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A research team associated with Dr. Carl June announces it has discovered a way to engineer a patient’s own immune cells to recognize cancer-specific glycoantigens on tumor cells.
Although chimeric antigen receptor T-cell therapy (CAR-T) has been nothing short of a medical miracle for the treatment of blood cancers, the applications for use of CAR-T for solid tumors had not been as promising. This is because tumors do not share abnormal cell-surface proteins that appear just on the tumors and not on other, normal cells. Now, researchers from the Perelman School of Medicine at the University of Pennsylvania say they may have found a solution via the engineering of a T cell to produce a novel CAR that recognizes a carbohydrate (specifically, a glycosylation pattern) on the surface of many solid tumors. Making T cells more specific to tumor cells instead of to normal cells will allow treatment without the risks of side effects that are as severe, the researchers hypothesized, and could bring research closer to the identification of a universal CAR to treat all types of cancers.
Working with researchers from the University of Copenhagen and the University of Chicago, the Penn Researchers developed novel CAR-T cells that express a monoclonal antibody (5E5) that recognizes a common glycosylation pattern on many tumor cells (the Tn glycan on the mucin 1 protein [Tn-MUC1]). This glycosylation pattern is primarily absent on normal cells but present on a variety of cancer cells, including leukemia, ovarian, breast, and pancreatic cancer cells. These “aberrant glycoform epitopes” are valid clinical targets for T cells, the researchers wrote in an article published in Immunity, and fairly safe, as the epitopes are minimally expressed on normal tissues.
First co-author Avery Posey, an instructor at the Perelman School of Medicine, tells this publication that even though a small portion of normal tissues express the epitope of interest, “confocal immunofluorescence microscopy revealed the antigen only occurred intracellularly in these normal tissues.” Posey states, “This is important because CAR-T cells can only target extracellular epitopes and would not target these normal tissues. We also evaluated whether our 5E5 CAR-T cells could kill normal human primary cells and saw no cytotoxicity, suggesting that this is a very safe cancer target.” Posey adds that there are also other potential epitopes that could serve as valid tumor targets besides the 5E5 epitope, and that the Penn team and one of the co-authors from the University of Copenhagen, Catharina Steentoft, are currently evaluating new CAR-T cells for those targets.
In the study, there were 40 mice in the leukemia group, and 16 of these animals were treated with the 5E5 CAR (8 animals with a small dose and 8 with a larger dose). There were 22 mice in the pancreatic cancer group, and 6 of these animals were treated with a CAR. All 6 mice (100%) in the pancreatic group survived 113 days after treatment with the 5E5 CAR-T cells compared with 40% and 33% survival of mice treated with non-transduced and CD19 CAR-T cells, respectively. “We did observe better survival and effect in the pancreatic cancer treatment group,” admits Posey, “although the effect we observed in the leukemia group is consistent with results observed by the few other groups that have used this cell line model-and I believe it is a limitation of the animal model.”
Although the team has not yet evaluated the antitumor effects of 5E5 in an animal model with human ovarian cancer (only in vitro) and has not published its animal models of breast cancer yet, the researchers say they saw significant antitumor effects against human leukemia, breast, and pancreatic cancer in mice. When asked what disease would likely be the first focus of a clinical trial in human models, Posey responded, "My hope is that we can use this advancement to add treatment options for triple-negative breast cancer and then expand to other cancers."
Co-senior author Laura Johnson, director, solid tumor immunotherapy laboratory at the Center for Cellular Immunotherapies at the Perelman School of Medicine, commented in a press release, "This is really the first description of a CAR that can target multiple different solid or liquid tumors, without apparent toxicity to normal cells. While it may not be a universal CAR, it is currently the closest thing we have."
While the work with 5E5 published in Immunity is supported by Novartis, the National Institutes of Health, and the Danish Research Councils, the University of Chicago has already filed a patent on the 5E5 CAR in development. Novartis and Penn are in a strategic alliance to develop CARs.
Third co-author of the study, Carl June, the Richard W. Vague Professor in Immunotherapy at the Perelman School of Medicine at Penn, is well-known in the immunotherapy world. His work on CARs designed to bind to a protein called CD19 found on the surface of cancerous B cell for the treatment of leukemia was highly lauded in 2013 when it was published. June and Penn recently acknowledged that some of the work done to develop the CAR for the groundbreaking research was done by Dario Campana and Chihaya Imai, who worked at St. Jude Children’s Research Hospital. According to a correction posted in the New England Journal of Medicine, the physicians from St. Jude and the facility “provided under material transfer agreements the chimeric antigen receptor (CAR) that was used in this study.”
June will propose the use of CRISPR for editing CAR-T cells in a meeting with NIH occurring from June 21–22, 2016, marking the first time the use of CRISPR in humans will be appraised. Posey says, “Combining [the 5E5] CAR with the work recently described [to NIH] using CRISPR/Cas9, disruption of PD-1, and the T-cell receptor could augment this therapy to generate a potent, allogeneic ‘off-the-shelf’ product for cancer with the potential to generate antitumor effects in virtually every cancer patient with the most lethal cancers.” Posey cautioned, however, that “safety and efficacy of the first CRISPR clinical trial must be completed and interrogated before we can discuss new approaches with these remarkable gene-editing techniques.”
Sources: MIT Technology Review, Immunity, Cell Press