Abstract
HER2 positive JIMT-1 breast tumors are resistant to trastuzumab treatment in vitro and develop resistance to trastuzumab in vivo in SCID mice. We explored whether these resistant tumors could still be eliminated by T cells redirected by a second-generation chimeric antigen receptor (CAR) containing a CD28 costimulatory domain and targeting HER2 with a trastuzumab-derived scFv. In vitro, T cells engineered with this HER2 specific CAR recognized HER2 positive target cells as judged by cytokine production and cytolytic activity. In vivo, the administration of trastuzumab twice weekly had no effect on the growth of JIMT-1 xenografts in SCID mice. At the same time, a single dose of 2.5 million T cells from congenic mice exhibited a moderate xenoimmune response and even stable disease in some cases. In contrast, when the same dose contained 7% (175,000) CAR T cells, complete remission was achieved in 57 days. Even a reduced dose of 250,000 T cells, including only 17,500 CAR T cells, yielded complete remission, although it needed nearly twice the time. We conclude that even a small number of CAR T lymphocytes can evoke a robust anti-tumor response against an antibody resistant xenograft by focusing the activity of xenogenic T cells. This observation may have significance for optimizing the dose of CAR T cells in the therapy of solid tumors.
Highlights
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–25% of breast cancer tumors [1]
We described the generation of HER2 specific chimeric antigen receptor (CAR)-modified mouse T cells that obtained their antigen specificity from trastuzumab, a HER2 specific monoclonal antibody applied in clinical practice
We demonstrated that these cells recognize trastuzumab resistant HER2 positive JIMT-1 target cells in vitro
Summary
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 20–25% of breast cancer tumors [1]. Specific monoclonal antibody therapy has revolutionized the treatment of HER2 positive breast cancer since the FDA (U.S Food and Drug Administration) approval of trastuzumab (Herceptin®) in 1998 [3]. The addition of trastuzumab to chemotherapy results in a lower rate of death after one year (22 percent vs 33 percent, P = 0.008), longer survival (median survival, 25.1 vs 20.3 months; P = 0.046), and a 20 percent reduction in the risk of death [4]. One of the underlying mechanisms is epitope masking by components of the tumor microenvironment (TME) such as the MUC4 (mucin 4) or the CD44/Hyaluronan complex [6,7,8,9,10,11]
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