Genetic Engineering & Biotechnology News

JUL 2018

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24 | JULY 2018 | Genetic Engineering & Biotechnology News | GENengnews.com Samantha Zaroff, Ph.D. Chimeric antigen receptor (CAR) T-cell ther- apy has matured rapidly. What used to be the "drug of the future" is suddenly the "drug of the now." The first CAR T-cell therapeutic, Kymriah, was approved by the FDA about 10 months ago, and there are at least 300 differ- ent CAR T-cell-based clinical trials being con- ducted across the globe. Even more numerous are the CAR T-cell projects currently in the dis- covery or preclinical phases of development. In these projects, multitudes of cancer types, targets, and formats are being evaluated. All this activity makes for a robust CAR T-cell market. Currently worth an estimated $168.7 million, the CAR T-cell market is expected to maintain a compound annual growth rate of 46.2% from 2019 to 2028. These enviable figures are partly due to Kym- riah's demonstrated efficacy in treating acute lymphoblastic leukemia. Kymriah targets CD19, the most preva- lent marker of B-cell malignancies, and shows a high overall response rate. After treatment commences, about 83% of patients experi- ence remission within three months. In up to half of all treated patients, however, remis- sion is only temporary because antigen es- cape occurs, allowing cancer to recur. Recognizing Antigen Escape Antigen escape is one of the key challenges for monomeric CAR T-cell therapies. It can be defined as the loss of a tumor-associated antigen (TAA), particularly after administra- tion of TAA targeting therapeutics. Despite the strong effect antigen escape has on CAR T-cell efficiency, there have not been many studies carried out to elucidate its cause. Research efforts led by Andrei Thomas- Tikhonenko, Ph.D., a professor of pathology and laboratory medicine at the Children's Hospital of Philadelphia, demonstrate that leukemias that reemerge after CD19-direct- ed therapy have a higher rate of CD19 splice variation and CD19 mutation. In these leu- kemias, the CD19 epitope is eliminated, such that newly derived leukemia cells prove in- vulnerable to any CD19-based therapeutic. Although antigen escape is not yet fully understood, it is recognized as a challenge that must be (and can be) addressed. In the case of CD19 loss, Dr. Thomas-Tikhonenko and colleagues speculated in 2015 that target- ing alternative CD19 ectodomains could im- prove patient outcomes. Subsequently, other investigators suggested that broader immune activation might prevent outgrowth of tumor antigen escape variants following targeted therapies. Currently, researchers are combin- ing CD19-based CAR T-cell approaches with bispecific antibody (bsAb) technologies to counter antigen escape. Taking bsAbs on Board Antibody therapeutics that rely on bsAbs simultaneously target two different anti- gens, leading to the co-stimulation of dif- ferent metabolic pathways within the same or different cell types. In terms of immuno- oncology, bsAb therapies resemble CAR T-cell therapies. Like CAR T-cell therapies, bsAb therapies can redirect various T cells to attack and kill tumors. In addition, bsAb therapies can direct other immunological ef- fector cells such as natural killer cells, macro- phages, and monocytes. Currently, there are more than 200 bsAb- based therapeutics entering or currently in clinical trials. Over 80% of these therapeu- tics induce a cytolytic synapse between im- mune cells and targeted cancer cells. The first bsAb-based therapeutic approved by the FDA was blinatumomab, a bispecific T-cell engager, or BiTE. Blinatumomab con- tains two different single-chain fragment vari- ables (scFvs)—one targeting CD19, and one targeting CD3—to treat acute lymphoblastic leukemia. This therapeutic has demonstrated efficacy, suggesting that bsAbs have promise. Nonetheless, like other therapeutics, bsAbs present difficulties. A major problem with using bsAbs to treat cancers is that the distance between the antigen-binding domains tends to be rather small due to the natural structure of bsAbs. In BiTEs, for example, this distance is around 60 kDa. Therefore, if one bsAb is to simulta- neously bind a cancer cell and an effector cell, the cells must be close to one another. To circumvent this issue, researchers be- gan developing bispecific CAR T-cell for- mats. Some of these formats looked promis- ing initially but were eventually found to be wanting. For example, one bispecific CAR T-cell format involved the mixing of two T- cell lines, each expressing a different scFv on its surface. Unfortunately, this approach led to preferential growth of one cell line over the other, basically resulting in a traditional monomeric CAR. Another bispecific CAR T-cell format in- volved the simultaneous transduction into T cells of two different scFv-based CAR plas- mids. Although this approach was conceptu- ally sound, it proved to be impractical. In the laboratory, attempts to transduce two CAR cassettes into one viral vector failed simply because sufficiently roomy vectors were un- available. Making Progress with TanCARs One of the more successful bispecific CAR T-cell formats is called tandem CAR (Tan- CAR). It involves transducing a T cell with one CAR plasmid that expresses two differ- ent scFvs. TanCAR-based therapeutics look promising because their scFv-based CARs possess bispecific functionality. The TanCAR approach, unlike the mix- ing or combining methods, generates a CAR T cell with even distribution of two distinct antigen-binding scFvs. TanCARs also exhib- it Boolean-like activity, meaning that a full T-cell response can be activated when either scFv becomes engaged. A highly effective TanCAR was developed by scientific team led by Yvonne Y. Chen, Ph.D., an assistant professor of chemical and biomolecular engineering at the University of California, Los Angeles. This TanCAR was the first to successfully target different epit- opes expressed on the same cancer cell. To Bypass Antigen Escape, TanCAR and NanoCAR Therapies Take the Bispecific Route CAR T-Cell Therapies with a Bispecific Twist Translational Medicine An illustration of a T cell's chimeric antigen receptor (CAR) binding to a cancer cell's antigen. The CAR depicted here incorporates a single-chain variable fragment (scFv) and is monomeric, like the CAR in Kymriah, the first approved CAR T-cell therapy. A monomeric CAR may target only one epitope of a tumor- associated antigen. Meletios Verras / Getty Images Schematic representation of nanobody and antibody domains. Human and rodent IgGs are composed of six constant heavy (C H ) regions, two constant light (C L ) regions, two variable heavy (V H ) regions, and two variable light (V L ) regions. Antibody fragments are built similarly, where scFvs are composed of a V H region and a V L region connected by a short peptide linker, and single domain antibodies are simply a V H or a V L region. To generate camelid nanobodies, researchers isolate one of the two variable heavy (V H H) domains present in camelid IgGs, commonly termed heavy chain–only antibodies because they are composed only of four C H regions and two V H H domains. The diagram, which originally appeared in Theranostics (2014; 4(4): 386–398), is adapted from a diagram that appeared in Nat. Biotechnol. (2005; 23: 1126–36).

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