (NCT04416984) trials for relapsed/refractory large B-cell lymphoma, a type of non-Hodgkin lymphoma, and in the ALPHA3 trial (NCT06500273) in patients with a low disease burden who have received cema-cel as consolidation treatment in the first line.

Continuing a discussion with Frederick L. Locke, MD, lead investigator on ALPHA and ALPHA2 and chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center and Research Institute, here he explains how the therapy is genetically engineered to lessen the risk of patient rejection.

This transcript was lightly edited for clarity; captions were auto-generated.

Transcript

Can you describe the gene editing process involved in creating cema-cel to mitigate the risk of graft-vs-host disease?

Cemacabtagene ansegedleucel, or cema-cel, is an allogeneic CAR T-cell therapy, which targets CD19, and cema-cel is what we tested out in the ALPHA [NCT03939026] and ALPHA2 [NCT04416984] clinical trials. Cema-cel takes healthy donor T cells, and using a gene-editing technique called TALEN, it removes 2 genes, and thereby 2 proteins, from the donor’s T cells.

One of those is CD52—that's just the name of a cell surface protein. CD52 exists on all the immune cells in the body, or all the lymphocytes in the body and other immune cells. By removing that protein from the donor’s CAR T cells, it allows us to use a monoclonal antibody against CD52 during the lymphodepletion regimen, so that we can lower patients’ immune cells and allow the cema-cel to be infused and expand in the patient's body. It gives us an extra advantage so that those donor cells aren't rejected by the patient's immune cells.

The other gene that's deleted in cema-cel is the TRAC gene. The TRAC gene is a gene and a protein that's necessary for the expression of the T-cell receptor. Each T cell recognizes a different target, and those T-cell receptors—if we get T cells infused into our blood from a healthy donor—those T-cell receptors could recognize the proteins of our body as abnormal because they're not used to our body. We need to remove the T-cell receptor from the donor cells so that when they are infused into the patient, they don't cause graft-vs-host disease; they don't attack the patient's body, recognizing it as foreign. Then, of course, the CAR, the chimeric antigen receptor, is a gene that's expressed in cema-cel against CD 19.

We're not replacing all the patient's blood cells with donor cells. We're simply giving a single infusion of cema-cel, healthy donor T cells that are engineered to react against the patient's lymphoma cells and not be rejected or cause graft-vs-host disease. We do have to lymphodeplete; all CAR T-cell patients get lymphodepletion. We transiently lower the normal lymphocytes and immune cells in the body, so that when the CAR T cells are infused into the blood, they have less competition. We do that with cema-cel as well with 2 drugs, fludarabine and cyclophosphamide, just like autologous CAR Ts, and we also use ALLO-647, which is a monoclonal antibody, against CD52