Abstract
New treatment options especially of solid tumors including for metastasized prostate cancer (PCa) are urgently needed. Recent treatments of leukemias with chimeric antigen receptors (CARs) underline their impressive therapeutic potential. However CARs currently applied in the clinics cannot be repeatedly turned on and off potentially leading to severe life threatening side effects. To overcome these problems, we recently described a modular CAR technology termed UniCAR: UniCAR T cells are inert but can be turned on by application of one or multiple target modules (TMs). Here we present preclinical data summarizing the retargeting of UniCAR T cells to PCa cells using TMs directed to prostate stem cell- (PSCA) or/and prostate specific membrane antigen (PSMA). In the presence of the respective TM(s), we see a highly efficient target-specific and target-dependent activation of UniCAR T cells, secretion of pro-inflammatory cytokines, and PCa cell lysis both in vitro and experimental mice.
Highlights
Prostate cancer (PCa) is still one of the leading cause of cancer-related death in men [1, 2]
Here we show proof of concept for both in vitro and in vivo retargeting of prostate cancer (PCa) cells with universal CAR (UniCAR) T cells armed with these target modules (TMs) directed against either prostate stem cell antigen (PSCA) or prostate specific membrane antigen (PSMA) or both TMs simultaneously
In order to show that the same TMs may work in combination with UniCAR T cells, the TMs were purified from cell culture supernatants of eucaryotic cells expressing the respective antibody derivates using Nickel affinity chromatography
Summary
Prostate cancer (PCa) is still one of the leading cause of cancer-related death in men [1, 2]. While primary localized tumors may be manageable by prostatectomy or radiotherapy approximately 20% of patients develop metastatic disease within the following fifteen years [1, 3, 4]. Highly promising antigen-specific immunotherapies were developed currently approaching the clinics which are based on either bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) [e.g. 5, 6]. At the site of interaction, immune synapse-like structures are formed resulting in killing of tumor cells in a TCR and MHC independent manner [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25] via the granzyme B/perforin pathway [16, 24, 25]
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