CAR T Cells Engineered to Target Solid Tumors

Samer A. Srour, MB, ChB, MS, assistant professor in the department of stem cell transplantation, division of cancer medicine at The University of Texas MD Anderson Cancer Center, discusses the design of ALLO-316, an agent investigated in the phase 2 TRAVERSE trial (NCT04696731) for patients with renal cell carcinoma (RCC).

Chimeric antigen receptor (CAR) T-cell therapy is challenging to use in solid tumors; Srour says that ALLO-216 is designed to counteract the barriers to use in RCC. It targets CD70, which is expressed in RCC and associated with aggressive and immune-resistant tumors.

ALLO-316 is an allogeneic CAR T-cell therapy with modifications such as edits to the TCRα constant gene to avoid graft-vs-host disease and the CD52 gene knocked out so ALLO-647, an anti-CD52 antibody, could be used to prevent lymphodepletion. It also masks CD70 expression in the CAR T cells to prevent fratricide, or killing other CAR T cells. Finally, it has a safety switch using CD20 mimotope expression so that if a patient has excessive toxicity from the CAR T cells, they can be neutralized with an anti-CD20 antibody such as rituximab (Rituxan).

TRANSCRIPTION:

0:08 | We carry our heavy experience from the hematologic malignancies into the solid tumor space. ALLO-316 is 1 of these novel attempts to counteract all the challenges in solid tumors, and particularly kidney cancer in this study.

It targets CD70, which is one of the tumor antigens highly expressed in kidney cancer. It has very low expression in normal tissues, or no expression on normal physiologic tissues. It is known from literature, preclinical studies, and early clinical studies that CD70, when expressed on tumor cells, can make the cancer aggressive, and it can suppress tumor microenvironment.

0:58 | ALLO-316 carries in its design all these benefits, targeting CD70 on the [patients with] kidney cancer. It has novel, unique edits; for instance, we are knocking out CD52 to allow us to use the ALLO-647, which are anti-CD52 antibodies, which contain our lymphodepletion and help us to expand and persist over time. There are additional edits, like masking the CD70 expression on the ALLO-316, and that prevents the fratricide which means the CAR T cell will not kill its own and will just be focused on the aberrant cancer cells. It also knocks out the [TCRα constant] gene, which prevents graft-vs-host disease. In addition to that, this novel agent has a safety switch, which is CD20 mimotope expression. If the patient has excessive, unexpected toxicity, we could use a CD20 antibody like rituximab to kill it.