TA99 (TRP1-specific) CAR T cells expressing a high-affinity (βγ-directed) IL-2 superkine (Super2) and IL-33 delayed growth of B16F10 melanoma tumors more effectively than control TA99 cells, independent of perforin, IFNγ, or even CAR expression, or the presence of T or NK cells alone, and controlled lung metastases. Super2/IL-33 engineering increased tumor accumulation of CAR T cells, endogenous effector lymphocytes, and activated macrophages, and improved CAR T efficacy targeting heterogeneously expressed B7H6 antigen in B16F10 tumors and NKG2D ligand Rae1 in MC38 tumors.
Contributed by Alex Najibi
ABSTRACT: Chimeric-antigen receptor (CAR) T-cell therapy has shown remarkable efficacy against hematologic tumors. Yet, CAR T-cell therapy has had little success against solid tumors due to obstacles presented by the tumor microenvironment (TME) of these cancers. Here, we show that CAR T cells armored with the engineered IL2 superkine Super2 and IL33 were able to promote tumor control as a single-agent therapy. IFN_ and perforin were dispensable for the effects of Super2 and IL33 armored CAR T cells. Super2 and IL33 synergized to shift leukocyte proportions in the TME and to recruit and activate a broad repertoire of endogenous innate and adaptive immune cells including tumor-specific T cells. However, depletion of CD8+ T cells or NK cells did not disrupt tumor control, suggesting that broad immune activation compensated for loss of individual cell subsets. Thus, we have shown that Super2 and IL33 CAR T cells can promote antitumor immunity in multiple solid tumor models and can potentially overcome antigen loss, highlighting the potential of this universal CAR T-cell platform for treatment of solid tumors.
Author Info: (1) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (2) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (3) Geisel School of Medicine at Dar
Author Info: (1) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (2) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (3) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (4) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (5) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (6) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (7) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (8) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (9) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States. (10) Dartmouth College, Hanover, New Hampshire, United States. (11) Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
