Send Orders of Reprints at reprints@benthamscience.net Recent Patents on Anti-Cancer Drug Discovery, 2013, 8, 239-254 239 Cancer T Cell Immunotherapy with Bispecific Antibodies and Chimeric Antigen Receptors Markus D. Lacher 1,* and Maurizio Provenzano 2 1 T cell Therapeutics, Inc., Lafayette, CA, 94549, USA; 2 University Hospital Zurich, Division of Urology, Zurich, 8091, Switzerland Received: March 8, 2013; Accepted: April 22, 2013; Revised: May 9, 2013 Abstract: Solid tumors contain several different types of malignant cells. This cellular heterogeneity complicates therapy for at least two reasons. First, each subpopulation may respond differently to a given treatment. Second, cancer cells are plastic, and thus may convert from a therapy-sensitive to a therapy-resistant cell type represented by another subpopula- tion. Therefore, successful therapies will have to target numerous malignant cell types, not just the rapidly proliferating cells as most standard treatments do. Immunotherapies with T cells engineered to recognize cancer cells via bispecific an- tibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells. Here, we discuss several patents associated with excep- tionally effective bsAbs of the tandem single-chain variable fragment (taFv) class and untangle a part of the complex net- work of patents directly or indirectly related to CARs. Furthermore, we speculate on the future of bsAbs and CARs for both treatment and prevention of solid tumors such as prostate cancer. Keywords: Antibody, BiTE, bispecific, cancer, CAR, scFv, taFv. INTRODUCTION Cancer cell heterogeneity is a major factor affecting ther- apy resistance. In particular, there is ample support for the hypothesis that progression of cancer is driven by small sub- populations of malignant cells referred to as tumor-initiating cells (TICs), or, more broadly, as cancer stem cells (CSCs), with both self-renewal and differentiation capacity [1-5]. Several lines of evidence indicate that CSCs are particularly resilient to therapy. Nevertheless, even though CSCs were initially considered as the Achilles heel of cancer whose se- lective elimination would halt tumor growth, a more current model stresses the need to target both CSCs and their proge- nies, as some of the latter cells may revert back to the CSC state [5, 6]. Furthermore, several in vitro models suggest that cancer cells induced to undergo epithelial-to-mesenchymal transition (EMT) may respond not only with an up- regulation of mesenchymal markers, but also with increased expression of genes associated with an embryonic stem cell phenotype. These observations are consistent with the con- cept proposed by Brabletz et al. which suggests that metasta- ses are derived from (stationary) CSCs that have acquired motility via EMT [7]. Therapies aimed at activating autologous immune cells to clear cancer cells are fundamentally different from conven- tional treatment strategies and thus pose unique challenges, but also offer distinct opportunities. For instance, in contrast to conventional cancer treatments that predominantly target *Address correspondence to this author at T cell Therapeutics, Inc.; Lafayette, 94549, CA, USA; Tel: +1 925-681-9553; E-mail: doublehelix.pb2k@gmail.com rapidly proliferating cells, therapies harnessing the innate power of the immune system may kill malignant cells irre- spective of their proliferation status. While some immuno- therapies nonspecifically enhance the immune system, others are aimed at specifically redirecting immune cells towards cancer cells [8]. Within the latter category are T cell thera- pies with bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) (Fig. 1A and 1B). Both approaches are designed to crosslink cytotoxic T cells and cancer cells. Binding to the cancer cells occurs at tumor-associated anti- gens (TAAs), here defined as cell-surface antigens expressed on cancer cells that may or may not be specific for the ma- lignant state of the cells. For instance, CD19, a marker for normal B cells, is a target in both bsAb and CAR therapies for B cell malignancies [9-12]. Since bsAbs or CAR-T cells do not depend on T cell receptor (TCR) - major histocom- patibility complex (MHC) interactions for binding to their target cells, cancer cell MHC down-regulation as an immune escape mechanism is not a primary concern [13, 14]. Never- theless, although not further discussed here, it should be noted that also MHC-restricted approaches with similarity to the CAR strategy have demonstrated anti-cancer effects in the clinic. In particular, clinically relevant responses were reported for adoptive therapies with T cells carrying ectopic TCRs specific for MHC-associated tumor antigens such as MART-1, gp100, CEA, or cancer-testis antigens such as NY- ESO-1 [15]. Among the key differences between bsAb and CAR therapies are the formulations of the therapeutics. While the bsAb approach may be carried out with systemically infused “off-the-shelf” protein products, CAR treatments are -9 /13 $100.00+.00 © 2013 Bentham Science Publishers